Startseite Anticancer activity mechanism of novelly synthesized and characterized benzofuran ring-linked 3-nitrophenyl chalcone derivative on colon cancer cells
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Anticancer activity mechanism of novelly synthesized and characterized benzofuran ring-linked 3-nitrophenyl chalcone derivative on colon cancer cells

  • Melih Oztepe , Demet Coskun und Ferda Ari ORCID logo EMAIL logo
Veröffentlicht/Copyright: 18. Oktober 2025
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Open Medicine
Aus der Zeitschrift Open Medicine Band 20 Heft 1

Abstract

Cancer is the second biggest cause of death after cardiovascular disorders and its incidence is rising significantly. One out of every ten cancer-related deaths is caused by colon cancer. The increasing incidence calls for creating focused therapeutic strategies with fewer adverse effects than traditional clinical techniques like radiation, chemotherapy, and immunotherapy. In this study, we evaluated the anticancer effects and mechanisms of a synthesized and characterized benzofuran ring-linked 3-nitrophenyl chalcone derivative, [1-(2-benzofuranyl)-3-(3-nitrophenyl)-2-propen-1-one], on colon cancer cells (HCT-116 and HT-29) as well as healthy colon cells (CCD-18Co). Cell viability analyses using the sulforhodamine B assay demonstrated that the IC₅₀ values after 48 h of treatment were 1.71 µM for HCT-116, 7.76 µM for HT-29, and higher than 10 µM for CCD-18Co cells. These results indicate a selective cytotoxic effect on cancer cells an essential criterion for evaluating anticancer compounds. Triple fluorescence staining, flow cytometry caspase 3/7 activity, along with protein expression analyses, confirmed that the compound induces apoptosis in both cancer cell lines. At IC₅₀ values, the derivative activated DR-4-mediated apoptosis at the membrane and BCL-2-mediated apoptosis intracellularly. Moreover, treatment with 12.5 µM of the compound for 24 h, corresponding to a cell cycle time, statistically significantly arrested the cell cycle at the G0/G1 phase. In addition, it inhibited cell migration and colony formation in a dose-dependent manner, starting from values as low as 1.56 µM. Additionally, the binding affinity of the derivative with target proteins was determined using artificial intelligence-assisted molecular modeling analysis. Collectively, these findings highlight the potential of this 3-nitrophenyl chalcone derivative as a promising candidate for the development of novel therapeutic agents against colon cancer.

Graphical abstract

Keywords: apoptosis; cancer; chalcone; colon; cytotoxicity

1 Introduction

One of the leading causes of death in the modern world is cancer, a disease marked by uncontrolled cell division brought on by genetic or epigenetic modifications and their dissemination to neighboring tissues [1]. According to the current data prepared by the International Agency for Research on Cancer worldwide, colorectal cancer, which accounts for 10% of cancer-related deaths, ranks third after breast and lung, respectively, in terms of incidence. In terms of mortality, it ranks second after the lung [2]. There are different approaches to cancer treatment (surgery, radiotherapy, immunotherapy, chemotherapy, etc.) [3,4,5,6]. Nevertheless, mortality rates are still high due to various reasons such as low stability and drug resistance [7]. Therefore, new treatment approaches with fewer undesirable side effects are needed than current approaches. When the homeostasis rate is disrupted in the cells of an adult organism, the pathway defined as apoptosis becomes active and physiological death occurs in an orderly manner [8]. Function or regulation disorders occurring in the apoptotic process are associated with various pathological conditions, especially cancer, autoimmune diseases, and the spread of viral infections [9]. In this regard, triggering the apoptotic death pathway is one of the primary goals of cancer treatment strategies.

The use of compounds synthesized from herbal or natural products in the treatment of cancer is very important considering that they have relatively fewer side effects compared to existing therapeutics [10]. Flavonoids, one of these compounds, have a polyphenolic structure and are found in pigment compounds in the plant [11]. Chalcones, from the flavonoid family, are compounds that can be found both naturally and synthetically in the laboratory [12]. It has been reported to affect biological activities such as anticancer activity, inhibition of free radical release in the body, chelating with metals [13]. Chalcone-derived chemicals have been shown to act on cancer cells through a variety of molecular processes, including apoptosis, DNA and mitochondrial damage induction, inhibition of angiogenesis, tubulin inhibition, kinase inhibition, and modifications in drug efflux protein activities [14,15].

A review of the literature indicated that chalcone derivatives with different structural changes had anticancer potential. However, no research was found for the 3-nitrophenyl chalcone derivative (Figure 1c), whose synthesis and characterization are complete. Therefore, in this study, the anticancer effects and mechanisms of 3-nitrophenyl chalcone derivative on colon cancer cells (HCT-116 and HT-29) were revealed by in-vitro analyses.

Figure 1 Synthesis reaction schemes of chalcone derivatives (a) containing different side groups (b). Molecular structure of 3-nitrophenyl chalcone derivative (c) (created with Chemsketch structure drawing software (https://www.acdlabs.com/products/chemsketch/, Research Resource Identifiers (RRID):SCR_019272)).
Figure 1

Synthesis reaction schemes of chalcone derivatives (a) containing different side groups (b). Molecular structure of 3-nitrophenyl chalcone derivative (c) (created with Chemsketch structure drawing software (https://www.acdlabs.com/products/chemsketch/, Research Resource Identifiers (RRID):SCR_019272)).

2 Methods

2.1 Chemistry

2.1.1 General

Solvents and reagents were bought from commercial suppliers and used according to their data sheets. We have produced chalcone derivatives by condensing different aromatic aldehydes with 2-acetylbenzofuran. First, a solution of 2-acetylbenzofuran (2.24 g, 14.0 mmol) and aldehyde (14.0 mmol) in methanol (25 mL) was cooled to 0–5°C. After that, this solution received 18 mL of water-soluble NaOH (1 mol/L) and was shaken for 3 h at room temperature. Overnight, the solution was let to stand in the refrigerator. After neutralization with HCl (%1 v/v), the solid precipitated upon the addition of water, and it was filtered and repeatedly rinsed with water. To obtain the chalcone, the solid substance was recrystallized using a suitable solvent.

Uncorrected melting points were determined with a Shimadzu DSC-50 differential scanning calorimeter. Elemental analyses were conducted using a Leco CHNS-932 device. KBr pellets were used to record infrared (IR) spectra using a Perkin-Elmer Spectrum One FTIR (Fourier transform infrared) spectrometer. Tetramethyl silane was used as the internal standard to determine 1H NMR spectra on a Bruker AC 300 (300 MHz) spectrometer and 13C NMR spectra were acquired on a Bruker (75.47 MHz) spectrometer. Chalcone derivatives were prepared at a stock value of 50 mM in dimethyl sulfoxide (DMSO). Following Baek’s procedure [16], 50 mM final DMSO value of derivatives was prepared to be 0.01(%) v/v. Fresh stock solutions were divided into 10 μL aliquots and stored in a −20°C freezer for use in further analyses.

2.1.2 General procedure for the synthesis of chalcone derivatives

2.1.2.1 3-(2-Hydroxyphenyl)-1-(benzofurane-2-yl)-2-propen-1-one (3a)

Yield: 2.03 g, 55%; mp193°C; FTIR (KBr, cm−1): 3,236, 3,000–3,100, 1,639, 1,614, 1,602, 1,575, 1,250, 1,141, 947, 764, 750; 1H NMR (300 MHz, CDCl3): δ 9.03 (s, 1H, OH), 8.08 (d, J = 8.37 Hz, 1H, b4-H), 7.72 (d, J = 7.20 Hz, 1H, b7-H), 7.22–7.68 (m, 9 H, all the others); 13C NMR: δ 179.68 (C =O), 155.90 (b8-C), 155.62 (b2-C), 152.53 (2-C), 141.91 (β-C), 132.01 (b9-C), 110.48–128.11 (the other Cs). Anal. calc. for C17H12O3: C, 77.29; H, 4.54. Found: C, 77.43; H, 4.35.

2.1.2.2 3-(3-Hydroxyphenyl)-1-(benzofurane-2-yl)-2-propen-1-one (3b)

Yield: 2.15 g, 58%; mp 176°C; FTIR (KBr, cm−1): 3,226, 3,000–3,100, 1,639, 1,646, 1,612, 1,582, 1,229, 1,145, 973, 853, 785, 679; 1H NMR (300 MHz, DMSO-d6): δ 9.70 (broad, OH), 8.31 (s, 1H, b3-H), 7.87 (d, J = 7.76 Hz, 1H, b4-H), 7.82 (d, J = 15.69 Hz, 1H, β-H), 7.76 (d, J = 7.90 Hz, 1H, b7-H), 7.75 (d, J = 15.72 Hz, 1H, α-H), 7.57 (dd, J = 7.80 Hz and 7.36 Hz, 1H, b6-H), 7.40 (dd, J = 7.75 Hz and 7.40 Hz, 1H, b5-H), 6.91 (d, J = 7.20 Hz, 1H, 4-H), 7.27–7.33 (m, 3 H, 2,5, 6-H). Anal. calc. for C17H12O3: C, 77.29; H, 4.54. Found: C, 77.54; H, 4.54.

2.1.2.3 3-(4-N,N-dimethylaminophenyl)-1-(benzofurane-2-yl)-2-propen-1-one (3c)

Yield: 3.26 g, 80%; mp 150°C; FTIR (KBr, cm−1): 3,000–3,100, 1,643, 1,611, 1,569, 1,544, 1,522, 1,375, 1,359, 1,267, 1,152, 804, 746; 1H NMR (300 MHz, DMSO-d6): δ 8.16 (s, 1H, b3-H), 7.86 (d, J = 7.74 Hz, 1H, b4-C), 7.76 (d, J = 15.50 Hz, 1H, β-H), 7.75 (d, J = 6.80 Hz, 1H, b7-H), 7.73 (d, J = 8.83 Hz, 2 H, 2, 6-H), 7.60 (d, J = 15.51 Hz, 1H, α-H), 7.54 (dd, J = 7.80 and 7.03 Hz, 1H, b6-H), 7.39 (dd, J = 7.55 and 7.20 Hz, 1H, b5-H), 6.78 (d, J = 8.91 Hz, 2 H, 3, 5-H), 3.03 (s, 6 H, N,N-dimethyl). Anal. calc. for C19H17O2N: C, 78.37; H, 5.84; N, 4.81. Found: C, 77.93; H, 5.56; N, 4.42.

