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Adriamycin-resistant cells are significantly less fit than adriamycin-sensitive cells in cervical cancer

  • Min Qi , Lijuan Xie and Guihua Duan EMAIL logo
Published/Copyright: January 20, 2021
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Open Life Sciences
From the journal Open Life Sciences Volume 16 Issue 1

Abstract

Adriamycin (ADR) is an important chemotherapy agent in many advanced cancers, but the emergence of drug resistance during treatment is a major limitation to its successful use. Recent studies have suggested that drug-resistant cells become less fit and their growth could be inhibited by parental cells without cytotoxic treatment. In this study, we examined the fitness differences between HeLa and HeLa/ADR cells. Compared with the parental cell line, HeLa/ADR cells showed significantly lower growth rates, both in vitro and in vivo. There was no difference in the apoptosis rate between them, but G1 arrest and reduced DNA synthesis were found in HeLa/ADR cells. Further study indicated that HeLa/ADR cells failed to compete for space and nutrition against parental cells