2.1.2.4 3-(2-Fluorophenyl)-1-(benzofurane-2-yl)-2-propen-1-one (3d)

Yield: 2.02 g, 54%; mp 100°C; FTIR (KBr, cm−1): 3,120, 3,067, 1,659, 1,611, 1,576, 1,550, 1,292, 1,160, 753; 1H NMR (300 MHz, DMSO-d6): δ 8.30 (s, 1H, b3-H), 8.11 (dd, J = 7.60 and 7.20 Hz, 1H, b6-H), 7.93 (d, J = 15.87 Hz, 1H, β-H), 7.90 (dd, J = 8.37 and 7.55 Hz, 1H, b5-H), 7.89 (d, J = 15.87 Hz, 1H, α-H), 7.76 (d, J = 8.41 Hz, 1H, b4-H), 7.29–7.61 (m, 5 H, b7, 3, 4, 5, 6-H). Anal. calc. for C17H11O2F: C, 76.71; H, 4.13. Found: C, 76.45; H, 4.05.

2.1.2.5 3-(3-Fluorophenyl)-1-(benzofurane-2-yl)-2-propen-1-one (3e)

Yield: 1.75 g, 47%; mp 99°C; FTIR (KBr, cm−1): 3,118, 3,073, 1,662, 1,611, 1,582, 1,545, 1,278, 1,156, 981, 850, 753; 1H NMR (300 MHz, DMSO-d6): δ 8.39 (s, 1H, b3-H), 7.97 (d, J = 15.60 Hz, 1H, β-H), 7.70–7.90 (m, 3 H, b4, b6, α-H), 7.35–7.63 (m, 6 H, b5, b6, 2, 4, 5, 6-H). Anal. calc. for C17H11O2F: C, 76.71; H, 4.13. Found: C, 76.57; H, 4.18.

2.1.2.6 3-(3-Nitrophenyl)-1-(benzofurane-2-yl)-2-propen-1-one (3f)

Yield: 2.13 g, 52%; mp 189°C; FTIR (KBr, cm−1): 3,000–3,120, 1,669, 1,615, 1,549, 1,521, 1,358, 1,282, 1,165, 1,040, 976, 812, 740; 1H NMR (300 MHz, DMSO-d6): δ 8.79 (s, 1H, 2-H), 8.43 (s, 1H, b3-H), 8.33 (d, J = 7.74 Hz, 1H, 4-H), 8.27 (dd, J = 7.41 and 1.52 Hz, 1H, 6-H), 8.08 (d, J = 15.77 Hz, 1H, β-H), 7.92 (d, J = 15.90 Hz, 1H, α-H), 7.90 (d, J = 7.50 Hz, 1H, b4-H), 7.74–7.79 (m, 2 H, 5, b7-H), 7.58 (dd, J = 7.60 and 7.62 Hz, 1H, b6-H), 7.40 (dd, J = 7.51 and 7.48 Hz, 1H, b5-H). Anal. calc. for C17H11O4N: C, 69.64; H, 3.75; N, 4.78. Found: C, 70.03; H, 3.59; N, 4.65.

2.2 Pharmacology/Biology

2.2.1 Cell lines

HCT-116 and HT-29 colon cancer cells were cultivated in Roswell Park Memorial Institute 1640 (including L-glutamine) medium that was enhanced with 1% non-essential amino acid, penicillin G (100 U/mL), streptomycin (100 μg/mL), and 10% fetal bovine serum. Healthy colon cells CCD-18Co cells were cultivated in Dulbecco’s Modified Eagle Medium (including L-glutamine) with additional supplements of 10% fetal bovine serum, penicillin G (100 U/mL), and streptomycin (100 μg/mL). All cells have been attained from American Type Cell Culture Collection (ATCC, USA) and cultured in incubator at 37℃ with 5% CO2 throughout the analyses.

2.2.2 Detection of cell cytotoxicity by sulforhodamine B (SRB) viability analysis

SRB is a bright-purple amino xanthene stain with sulfonic groups that bind to basic amino acid side chains below acidic situations and dissociate below basic situations. The method allows quantitative analysis of cell viability as a result of reading the SRB dye [17]. To ascertain the potential cytotoxic effect, 3 replicates of HCT-116, HT-29, and CCD-18Co cells were first added to 96-well plate at 5 × 103 cells/well in 100 μL. It was incubated overnight to ensure that the cells adhered to the plate surface. To obtain preliminary data, 6 chalcone derivatives (3a–f) (0.78–50 μM) were added to the experimental group. Additionally, viability analysis was performed similarly to determine the possible effect of the solvent (DMSO) of the derivative. Following 24 and 48 h treatment, SRB viability analysis was carried out as previously mentioned [18]. At the end of the treatment periods, the cells were fixed to the plate bottom with 50% (w/v) trichloroacetic acid for 1 h at 4℃. After the plate was washed five times with distilled water, it was incubated with 0.4% (w/v) SRB for 30 min at 37℃. To remove unbound dye, the wells were washed five times with 1% (v/v) acetic acid solution. 10 mM Tris base (pH: 10.0) was added to the wells to solubilize the dye bound to the fixed cells. To measure the percentage of viability spectrophotometrically, absorbance (Abs) was measured at a wavelength of 564 nm on the Elisa Reader. As a result of SRB analysis, the most effective derivative was selected and further analysis was performed. Viability rates (%) in cells were calculated using the formula below. Subsequently, IC50 (Half-maximal inhibitory value) values were calculated according to the viability (%) results. IC50 values were determined by normalizing each cell group to the groups without chalcone derivative (negative control).

Viability ( % ) = 100 × “ Abs value of experimental group / Abs value of control group ”

To more comprehensively evaluate the antiproliferative activity of the compound, the ratio of IC50 of healthy cells to cancerous cells must be determined. The Selectivity Index (SI) values were computed for this purpose using the following formula [19]:

SI = IC 50 value of healthy cells / IC 50 value of cancer cells

2.2.3 Detection of cell death pathway

Fluorescent dyes generally bind to different compartments of the cell and provide morphological status information [20,21]. To determine the state of the cell in the apoptotic and necrotic death pathway, first, HCT-116 and HT-29 cells were added to 96-well plate at 5 × 103 cells/well in 100 μL and three replicates. It was incubated overnight to ensure that the cells adhered to the plate surface. 3-nitrophenyl chalcone derivative (3.125–25 μM) was added to the experimental group. Following 24 h treatment, staining was carried out using the previously mentioned dyes Hoechst 33,342 (4 μg/mL), Annexin-V (AnxV; 3 μg/mL), and Propidium Iodide (PI; 1 μg/mL) [22] and examined under a fluorescent microscope. The densitometric analysis was carried out with Image-J (https://imagej.net/ij/, RRID:SCR_003070). After normalization, the stages of apoptosis in the cells were determined.

Cell death is regulated by caspases involved in the apoptosis [23]. To determine caspase 3/7 activity, first, HCT-116 and HT-29 cells were added to 6-well plate at 1 × 105 cells/well in 1 mL and three replicates. It was incubated overnight to ensure that the cells adhered to the plate surface. 3-nitrophenyl chalcone derivative (3.125–12.5 μM) was added to the experimental group. Following 48 h treatment, analysis was carried out at the Muse Cell Analyzer (Millipore, Germany) using the caspase 3/7 kit (Luminex, USA) in compliance with the manufacturer’s instructions.

Western blotting technique enables the detection of proteins, which is the last step of the genetic information flow. In brief, it relies on the migration of proteins in a polyacrylamide gel through an electrophoresis process to a support membrane, with the proteins in the membrane being measured using immunological techniques [24]. First, HCT-116 and HT-29 cells were added to 6-well plate at 1 × 105 cells/well in 1 mL volume and three replicates. It was incubated overnight to ensure that the cells adhered to the plate surface. 3-nitrophenyl chalcone derivative (1.56–12.5 μM) was added to the experimental group. Following 48 h treatment, cell lysate preparation and western blot analysis were carried out as previously mentioned [25]. Western blot was performed using GAPDH (Glyceraldehyde 3‐phosphate dehydrogenase; Cat# 5174; RRID: AB_10622025), PARP (Poly (ADP‐ribose) polymerase 1; Cat# 9542, RRID: AB_2160739), c-PARP (cleaved PARP, Large fragment; Cat# 9546; RRID: AB_2160593) BIP (Binding-immunoglobulin protein; Cat# 3177; RRID: AB_2119845), DR-4 (Death Receptor 4; Cat# 42533; RRID: AB_2799223), and BCL-2 (B‐cell lymphoma 2; Cat# 2876; RRID: AB_2064177) primary antibodies (Cell Signaling Technology). The HRP-linked anti-rabbit Ig (Cat# 7074; RRID: AB_2099233) seconder antibody (Cell Signaling Technology) was then used for the second antibody incubation. The Image Quant LAS 4000 (GE Healthcare 9410 Variable Mode Imager; RRID:SCR_018047) was utilized to visualize bound antibodies. The densitometric analysis was carried out with Image-J. Blot images of both cells normalized according to GAPDH and compared to control, which is set to 1.0.

2.2.4 Analysis based on measurement of growth and proliferation abilities

As a result of possible mutations or changes, cells escape from the Cyclin-Dependent Kinase (CDK) proteins that control cellular proliferation and enter the process of carcinogenesis as they proliferate excessively. Over time, these cells divide uncontrollably, becoming more resistant to tumor suppressor proteins such as p53 that protect healthy tissue, and become less dependent on signals from other cells [26]. Therefore, targeting the cell cycle is one of the main goals in cancer treatment. First, HCT-116 and HT-29 cells were added to 6-well plate at 1 × 105 cells/well in 1 mL and three replicates. To enable the cells adhesive to the plate surface, it was incubated for the entire night. 3-nitrophenyl chalcone derivative (3.125–12.5 μM) was added to the experimental group. The cells were taken off the plate surface after 24 h, and their lysates were extracted in 70% cold ethanol. The “Muse® Cell Cycle Reagent” on the Muse Cell Analyzer (Millipore, Germany) was used to determine the distribution of cells in the cycle phases following the Muse Cell Cycle Kit (Luminex, USA) process.

Monolayer wound healing analysis was performed to determine the cell migration rate. First, HCT-116 and HT-29 cells were added to 6-well plate at 15 × 104 cells/well in 1 mL and three replicates. Using 200 μL pipette tip, horizontal and vertical lines were drawn on each well surface once the cells had reached 90% occupancy (confluent condition) and 3-nitrophenyl chalcone derivative (1.56–12.5 μM) was added to the experimental group. The moment of wound creation was considered as the beginning and healing was recorded from the same point at regular intervals throughout the 48 h treatment. The densitometric analysis was carried out with Image-J. Migration rate normalized and compared to 0th h, which is set to 0(%) [27,28].

Using this technique, the population’s capacity for “unlimited” division is assessed for every cell [29,30]. First, HCT-116 and HT-29 cells were added to 6-well plate at 2,000 cells/well in 1 mL and three replicates. Since the cells were seeded in relatively small amounts, they were incubated overnight to ensure adhesion to the plate surface. 3-nitrophenyl chalcone derivative (1.56–6.25 μM) was added to the experimental group. The derivative was taken out of the well at the end of the 48 h and fresh medium was applied. The media in the wells were replaced with fresh media every 3 days until at least 50 cells per colony were formed in the control group cells, and the growth of the cells was examined under an inverted microscope at regular intervals. After a sufficient density of colonies was formed in the control group cells, the medium in the wells was removed, 1 mL of cold methanol was added to each well and fixed at −20°C for 15 min. To remove methanol, the wells were washed once with 1 mL Phosphate buffer saline (PBS, 1×, Sigma-Aldrich). Then, they were stained with 1 mL of 0.05% crystal violet (prepared in methanol) by incubating them in a dark environment at room conditions for 20 min. At the end of the time, it was washed once again with 1 mL PBS (1×) and images of the cells were recorded. The densitometric analysis was carried out with Image-J. Colony formation rate was compared to control, which is set to 100(%).

2.3 Molecular docking analysis

The data file (.pdb format) for the 3D model of the 3-nitrophenyl chalcone derivative used in this study was generated from the SMILES representation using the RDKit library in Python and energy optimization was performed. Then, 3D structures of DR-4 and BCL-2 proteins (.pdb format), which were predicted to be associated with the 3-nitrophenyl chalcone derivative, were obtained using a similar method [31].

In the second stage, molecular docking interaction analysis was conducted using the CB-Dock2 (Cavity-detection guided Blind Docking) protein-ligand interaction database [32]. AutoDock Vina scores (kcal/mol), obtained from docking analysis performed in the CB-Dock2 system, estimate how strongly a compound interacts with its target protein. Each protein-ligand molecule has a CurPocket ID number, defined according to its interaction pattern at different coordinates in the 3D model. In this context, the interaction type with the lowest negative level has the potential to create strong bonds from a chemoinformatical perspective [33].

2.4 Statistical data analysis

The mean of at least three separate investigations was calculated to display the experiment outcomes with ± standard deviation (SD). GraphPad Prism v9.2.0 (RRID:SCR_002798) was used to evaluate all statistical analyses and one-way analysis of variance was used for testing. Values of *p < 0.05; **p < 0.01; and ***p < 0.001 were deemed statistically significant [34].

3 Results

3.1 Chemistry

For biological activity analyses, six chalcone derivatives with different side groups were re-synthesized following the method previously synthesized and characterized by our group [35]. Chalcone derivatives with the 3-(substituted aryl)-1-benzofuranyl-2-propenone skeleton (Figure 1a and b) were obtained by condensation of 2-acetylbenzofuran(1) and six aromatic aldehydes (2a–f). These aldehyde substrates are 2-hydroxybenzaldehyde, 3-hydroxybenzaldehyde, 4-(dimethylamino) benzaldehyde, 2-fluorobenzaldehyde, 3-fluorobenzaldehyde, 2-nitrobenzaldehyde, respectively. The most common method for the synthesis of chalcones is the Claisen–Schmidt reaction, which involves the condensation of a benzaldehyde derivative with an acetophenone derivative in ethanol solvent using sodium hydroxide [36]. All chalcones were purified by recrystallization from ethanol. All derivatives were characterized by elemental analysis, Fourier transform infrared (FT-IR), 1H NMR, and 13C NMR (only 3a). Derivatives showed characteristic bands between 1,639 and 1,662 cm−1 (C═O stretching) and 1,605 and 1,615 cm−1 (C═C stretching) at wavelengths varying according to the structure. In 1H NMR spectra, the most characteristic bands were observed at 8.08–8.43 ppm (3b–h) and 7.60–8.00 ppm (α-H and β-H, the resonance of β-H is in a lower area than α-H) and a coupling constant of about 15 Hz characterized the trans-configuration.

3.2 Pharmacology/biology

3.2.1 3-nitrophenyl chalcone derivative selectively reduces the viability of cancer cells

First, six types of chalcone derivatives (3a–f) were applied to colon cancer (HCT-116 and HT-29) cells with different genomic and morphological features for 48 h and the most effective derivative was determined as 3-nitrophenyl chalcone (3f) as a result of SRB viability analysis (IC50 2.38; 7.89, respectively) (Figure 2). It was observed that the solvent of the derivative (DMSO) did not affect cancer cells, which would reduce their viability.

Figure 2 Line diagrams of SRB analysis results after treatment with six chalcone derivatives on HCT-116 (a) and HT-29 (b) cells for 48 h.
Figure 2

Line diagrams of SRB analysis results after treatment with six chalcone derivatives on HCT-116 (a) and HT-29 (b) cells for 48 h.

Then, viability analysis was performed for 24 h (Figure 3a) and 48 h (Figure 3b) to determine the possible selective effect between healthy (CCD-18Co) and cancer (HCT-116 and HT-29) cells. It was observed that there was a general decrease in the viability percentages (%) in cancer cells (HCT-116 and HT-29) as the dose increased at both times, and that it was statistically significantly (*p < 0.05; ***p < 0.001) lower in HCT-116 cells, especially at low doses (0.391–6.25 μM). Depending on the change in treatment (from 24 to 48 h), it was revealed that cytotoxicity increased more in HCT-116 cells (51%) than in HT-29 cells (25%). It was observed that the viability of healthy cells was higher than cancer cells, even though it decreased depending on time and dose. It was determined that cytotoxicity was very low (>25 μM) at the 24 h, and viability was decreased by half at the 15.22 μM dose at 48 h. Additionally, the formulated SI value was calculated to determine the cell-specific selectivity of the derivative. According to the results, it was concluded that the SI value increased in HCT-116 cells (from 8.18 to 8.9 μM) and decreased in HT-29 cells (from 2.73 to 1.96 μM) depending on time (Table 1).

Figure 3 Line diagrams of SRB analysis results after treatment with 3-nitrophenyl chalcone derivative (0.391–25 μM) on HCT-116, HT-29, and CCD-18Co cells for 24 h (a) and 48 h (b). * Indicates statistically significant differences compared to the control (*p < 0.05; **p < 0.01; ***p < 0.001). Data are shown as mean value ± SD (n = 3).
Figure 3

Line diagrams of SRB analysis results after treatment with 3-nitrophenyl chalcone derivative (0.391–25 μM) on HCT-116, HT-29, and CCD-18Co cells for 24 h (a) and 48 h (b). * Indicates statistically significant differences compared to the control (*p < 0.05; **p < 0.01; ***p < 0.001). Data are shown as mean value ± SD (n = 3).

Table 1

SI values of 3-nitrophenyl chalcone derivative on HCT-116 and HT-29 cells according to the SRB analysis results obtained after 24 h (a) and 48 h (b) treatment

SI 24 h 48 h
HCT-116 HT-29 HCT-116 HT-29
3-nitrophenyl chalcone derivative 8.18 2.73 8.9 1.96

3.2.2 3-nitrophenyl chalcone derivative promotes apoptotic cell death

To detect the death mode, HCT-116 and HT-29 cells were subjected to 3-nitrophenyl chalcone derivative (3.125–25 μM, determined according to the viability analysis results) for 24 h. According to the results, in HCT-116 (Figure 4a) and HT-29 (Figure 4b) cells decrease in the density of Hoechst + cells and increase in the density of apoptosis-specific pyknotic cells were generally observed as the dose increased. In HCT-116 (Figure 4a1) cells, it was revealed that early apoptotic (AnxV+/PI−) cells were statistically significantly (***p < 0.001) more dense at low doses (3.125 and 6.25 μM), while late apoptotic (AnxV+/PI+) cells were more dense at higher doses (12.5 and 25 μM). In HT-29 (Figure 4b1) cells, it was revealed that the cell density in both stages increased at similar rate as the dose increased. At the 25 μM dose, unlike other doses, late apoptotic (AnxV+/PI+) cells were statistically significantly (***p < 0.001) more dense. It was seen that the fluorescence microscopy results in both cells supported our viability results.

Figure 4 Fluorescent staining images of Hoechst (blue labeled), Annexin V (green labeled), and Propidium Iodide (red labeled) after treatment with 3-nitrophenyl chalcone derivative (3.125–25 μM) on HCT-116 (a) and HT-29 (b) cells for 24 h. White arrows indicate Pyknotic nuclei. The histogram graphs express the density (%) and late apoptotic cells on HCT-116 (a1) and HT-29 (b1) cells according to the densitometric data. *Indicates statistically significant differences compared to the control (***p < 0.001). Data are shown as mean value ± SD (n = 3). Objective magnification ×20 and the scale bar length 50 μm.
Figure 4

Fluorescent staining images of Hoechst (blue labeled), Annexin V (green labeled), and Propidium Iodide (red labeled) after treatment with 3-nitrophenyl chalcone derivative (3.125–25 μM) on HCT-116 (a) and HT-29 (b) cells for 24 h. White arrows indicate Pyknotic nuclei. The histogram graphs express the density (%) and late apoptotic cells on HCT-116 (a1) and HT-29 (b1) cells according to the densitometric data. *Indicates statistically significant differences compared to the control (***p < 0.001). Data are shown as mean value ± SD (n = 3). Objective magnification ×20 and the scale bar length 50 μm.

To determine the level of Caspase 3/7, which is involved in the death through apoptosis, HCT-116 and HT-29 cells were subjected to 3-nitrophenyl chalcone derivative (3.125–12.5 μM, determined according to the viability analysis results) for 48 h. According to the results, it was observed that the apoptotic rate in HCT-116 (Figure 5a) cells increased statistically significantly (***p < 0.001) starting from low doses (3.125 μM) and approached the maximum value at the dose of 12.5 μM. Moreover, it (Figure 5a1) was revealed that death due to dose increase generally occurred in the early stage of apoptosis (Q4). Although the increase in apoptotic rate was observed to be low (<⁓22%) in HT-29 (Figure 5b) cells at doses of 3.125 and 6.25 μM, it was determined to be statistically significantly (***p < 0.001) higher (⁓93%) at the dose of 12.5 μM. Similar to HCT-116 cells, it (Figure 5b1) was revealed that death due to dose increase generally occurred in the early stage of apoptosis (Q4). It was seen that the Caspase 3/7 results in both cells supported our viability results.

Figure 5 Results of Caspase-3/7 activation analysis using flow cytometry after treatment with 3-nitrophenyl chalcone derivative (3.125–12.5 μM) on HCT-116 (a) and HT-29 (b) cells for 48 h. The histogram graphs express the percentage (%) early (Q4), late (Q2), and total (Q2 + Q4) apoptotic cells according to the quantitative data of HCT-116 (a1) and HT-29 (b1) cells, respectively. *Indicates statistically significant differences compared to the control (***p < 0.001). Data are shown as mean value ± SD (n = 3).
Figure 5

Results of Caspase-3/7 activation analysis using flow cytometry after treatment with 3-nitrophenyl chalcone derivative (3.125–12.5 μM) on HCT-116 (a) and HT-29 (b) cells for 48 h. The histogram graphs express the percentage (%) early (Q4), late (Q2), and total (Q2 + Q4) apoptotic cells according to the quantitative data of HCT-116 (a1) and HT-29 (b1) cells, respectively. *Indicates statistically significant differences compared to the control (***p < 0.001). Data are shown as mean value ± SD (n = 3).

To measure the amounts of certain proteins involved in apoptosis-induced death, HCT-116 and HT-29 cells were subjected to 3-nitrophenyl chalcone derivative (1.56–12.5 μM, determined according to the viability analysis results) for 48 h. The results are shown from top to bottom according to the kDa values of the proteins (Figure 6a and b). In both cells, PARP decreased and c-PARP increased depending on the dose increase. BIP increased significantly in both cells starting from the dose of 1.56 μM (Figure 6a1) and 6.25 μM (Figure 6b1), respectively. Similarly, an increase at DR-4 was observed in both cells. Finally, it was observed that “anti-apoptotic” BCL-2, which plays a role in the intrinsic pathway of apoptosis, decreased more in HT-29 cells at the same dose values. In parallel with our viability and caspase 3/7 activity results, it was concluded that the derivative was more effective in HCT-116 cells when compared to western blot results at the same dose values.

Figure 6 Blot images and fold change values of some apoptosis pathway proteins acquired with western blot analysis after treatment with 3-nitrophenyl chalcone derivative (1.56–12.5 μM) on HCT-116 (a) and HT-29 (b) cells for 48 h. Equal protein loading confirmed by GAPDH. The histogram graphs express the relative intensity of some apoptosis pathway proteins on HCT-116 (a1) and HT-29 (b1) cells, respectively.
Figure 6

Blot images and fold change values of some apoptosis pathway proteins acquired with western blot analysis after treatment with 3-nitrophenyl chalcone derivative (1.56–12.5 μM) on HCT-116 (a) and HT-29 (b) cells for 48 h. Equal protein loading confirmed by GAPDH. The histogram graphs express the relative intensity of some apoptosis pathway proteins on HCT-116 (a1) and HT-29 (b1) cells, respectively.

3.2.3 Analyses based on measurement of growth and proliferation abilities

To detect the stage at which division is suppressed, HCT-116 and HT-29 cells were subjected to 3-nitrophenyl chalcone derivative (3.125–12.5 μM, determined according to viability analysis results) for 24 h. According to the results, the cell arresting rate in HCT-116 (Figure 7a) cells increased and decreased starting from 3.125 μM dose in the G0-G1 phase, and finally increased to 56.5% at the 12.5 μM dose, resulting in a statistically significant (***p < 0.001) increase. It was concluded that the cycle was suppressed before entering the DNA synthesis phase (Figure 7a1). In the S phase, it was observed that the arresting rate decreased and increased depending on the increase in dose, and it was determined that there was 20.5% arrest rate at 12.5 μM.

Figure 7 Results of cell cycle analysis using flow cytometry after treatment with 3-nitrophenyl chalcone derivative (3.125–12.5 μM) on HCT-116 (a) and HT-29 (b) cells for 24 h. The histogram graphs express the distribution (%) of cell cycle stages according to the quantitative data of HCT-116 (a1) and HT-29 (b1) cells, respectively. *Indicates statistically significant differences compared to the control (***p < 0.001). Data are shown as mean value ± SD (n = 3).
Figure 7

Results of cell cycle analysis using flow cytometry after treatment with 3-nitrophenyl chalcone derivative (3.125–12.5 μM) on HCT-116 (a) and HT-29 (b) cells for 24 h. The histogram graphs express the distribution (%) of cell cycle stages according to the quantitative data of HCT-116 (a1) and HT-29 (b1) cells, respectively. *Indicates statistically significant differences compared to the control (***p < 0.001). Data are shown as mean value ± SD (n = 3).

It was concluded that in the G2/M phase, which is the preparation phase for entry into mitosis, a cell arresting rate of 42.9% was observed in the control group, while the arresting rate decreased steadily depending on the increase in dose. In HT-29 (Figure 7b) cells, the cell arresting rate increased statistically significantly (***p < 0.001) from 22.5 to 52.4% depending on the dose increase in the G0-G1 phase, and it was concluded that the cycle was suppressed (Figure 7b1). While there was 23% arresting rate in control group cells in S phase, it decreased and increased depending on the increase in dose, and it was observed that it decreased to 14.6% at a dose of 12.5 μM. It was concluded that in the G2/M phase, while 50.8% cell arresting was observed in the control group, the rate decreased regularly depending on the increase in dose. Cell cycle results support the anticancer activity of the derivative observed in our other analyses.

To observe the ability to migration, HCT-116 and HT-29 cells were subjected to 3-nitrophenyl chalcone derivative (1.56–12.5 μM, determined based on viability analysis results) for 48 h. According to the results, it was observed that migration in HCT-116 (Figure 8a) and HT-29 (Figure 8b) cells generally decreased with increasing dose. When comparing same doses of the derivative, it was revealed that there was more effect at low doses (1.56 and 3.125 μM) in HCT-116 (Figure 8a1) cells, while there was more effect at high doses (6.25 and 12.5 μM) in HT-29 (Figure 8b1) cells. In this context, the dose values that affected both cells in the migration results were found to be compatible with the cytotoxic dose values determined in our 48-h viability results. Additionally, when the migration rates at the 48th h were compared, it was observed that it was statistically significantly (***p < 0.001) lower (⁓10%) at the 12.5 μM dose in both cells. Yellow bars indicate the area examined in the statistical analysis of the migration ability of cells.

Figure 8 Results of wound healing analysis after treatment with 3-nitrophenyl chalcone derivative (1.56–12.5 μM) on HCT-116 (a) and HT-29 (b) cells up to 48th h. The line graphs express the cellular migration rate (%) of HCT-116 (a1) and HT-29 (b1) cells within the yellow vertical bar according to the densitometric data. *Indicates statistically significant differences compared to the control (***p < 0.001). Data are shown as mean value ± SD (n = 3). Objective magnification ×4.
Figure 8

Results of wound healing analysis after treatment with 3-nitrophenyl chalcone derivative (1.56–12.5 μM) on HCT-116 (a) and HT-29 (b) cells up to 48th h. The line graphs express the cellular migration rate (%) of HCT-116 (a1) and HT-29 (b1) cells within the yellow vertical bar according to the densitometric data. *Indicates statistically significant differences compared to the control (***p < 0.001). Data are shown as mean value ± SD (n = 3). Objective magnification ×4.

To ascertain whether every cell in the surroundings is capable of “unlimited” division, HCT-116 and HT-29 cells were subjected to 3-nitrophenyl chalcone derivative (1.56–12.5 μM, determined based on viability analysis results) for 48 h. According to the results, it was observed that there were statistically significant (***p < 0.001) decreases in colony formation ability in both cells depending on the dose increase (Figure 9a and b). When the same doses were compared in both cells, it was revealed that there was a greater effect at low doses (1.56 and 3.125 μM) in HCT-116 (Figure 9a1) cells and at higher dose (6.25 μM) in HT-29 (Figure 9b1) cells. Colony formation results of both cells support our viability results.

Figure 9 Results of colony formation analysis after treatment of HCT-116 (a) and HT-29 (b) with 3-nitrophenyl chalcone derivates (1.56–6.25 μM) for 48 h. The histogram graphs express the colony formation rate (%) of HCT-116 (a1) and HT-29 (b1) cells, respectively, according to the densitometric data of ×4 objective magnification. *Indicates statistically significant differences compared to the control (***p < 0.001). Data are shown as mean value ± SD (n = 3).
Figure 9

Results of colony formation analysis after treatment of HCT-116 (a) and HT-29 (b) with 3-nitrophenyl chalcone derivates (1.56–6.25 μM) for 48 h. The histogram graphs express the colony formation rate (%) of HCT-116 (a1) and HT-29 (b1) cells, respectively, according to the densitometric data of ×4 objective magnification. *Indicates statistically significant differences compared to the control (***p < 0.001). Data are shown as mean value ± SD (n = 3).

3.3 Molecular docking between 3-nitrophenyl chalcone derivative and target proteins

Molecular docking was used to investigate the atomic-level interactions between 3-nitrophenyl chalcone derivative and target protein (DR-4 and BCL-2). Three-dimensional structures of 3-nitrophenyl chalcone derivative and target protein are shown in Figure 10. According to the results, the binding scores of the target proteins DR-4 and BCL-2, which may interact with the 3-nitrophenyl chalcone derivative, were determined to be (−6.0) and (−6.6) kcal/mol, respectively (Table 2). These values indicate that the chalcone derivative could potentially interact significantly with these proteins.

Figure 10 2D projection of the 3-nitrophenyl chalcone derivative (a); 3D-docked model of the derivative within the DR-4 active site (b); and 3D-docked model of the derivative within the BCL-2 active site (c).
Figure 10

2D projection of the 3-nitrophenyl chalcone derivative (a); 3D-docked model of the derivative within the DR-4 active site (b); and 3D-docked model of the derivative within the BCL-2 active site (c).

Table 2

CB-Dock2 results of the molecular docking between 3-nitrophenyl chalcone derivative and DR-4/BCL-2 proteins

Cb-Dock2 data CurPocket ID Vina score  Cavity volume (Å3)  Center (x, y, z) Docking size (x, y, z) Contact residues (highest Vina score)
3-nitrophenyl chalcone and DR-4 interaction C4 −6.0 150 4, 3, 32 24, 24, 24 Chain A: GLN347 ARG348 ARG349 ARG350 LEU351 HIS426 LEU429 ASP430 ARG441 GLU442 GLN445 ASP446 VAL449 GLY452 PHE454 ILE455 TYR456 LEU457 GLU458 ASP459 THR461
C5 −5.8 121 −5, 0, 18 24, 24, 24
C1 −5.7 709 10, 5, 25 24, 24, 24
C2 −5.7 278 −41, 28, 52 24, 24, 24
C3 −5.4 229 −51, 18, 11 24, 24, 24
3-nitrophenyl chalcone and BCL-2 interaction C1 −6.6 432 6, 11, −2 24, 24, 24 Chain A: TYR21 LYS22 GLN25 ARG26 ASP102 SER105 ARG106 ARG109 ARG110 PHE112 ALA113 SER116 GLU152 GLY155 VAL156 VAL159 GLU160 ASN163
C2 −6.6 289 −9, 11, 12 24, 24, 24
C5 −6.6 162 13, −2, 1 24, 24, 24
C3 −5.8 191 −6 −11 −11 24, 24, 24
C4 −5.8 167 12, −8, −11 24, 24, 24

4 Discussion

Incidence and mortality in cancer continue to increase rapidly worldwide due to etiological factors [37]. Due to the development of multiple resistance to chemotherapeutic drugs, targeted treatment regimen research is gaining importance day by day [38]. Nowadays, a large number of anticancer agents obtained from various natural sources are used in the clinic. Chalcone derivatives belonging to the flavonoid family attract great attention due to their bioactive components in their side groups [39]. In the literature, many natural or synthetic chalcone derivatives have been shown to cause various biological activities, especially anticancer activity [40,41,42]. In addition, the anticancer properties of various chalcone derivatives have been investigated in many studies involving our group [43,44,45]. This study contains findings on the mechanistic effect of the synthesized and characterized 3-nitrophenyl chalcone derivative on colon cancer cells.

According to our SRB results, while there was no effect on healthy colon cells (CCD-18Co) at low doses as a result of both 24 h and 48 h of treatment, a decrease in viability was observed in cancer cells starting from low dose. This revealed that the derivative was specific to the cancer cell. The low IC₅₀ value indicates that the compound may exert its effect with minimal systemic toxicity, due to its efficacy at lower concentrations [46,47,48]. An in vitro study conducted on HCT-116 cells, the effect of quinazolinone chalcone derivative was investigated and IC50 values were calculated as 600, 140, 26, and 16 μM after 6, 12, 24, and 48 h, respectively [49]. In our study, as a result of the treatment applied to the same cells, it was observed that the cytotoxic effect was higher with IC50 values of 3.47 μM for 24 h and 1.7 μM for 48 h. This difference may have emerged thanks to 3-nitrophenyl ring in the chemical structure of our derivative. The low IC₅₀ value (∼1.71 µM) observed in HCT‑116 cells reveals that the derivative exhibits strong cytotoxic effects at low concentrations and is consistent with similar chalcone analogues in the literature, such as chalcone 6a which shows IC₅₀  =  2.37 ± 0.73 µM in HCT‑116 cells. It is estimated that this effect occurs due to the nitro group in the B ring and the acetyl group in the A ring increasing the electron-withdrawing capacity of the chalcone compound [50]. Additionally, in various studies, the SI of compounds with an SI value >3 was considered significant [51,52]. According to the index values obtained in this study, it is seen that there is a selective effect (⁓8) on HCT-116 cells in both times.

Apoptotic markers were analyzed to determine whether the observed decrease in cell viability was due to apoptosis-mediated cell death. Considering our triple fluorescent staining and caspase 3/7 flow cytometry results together, it was observed that late apoptosis pathway was active in the same dose groups in both cells at 24 h, and early apoptosis pathway was active at 48 h. In a recent study, the effects of Pd(ii) complex on breast cancer were investigated, and similar to our results, an increase in the early stage of apoptosis was observed in the transition from 24 to 48 h as a result of fluorescent staining [53]. This increase was thought to result from the upregulation of receptors involved in the extrinsic apoptosis pathway, such as phosphatidylserine. Similarly, according to our western blot results, the level of DR-4 protein, which is involved in TNFR1-mediated apoptosis in the extrinsic pathway, increased dose-dependently after 48 h of treatment, supporting our idea. Additionally, the increase in DR-4 levels and caspase 3 activation according to flow cytometry results revealed that the caspase 8 signaling cascade was stimulated by the extrinsic pathway [54,55]. Additionally, PARP, c-PARP, BIP, and BCL-2 protein levels were investigated by western blot. It was observed that the level of PARP protein decreased and the level of the c-PARP subunit increased. Considering that PARP is the substrate of caspase 3 and 7 proteases and that a c-PARP subunit is formed as a result of enzymatic cleavage, a correlation was revealed in our western blot and flow cytometry results. Enzymatically active c-PARP plays a role in the process of apoptosis by irreversibly binding to the ends of DNA and causing DNA damage [56,57]. BIP protein ensures that proteins produced in the ribosome are folded correctly in the ER. One of the characteristics of cancer cells is the need for high protein synthesis to produce cellular metabolites [58,59]. ER-mediated apoptosis, which occurs through the PERK/ATF4/IRE1 pathway due to the increase in the amount of BIP protein, which recognizes protein redox imbalance, is one of the main targets in treatment [59,60]. In this study, the dose-dependent increase in BIP level in both cells revealed that ER-mediated apoptosis was activated. BCL-2 is an antiapoptotic protein that prevents the process of apoptosis by inhibiting the formation of the apoptosome complex. As a result of various 3D-QSAR, in vitro and in vivo studies, it has been observed that chalcone derivatives with anticancer potential initiate mitochondria-mediated caspase activation by suppressing BCL-2 [61,62]. In line with findings from the literature, our results showed a dose-dependent reduction in BCL-2 protein levels in colon cancer cells. When the molecular mechanisms of action of the DR-4 and BCL-2 pathways are examined together, molecular findings support the notion that the apoptosis-inducing potential of 3-nitrophenyl chalcone derivative occurs through both extrinsic and intrinsic apoptotic pathways (Figure 6). The IC50 values determined in HCT-116 and HT-29 cells and the increase in DR-4 expression after 48 h of treatment are consistent with literature data indicating that chalcone derivatives increase sensitivity to TRAIL by increasing DR-4/5 receptor levels on the cell membrane [63]. The fact that this effect is more pronounced in HCT-116 cells with an intact p53 gene is consistent with studies showing that p53 upregulates the response to TRAIL by increasing DR-4 expression [64,65]. Moreover, the dose-dependent reduction in anti-apoptotic BCL-2 expression supports the involvement of the intrinsic (mitochondria-mediated) apoptotic pathway. This finding is consistent with studies demonstrating that nitro-substituted chalcone derivatives disrupt mitochondrial membrane integrity and induce apoptosis by suppressing BCL-2 expression. For example, in one study, a hybrid chalcone, chalcone 1C, decreased BCL-2 protein levels in hepatocellular carcinoma cells. This resulted in disruption of mitochondrial membrane integrity and cytochrome c release. Apoptosome complex formation together with cytochrome c increased caspase 3 and 9 protein levels resulting in apoptotic responses in the nucleus. [66]. However, despite the more pronounced suppression of BCL-2 levels in HT-29 cells, the earlier and more intense onset of apoptosis in HCT-116 cells (Figures 4 and 5) may be attributable to the presence of an activated p53 signaling pathway, which leads to increased DR-4 expression.

The cell cycle is regulated by cyclin and CDK proteins depending on factors such as growth factors, cytokines, and oncogenes. It is known that uncontrolled cell division occurs in cancer cells as a result of the inhibition of cycle control [67]. In a study, 3, 4, 4, 5-tetramethoxy chalcone derivatives were found to cause an antiproliferative effect by suppressing division in colon and prostate cancer cells in the G1 and G2 stages, respectively [13]. Similarly, in this study, arrest in the G0/G1 phase was observed in both cancer cells as a result of treatment with 3-nitrophenyl chalcone derivative for 24 h. The presence of cells in this phase indicates that CDKs at the G1-S cycle checkpoint are activated. The treatment period was determined by taking into account the duration of each division cycle of HCT-116 and HT-29 cells as a result of literature analysis.

Another feature of cancer cells is that they gain the ability to metastasize and invade [68]. There are many studies in the literature using chalcone derivatives to reduce the migration and colony formation ability of cancer cells. For instance, it has been demonstrated that the L2H17 chalcone derivative inhibits the invasion and migration of mouse colon cancer (CT26.WT) cells [69]. In another recent study conducted on esophageal cancer cells, they observed that the derivative formed as a result of the hybridization of the heterocyclic chalcone skeleton and the dithiocarbamate compound slowed down growth depending on the dose and suppressed invasion and migration as a result of the decrease in N-cadherin and Slug biomarkers [70]. In this study, as a result of 48 h treatment with 3-nitrophenyl chalcone derivative, it was observed that the migration and colony formation abilities of colon cancer cells were suppressed dose-dependently. In addition, when the migration results in both cells were compared (Figure 8a and b), it was observed that the cells that lost their adhesion ability left from the plate surface, especially since the 12.5 uM dose showed a toxic effect on HCT-116 cells. In conclusion, the chalcone derivative showed stronger anticancer effects in HCT-116 cells, potentially due to their p53-positive genetic background, which enhances the suppression of cell growth and proliferation.

Recent advances in artificial intelligence have been playing an increasingly critical role in drug design and molecular modeling processes [71,72]. In this study, the anticancer potential of a 3-nitrophenyl chalcone derivative was evaluated using AI-assisted 3D modeling and molecular docking analyses. Binding affinity calculations performed with AutoDock Vina revealed that the compound exhibited binding energies in the range of –6 to –7 kcal/mol with its target proteins. These values are considered moderate-to-good binding affinities in the literature and indicate that the compound may form biologically meaningful interactions [73]. In particular, the observed binding score of –6.6 kcal/mol with the anti-apoptotic protein BCL-2 suggests that the compound may have the potential to inhibit BCL-2. This finding is significant as it may contribute to the activation of apoptosis mechanisms in cancer cells. Overall, the docking results suggest that the 3-nitrophenyl chalcone derivative could be a promising multi-target anticancer drug candidate.

Based on the results of this study, it was revealed that 3-nitrophenyl chalcone derivative caused a strong cytotoxic effect on colon cells and death occurred by apoptosis in both cell lines (HCT-116 and HT-29). In the next investigation step, genes and proteins that are effective in metastasis, cell cycle, and life pathways will be determined through bioinformatic analysis. Thus, we aim to demonstrate the multifaceted biological effects of chalcone, which holds therapeutic potential in colon cancer.

Acknowledgments

We want to thank the members of our Bursa Uludag University Molecular Cancer Research Laboratory (BUMKAL) group, who are not listed in authors, for contributing to the methodology and data analysis. We thank Assoc. Prof. Dr. Semih DALKILIÇ for molecular docking analysis.

  1. Funding information: This study was supported within the project numbered FYL-2021-720.

  2. Author contributions: Concept: F.A.; design: F.A.; supervision: F.A.; fundings: M.O. and F.A.; Materials: M.O., D.C., and F.A.; data collection or processing: M.O.; analysis or interpretation: F.A.; literature search: M.O.; writing: M.O. and F.A.; critical review: D.C. and F.A.

  3. Conflict of interest: The authors have no competing interests to declare relevant to this article’s content.

  4. Data availability statement: The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.

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Received: 2025-02-25
Revised: 2025-07-21
Accepted: 2025-09-19
Published Online: 2025-10-18

© 2025 the author(s), published by De Gruyter

This work is licensed under the Creative Commons Attribution 4.0 International License.

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  121. Development of a nomogram for predicting cancer-specific survival in patients with renal pelvic cancer following surgery
  122. Inhibition of ATG7 promotes orthodontic tooth movement by regulating the RANKL/OPG ratio under compression force
  123. A machine learning-based prognostic model integrating mRNA stemness index, hypoxia, and glycolysis‑related biomarkers for colorectal cancer
  124. Glutathione attenuates sepsis-associated encephalopathy via dual modulation of NF-κB and PKA/CREB pathways
  125. FAHD1 prevents neuronal ferroptosis by modulating R-loop and the cGAS–STING pathway
  126. Association of placenta weight and morphology with term low birth weight: A case–control study
  127. Investigation of the pathogenic variants induced Sjogren’s syndrome in Turkish population
  128. Nucleotide metabolic abnormalities in post-COVID-19 condition and type 2 diabetes mellitus patients and their association with endocrine dysfunction
  129. TGF-β–Smad2/3 signaling in high-altitude pulmonary hypertension in rats: Role and mechanisms via macrophage M2 polarization
  130. Ultrasound-guided unilateral versus bilateral erector spinae plane block for postoperative analgesia of patients undergoing laparoscopic cholecystectomy
  131. Profiling gut microbiome dynamics in subacute thyroiditis: Implications for pathogenesis, diagnosis, and treatment
  132. Delta neutrophil index, CRP/albumin ratio, procalcitonin, immature granulocytes, and HALP score in acute appendicitis: Best performing biomarker?
  133. Anticancer activity mechanism of novelly synthesized and characterized benzofuran ring-linked 3-nitrophenyl chalcone derivative on colon cancer cells
  134. H2valdien3 arrests the cell cycle and induces apoptosis of gastric cancer
  135. Prognostic relevance of PRSS2 and its immune correlates in papillary thyroid carcinoma
  136. Review Articles
  137. The effects of enhanced external counter-pulsation on post-acute sequelae of COVID-19: A narrative review
  138. Diabetes-related cognitive impairment: Mechanisms, symptoms, and treatments
  139. Microscopic changes and gross morphology of placenta in women affected by gestational diabetes mellitus in dietary treatment: A systematic review
  140. Review of mechanisms and frontier applications in IL-17A-induced hypertension
  141. Research progress on the correlation between islet amyloid peptides and type 2 diabetes mellitus
  142. The safety and efficacy of BCG combined with mitomycin C compared with BCG monotherapy in patients with non-muscle-invasive bladder cancer: A systematic review and meta-analysis
  143. The application of augmented reality in robotic general surgery: A mini-review
  144. The effect of Greek mountain tea extract and wheat germ extract on peripheral blood flow and eicosanoid metabolism in mammals
  145. Neurogasobiology of migraine: Carbon monoxide, hydrogen sulfide, and nitric oxide as emerging pathophysiological trinacrium relevant to nociception regulation
  146. Plant polyphenols, terpenes, and terpenoids in oral health
  147. Laboratory medicine between technological innovation, rights safeguarding, and patient safety: A bioethical perspective
  148. End-of-life in cancer patients: Medicolegal implications and ethical challenges in Europe
  149. The maternal factors during pregnancy for intrauterine growth retardation: An umbrella review
  150. Intra-abdominal hypertension/abdominal compartment syndrome of pediatric patients in critical care settings
  151. PI3K/Akt pathway and neuroinflammation in sepsis-associated encephalopathy
  152. Screening of Group B Streptococcus in pregnancy: A systematic review for the laboratory detection
  153. Giant borderline ovarian tumours – review of the literature
  154. Leveraging artificial intelligence for collaborative care planning: Innovations and impacts in shared decision-making – A systematic review
  155. Cholera epidemiology analysis through the experience of the 1973 Naples epidemic
  156. Risk factors of frailty/sarcopenia in community older adults: Meta-analysis
  157. Supplement strategies for infertility in overweight women: Evidence and legal insights
  158. Scurvy, a not obsolete disorder: Clinical report in eight young children and literature review
  159. A meta-analysis of the effects of DBS on cognitive function in patients with advanced PD
  160. Case Reports
  161. Delayed graft function after renal transplantation
  162. Semaglutide treatment for type 2 diabetes in a patient with chronic myeloid leukemia: A case report and review of the literature
  163. Diverse electrophysiological demyelinating features in a late-onset glycogen storage disease type IIIa case
  164. Giant right atrial hemangioma presenting with ascites: A case report
  165. Laser excision of a large granular cell tumor of the vocal cord with subglottic extension: A case report
  166. EsoFLIP-assisted dilation for dysphagia in systemic sclerosis: Highlighting the role of multimodal esophageal evaluation
  167. Molecular hydrogen-rhodiola as an adjuvant therapy for ischemic stroke in internal carotid artery occlusion: A case report
  168. Coronary artery anomalies: A case of the “malignant” left coronary artery and its surgical management
  169. Rapid Communication
  170. Biological properties of valve materials using RGD and EC
  171. A single oral administration of flavanols enhances short-term memory in mice along with increased brain-derived neurotrophic factor
  172. Letter to the Editor
  173. Role of enhanced external counterpulsation in long COVID
  174. Expression of Concern
  175. Expression of concern “A ceRNA network mediated by LINC00475 in papillary thyroid carcinoma”
  176. Expression of concern “Notoginsenoside R1 alleviates spinal cord injury through the miR-301a/KLF7 axis to activate Wnt/β-catenin pathway”
  177. Expression of concern “circ_0020123 promotes cell proliferation and migration in lung adenocarcinoma via PDZD8”
  178. Corrigendum
  179. Corrigendum to “Empagliflozin improves aortic injury in obese mice by regulating fatty acid metabolism”
  180. Corrigendum to “Comparing the therapeutic efficacy of endoscopic minimally invasive surgery and traditional surgery for early-stage breast cancer: A meta-analysis”
  181. Corrigendum to “The progress of autoimmune hepatitis research and future challenges”
  182. Retraction
  183. Retraction of “miR-654-5p promotes gastric cancer progression via the GPRIN1/NF-κB pathway”
  184. Special Issue Advancements in oncology: bridging clinical and experimental research - Part II
  185. Unveiling novel biomarkers for platinum chemoresistance in ovarian cancer
  186. Lathyrol affects the expression of AR and PSA and inhibits the malignant behavior of RCC cells
  187. The era of increasing cancer survivorship: Trends in fertility preservation, medico-legal implications, and ethical challenges
  188. Bone scintigraphy and positron emission tomography in the early diagnosis of MRONJ
  189. Meta-analysis of clinical efficacy and safety of immunotherapy combined with chemotherapy in non-small cell lung cancer
  190. Special Issue Computational Intelligence Methodologies Meets Recurrent Cancers - Part IV
  191. Exploration of mRNA-modifying METTL3 oncogene as momentous prognostic biomarker responsible for colorectal cancer development
  192. Special Issue The evolving saga of RNAs from bench to bedside - Part III
  193. Interaction and verification of ferroptosis-related RNAs Rela and Stat3 in promoting sepsis-associated acute kidney injury
  194. The mRNA MOXD1: Link to oxidative stress and prognostic significance in gastric cancer
  195. Special Issue Exploring the biological mechanism of human diseases based on MultiOmics Technology - Part II
  196. Dynamic changes in lactate-related genes in microglia and their role in immune cell interactions after ischemic stroke
  197. A prognostic model correlated with fatty acid metabolism in Ewing’s sarcoma based on bioinformatics analysis
  198. Red cell distribution width predicts early kidney injury: A NHANES cross-sectional study
  199. Special Issue Diabetes mellitus: pathophysiology, complications & treatment
  200. Nutritional risk assessment and nutritional support in children with congenital diabetes during surgery
  201. Correlation of the differential expressions of RANK, RANKL, and OPG with obesity in the elderly population in Xinjiang
  202. A discussion on the application of fluorescence micro-optical sectioning tomography in the research of cognitive dysfunction in diabetes
  203. A review of brain research on T2DM-related cognitive dysfunction
  204. Metformin and estrogen modulation in LABC with T2DM: A 36-month randomized trial
  205. Special Issue Innovative Biomarker Discovery and Precision Medicine in Cancer Diagnostics
  206. CircASH1L-mediated tumor progression in triple-negative breast cancer: PI3K/AKT pathway mechanisms
https://doi.org/10.1515/med-2025-1310
Schlagwörter für diesen Artikel
apoptosis; cancer; chalcone; colon; cytotoxicity
Creative Commons
BY 4.0

Artikel in diesem Heft

  1. Research Articles
  2. Network pharmacological analysis and in vitro testing of the rutin effects on triple-negative breast cancer
  3. Impact of diabetes on long-term survival in elderly liver cancer patients: A retrospective study
  4. Knockdown of CCNB1 alleviates high glucose-triggered trophoblast dysfunction during gestational diabetes via Wnt/β-catenin signaling pathway
  5. Risk factors for severe adverse drug reactions in hospitalized patients
  6. Analysis of the effect of ALA-PDT on macrophages in footpad model of mice infected with Fonsecaea monophora based on single-cell sequencing
  7. Development and validation of headspace gas chromatography with a flame ionization detector method for the determination of ethanol in the vitreous humor
  8. CMSP exerts anti-tumor effects on small cell lung cancer cells by inducing mitochondrial dysfunction and ferroptosis
  9. Predictive value of plasma sB7-H3 and YKL-40 in pediatric refractory Mycoplasma pneumoniae pneumonia
  10. Antiangiogenic potential of Elaeagnus umbellata extracts and molecular docking study by targeting VEGFR-2 pathway
  11. Comparison of the effectiveness of nurse-led preoperative counseling and postoperative follow-up care vs standard care for patients with gastric cancer
  12. Comparing the therapeutic efficacy of endoscopic minimally invasive surgery and traditional surgery for early-stage breast cancer: A meta-analysis
  13. Adhered macrophages as an additional marker of cardiomyocyte injury in biopsies of patients with dilated cardiomyopathy
  14. Association between statin administration and outcome in patients with sepsis: A retrospective study
  15. Exploration of the association between estimated glucose disposal rate and osteoarthritis in middle-aged and older adults: An analysis of NHANES data from 2011 to 2018
  16. A comparative analysis of the binary and multiclass classified chest X-ray images of pneumonia and COVID-19 with ML and DL models
  17. Lysophosphatidic acid 2 alleviates deep vein thrombosis via protective endothelial barrier function
  18. Transcription factor A, mitochondrial promotes lymph node metastasis and lymphangiogenesis in epithelial ovarian carcinoma
  19. Serum PM20D1 levels are associated with nutritional status and inflammatory factors in gastric cancer patients undergoing early enteral nutrition
  20. Hydromorphone reduced the incidence of emergence agitation after adenotonsillectomy in children with obstructive sleep apnea: A randomized, double-blind study
  21. Vitamin D replacement therapy may regulate sleep habits in patients with restless leg syndrome
  22. The first-line antihypertensive nitrendipine potentiated the therapeutic effect of oxaliplatin by downregulating CACNA1D in colorectal cancer
  23. Health literacy and health-related quality of life: The mediating role of irrational happiness
  24. Modulatory effects of Lycium barbarum polysaccharide on bone cell dynamics in osteoporosis
  25. Mechanism research on inhibition of gastric cancer in vitro by the extract of Pinellia ternata based on network pharmacology and cellular metabolomics
  26. Examination of the causal role of immune cells in non-alcoholic fatty liver disease by a bidirectional Mendelian randomization study
  27. Clinical analysis of ten cases of HIV infection combined with acute leukemia
  28. Investigating the cardioprotective potential of quercetin against tacrolimus-induced cardiotoxicity in Wistar rats: A mechanistic insights
  29. Clinical observation of probiotics combined with mesalazine and Yiyi Baitouweng Decoction retention enema in treating mild-to-moderate ulcerative colitis
  30. Diagnostic value of ratio of blood inflammation to coagulation markers in periprosthetic joint infection
  31. Sex-specific associations of sex hormone binding globulin and risk of bladder cancer
  32. Core muscle strength and stability-oriented breathing training reduces inter-recti distance in postpartum women
  33. The ERAS nursing care strategy for patients undergoing transsphenoidal endoscopic pituitary tumor resection: A randomized blinded controlled trial
  34. The serum IL-17A levels in patients with traumatic bowel rupture post-surgery and its predictive value for patient prognosis
  35. Impact of Kolb’s experiential learning theory-based nursing on caregiver burden and psychological state of caregivers of dementia patients
  36. Analysis of serum NLR combined with intraoperative margin condition to predict the prognosis of cervical HSIL patients undergoing LEEP surgery
  37. Commiphora gileadensis ameliorate infertility and erectile dysfunction in diabetic male mice
  38. The correlation between epithelial–mesenchymal transition classification and MMP2 expression of circulating tumor cells and prognosis of advanced or metastatic nasopharyngeal carcinoma
  39. Tetrahydropalmatine improves mitochondrial function in vascular smooth muscle cells of atherosclerosis in vitro by inhibiting Ras homolog gene family A/Rho-associated protein kinase-1 signaling pathway
  40. A cross-sectional study: Relationship between serum oxidative stress levels and arteriovenous fistula maturation in maintenance dialysis patients
  41. A comparative analysis of the impact of repeated administration of flavan 3-ol on brown, subcutaneous, and visceral adipose tissue
  42. Identifying early screening factors for depression in middle-aged and older adults: A cohort study
  43. Perform tumor-specific survival analysis for Merkel cell carcinoma patients undergoing surgical resection based on the SEER database by constructing a nomogram chart
  44. Unveiling the role of CXCL10 in pancreatic cancer progression: A novel prognostic indicator
  45. High-dose preoperative intraperitoneal erythropoietin and intravenous methylprednisolone in acute traumatic spinal cord injuries following decompression surgeries
  46. RAB39B: A novel biomarker for acute myeloid leukemia identified via multi-omics and functional validation
  47. Impact of peripheral conditioning on reperfusion injury following primary percutaneous coronary intervention in diabetic and non-diabetic STEMI patients
  48. Clinical efficacy of azacitidine in the treatment of middle- and high-risk myelodysplastic syndrome in middle-aged and elderly patients: A retrospective study
  49. The effect of ambulatory blood pressure load on mitral regurgitation in continuous ambulatory peritoneal dialysis patients
  50. Expression and clinical significance of ITGA3 in breast cancer
  51. Single-nucleus RNA sequencing reveals ARHGAP28 expression of podocytes as a biomarker in human diabetic nephropathy
  52. rSIG combined with NLR in the prognostic assessment of patients with multiple injuries
  53. Toxic metals and metalloids in collagen supplements of fish and jellyfish origin: Risk assessment for daily intake
  54. Exploring causal relationship between 41 inflammatory cytokines and marginal zone lymphoma: A bidirectional Mendelian randomization study
  55. Gender beliefs and legitimization of dating violence in adolescents
  56. Effect of serum IL-6, CRP, and MMP-9 levels on the efficacy of modified preperitoneal Kugel repair in patients with inguinal hernia
  57. Effect of smoking and smoking cessation on hematological parameters in polycythemic patients
  58. Pathogen surveillance and risk factors for pulmonary infection in patients with lung cancer: A retrospective single-center study
  59. Necroptosis of hippocampal neurons in paclitaxel chemotherapy-induced cognitive impairment mediates microglial activation via TLR4/MyD88 signaling pathway
  60. Celastrol suppresses neovascularization in rat aortic vascular endothelial cells stimulated by inflammatory tenocytes via modulating the NLRP3 pathway
  61. Cord-lamina angle and foraminal diameter as key predictors of C5 palsy after anterior cervical decompression and fusion surgery
  62. GATA1: A key biomarker for predicting the prognosis of patients with diffuse large B-cell lymphoma
  63. Influencing factors of false lumen thrombosis in type B aortic dissection: A single-center retrospective study
  64. MZB1 regulates the immune microenvironment and inhibits ovarian cancer cell migration
  65. Integrating experimental and network pharmacology to explore the pharmacological mechanisms of Dioscin against glioblastoma
  66. Trends in research on preterm birth in twin pregnancy based on bibliometrics
  67. Four-week IgE/baseline IgE ratio combined with tryptase predicts clinical outcome in omalizumab-treated children with moderate-to-severe asthma
  68. Single-cell transcriptomic analysis identifies a stress response Schwann cell subtype
  69. Acute pancreatitis risk in the diagnosis and management of inflammatory bowel disease: A critical focus
  70. Effect of subclinical esketamine on NLRP3 and cognitive dysfunction in elderly ischemic stroke patients
  71. Interleukin-37 mediates the anti-oral tumor activity in oral cancer through STAT3
  72. CA199 and CEA expression levels, and minimally invasive postoperative prognosis analysis in esophageal squamous carcinoma patients
  73. Efficacy of a novel drainage catheter in the treatment of CSF leak after posterior spine surgery: A retrospective cohort study
  74. Comprehensive biomedicine assessment of Apteranthes tuberculata extracts: Phytochemical analysis and multifaceted pharmacological evaluation in animal models
  75. Relation of time in range to severity of coronary artery disease in patients with type 2 diabetes: A cross-sectional study
  76. Dopamine attenuates ethanol-induced neuronal apoptosis by stimulating electrical activity in the developing rat retina
  77. Correlation between albumin levels during the third trimester and the risk of postpartum levator ani muscle rupture
  78. Factors associated with maternal attention and distraction during breastfeeding and childcare: A cross-sectional study in the west of Iran
  79. Mechanisms of hesperetin in treating metabolic dysfunction-associated steatosis liver disease via network pharmacology and in vitro experiments
  80. The law on oncological oblivion in the Italian and European context: How to best uphold the cancer patients’ rights to privacy and self-determination?
  81. The prognostic value of the neutrophil-to-lymphocyte ratio, platelet-to-lymphocyte ratio, and prognostic nutritional index for survival in patients with colorectal cancer
  82. Factors affecting the measurements of peripheral oxygen saturation values in healthy young adults
  83. Comparison and correlations between findings of hysteroscopy and vaginal color Doppler ultrasonography for detection of uterine abnormalities in patients with recurrent implantation failure
  84. The effects of different types of RAGT on balance function in stroke patients with low levels of independent walking in a convalescent rehabilitation hospital
  85. Causal relationship between asthma and ankylosing spondylitis: A bidirectional two-sample univariable and multivariable Mendelian randomization study
  86. Correlations of health literacy with individuals’ understanding and use of medications in Southern Taiwan
  87. Correlation of serum calprotectin with outcome of acute cerebral infarction
  88. Comparison of computed tomography and guided bronchoscopy in the diagnosis of pulmonary nodules: A systematic review and meta-analysis
  89. Curdione protects vascular endothelial cells and atherosclerosis via the regulation of DNMT1-mediated ERBB4 promoter methylation
  90. The identification of novel missense variant in ChAT gene in a patient with gestational diabetes denotes plausible genetic association
  91. Molecular genotyping of multi-system rare blood types in foreign blood donors based on DNA sequencing and its clinical significance
  92. Exploring the role of succinyl carnitine in the association between CD39⁺ CD4⁺ T cell and ulcerative colitis: A Mendelian randomization study
  93. Dexmedetomidine suppresses microglial activation in postoperative cognitive dysfunction via the mmu-miRNA-125/TRAF6 signaling axis
  94. Analysis of serum metabolomics in patients with different types of chronic heart failure
  95. Diagnostic value of hematological parameters in the early diagnosis of acute cholecystitis
  96. Pachymaran alleviates fat accumulation, hepatocyte degeneration, and injury in mice with nonalcoholic fatty liver disease
  97. Decrease in CD4 and CD8 lymphocytes are predictors of severe clinical picture and unfavorable outcome of the disease in patients with COVID-19
  98. METTL3 blocked the progression of diabetic retinopathy through m6A-modified SOX2
  99. The predictive significance of anti-RO-52 antibody in patients with interstitial pneumonia after treatment of malignant tumors
  100. Exploring cerebrospinal fluid metabolites, cognitive function, and brain atrophy: Insights from Mendelian randomization
  101. Development and validation of potential molecular subtypes and signatures of ocular sarcoidosis based on autophagy-related gene analysis
  102. Widespread venous thrombosis: Unveiling a complex case of Behçet’s disease with a literature perspective
  103. Uterine fibroid embolization: An analysis of clinical outcomes and impact on patients’ quality of life
  104. Discovery of lipid metabolism-related diagnostic biomarkers and construction of diagnostic model in steroid-induced osteonecrosis of femoral head
  105. Serum-derived exomiR-188-3p is a promising novel biomarker for early-stage ovarian cancer
  106. Enhancing chronic back pain management: A comparative study of ultrasound–MRI fusion guidance for paravertebral nerve block
  107. Peptide CCAT1-70aa promotes hepatocellular carcinoma proliferation and invasion via the MAPK/ERK pathway
  108. Electroacupuncture-induced reduction of myocardial ischemia–reperfusion injury via FTO-dependent m6A methylation modulation
  109. Hemorrhoids and cardiovascular disease: A bidirectional Mendelian randomization study
  110. Cell-free adipose extract inhibits hypertrophic scar formation through collagen remodeling and antiangiogenesis
  111. HALP score in Demodex blepharitis: A case–control study
  112. Assessment of SOX2 performance as a marker for circulating cancer stem-like cells (CCSCs) identification in advanced breast cancer patients using CytoTrack system
  113. Risk and prognosis for brain metastasis in primary metastatic cervical cancer patients: A population-based study
  114. Comparison of the two intestinal anastomosis methods in pediatric patients
  115. Factors influencing hematological toxicity and adverse effects of perioperative hyperthermic intraperitoneal vs intraperitoneal chemotherapy in gastrointestinal cancer
  116. Endotoxin tolerance inhibits NLRP3 inflammasome activation in macrophages of septic mice by restoring autophagic flux through TRIM26
  117. Lateral transperitoneal laparoscopic adrenalectomy: A single-centre experience of 21 procedures
  118. Petunidin attenuates lipopolysaccharide-induced retinal microglia inflammatory response in diabetic retinopathy by targeting OGT/NF-κB/LCN2 axis
  119. Procalcitonin and C-reactive protein as biomarkers for diagnosing and assessing the severity of acute cholecystitis
  120. Factors determining the number of sessions in successful extracorporeal shock wave lithotripsy patients
  121. Development of a nomogram for predicting cancer-specific survival in patients with renal pelvic cancer following surgery
  122. Inhibition of ATG7 promotes orthodontic tooth movement by regulating the RANKL/OPG ratio under compression force
  123. A machine learning-based prognostic model integrating mRNA stemness index, hypoxia, and glycolysis‑related biomarkers for colorectal cancer
  124. Glutathione attenuates sepsis-associated encephalopathy via dual modulation of NF-κB and PKA/CREB pathways
  125. FAHD1 prevents neuronal ferroptosis by modulating R-loop and the cGAS–STING pathway
  126. Association of placenta weight and morphology with term low birth weight: A case–control study
  127. Investigation of the pathogenic variants induced Sjogren’s syndrome in Turkish population
  128. Nucleotide metabolic abnormalities in post-COVID-19 condition and type 2 diabetes mellitus patients and their association with endocrine dysfunction
  129. TGF-β–Smad2/3 signaling in high-altitude pulmonary hypertension in rats: Role and mechanisms via macrophage M2 polarization
  130. Ultrasound-guided unilateral versus bilateral erector spinae plane block for postoperative analgesia of patients undergoing laparoscopic cholecystectomy
  131. Profiling gut microbiome dynamics in subacute thyroiditis: Implications for pathogenesis, diagnosis, and treatment
  132. Delta neutrophil index, CRP/albumin ratio, procalcitonin, immature granulocytes, and HALP score in acute appendicitis: Best performing biomarker?
  133. Anticancer activity mechanism of novelly synthesized and characterized benzofuran ring-linked 3-nitrophenyl chalcone derivative on colon cancer cells
  134. H2valdien3 arrests the cell cycle and induces apoptosis of gastric cancer
  135. Prognostic relevance of PRSS2 and its immune correlates in papillary thyroid carcinoma
  136. Review Articles
  137. The effects of enhanced external counter-pulsation on post-acute sequelae of COVID-19: A narrative review
  138. Diabetes-related cognitive impairment: Mechanisms, symptoms, and treatments
  139. Microscopic changes and gross morphology of placenta in women affected by gestational diabetes mellitus in dietary treatment: A systematic review
  140. Review of mechanisms and frontier applications in IL-17A-induced hypertension
  141. Research progress on the correlation between islet amyloid peptides and type 2 diabetes mellitus
  142. The safety and efficacy of BCG combined with mitomycin C compared with BCG monotherapy in patients with non-muscle-invasive bladder cancer: A systematic review and meta-analysis
  143. The application of augmented reality in robotic general surgery: A mini-review
  144. The effect of Greek mountain tea extract and wheat germ extract on peripheral blood flow and eicosanoid metabolism in mammals
  145. Neurogasobiology of migraine: Carbon monoxide, hydrogen sulfide, and nitric oxide as emerging pathophysiological trinacrium relevant to nociception regulation
  146. Plant polyphenols, terpenes, and terpenoids in oral health
  147. Laboratory medicine between technological innovation, rights safeguarding, and patient safety: A bioethical perspective
  148. End-of-life in cancer patients: Medicolegal implications and ethical challenges in Europe
  149. The maternal factors during pregnancy for intrauterine growth retardation: An umbrella review
  150. Intra-abdominal hypertension/abdominal compartment syndrome of pediatric patients in critical care settings
  151. PI3K/Akt pathway and neuroinflammation in sepsis-associated encephalopathy
  152. Screening of Group B Streptococcus in pregnancy: A systematic review for the laboratory detection
  153. Giant borderline ovarian tumours – review of the literature
  154. Leveraging artificial intelligence for collaborative care planning: Innovations and impacts in shared decision-making – A systematic review
  155. Cholera epidemiology analysis through the experience of the 1973 Naples epidemic
  156. Risk factors of frailty/sarcopenia in community older adults: Meta-analysis
  157. Supplement strategies for infertility in overweight women: Evidence and legal insights
  158. Scurvy, a not obsolete disorder: Clinical report in eight young children and literature review
  159. A meta-analysis of the effects of DBS on cognitive function in patients with advanced PD
  160. Case Reports
  161. Delayed graft function after renal transplantation
  162. Semaglutide treatment for type 2 diabetes in a patient with chronic myeloid leukemia: A case report and review of the literature
  163. Diverse electrophysiological demyelinating features in a late-onset glycogen storage disease type IIIa case
  164. Giant right atrial hemangioma presenting with ascites: A case report
  165. Laser excision of a large granular cell tumor of the vocal cord with subglottic extension: A case report
  166. EsoFLIP-assisted dilation for dysphagia in systemic sclerosis: Highlighting the role of multimodal esophageal evaluation
  167. Molecular hydrogen-rhodiola as an adjuvant therapy for ischemic stroke in internal carotid artery occlusion: A case report
  168. Coronary artery anomalies: A case of the “malignant” left coronary artery and its surgical management
  169. Rapid Communication
  170. Biological properties of valve materials using RGD and EC
  171. A single oral administration of flavanols enhances short-term memory in mice along with increased brain-derived neurotrophic factor
  172. Letter to the Editor
  173. Role of enhanced external counterpulsation in long COVID
  174. Expression of Concern
  175. Expression of concern “A ceRNA network mediated by LINC00475 in papillary thyroid carcinoma”
  176. Expression of concern “Notoginsenoside R1 alleviates spinal cord injury through the miR-301a/KLF7 axis to activate Wnt/β-catenin pathway”
  177. Expression of concern “circ_0020123 promotes cell proliferation and migration in lung adenocarcinoma via PDZD8”
  178. Corrigendum
  179. Corrigendum to “Empagliflozin improves aortic injury in obese mice by regulating fatty acid metabolism”
  180. Corrigendum to “Comparing the therapeutic efficacy of endoscopic minimally invasive surgery and traditional surgery for early-stage breast cancer: A meta-analysis”
  181. Corrigendum to “The progress of autoimmune hepatitis research and future challenges”
  182. Retraction
  183. Retraction of “miR-654-5p promotes gastric cancer progression via the GPRIN1/NF-κB pathway”
  184. Special Issue Advancements in oncology: bridging clinical and experimental research - Part II
  185. Unveiling novel biomarkers for platinum chemoresistance in ovarian cancer
  186. Lathyrol affects the expression of AR and PSA and inhibits the malignant behavior of RCC cells
  187. The era of increasing cancer survivorship: Trends in fertility preservation, medico-legal implications, and ethical challenges
  188. Bone scintigraphy and positron emission tomography in the early diagnosis of MRONJ
  189. Meta-analysis of clinical efficacy and safety of immunotherapy combined with chemotherapy in non-small cell lung cancer
  190. Special Issue Computational Intelligence Methodologies Meets Recurrent Cancers - Part IV
  191. Exploration of mRNA-modifying METTL3 oncogene as momentous prognostic biomarker responsible for colorectal cancer development
  192. Special Issue The evolving saga of RNAs from bench to bedside - Part III
  193. Interaction and verification of ferroptosis-related RNAs Rela and Stat3 in promoting sepsis-associated acute kidney injury
  194. The mRNA MOXD1: Link to oxidative stress and prognostic significance in gastric cancer
  195. Special Issue Exploring the biological mechanism of human diseases based on MultiOmics Technology - Part II
  196. Dynamic changes in lactate-related genes in microglia and their role in immune cell interactions after ischemic stroke
  197. A prognostic model correlated with fatty acid metabolism in Ewing’s sarcoma based on bioinformatics analysis
  198. Red cell distribution width predicts early kidney injury: A NHANES cross-sectional study
  199. Special Issue Diabetes mellitus: pathophysiology, complications & treatment
  200. Nutritional risk assessment and nutritional support in children with congenital diabetes during surgery
  201. Correlation of the differential expressions of RANK, RANKL, and OPG with obesity in the elderly population in Xinjiang
  202. A discussion on the application of fluorescence micro-optical sectioning tomography in the research of cognitive dysfunction in diabetes
  203. A review of brain research on T2DM-related cognitive dysfunction
  204. Metformin and estrogen modulation in LABC with T2DM: A 36-month randomized trial
  205. Special Issue Innovative Biomarker Discovery and Precision Medicine in Cancer Diagnostics
  206. CircASH1L-mediated tumor progression in triple-negative breast cancer: PI3K/AKT pathway mechanisms
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Heruntergeladen am 24.10.2025 von https://www.degruyterbrill.com/document/doi/10.1515/med-2025-1310/html
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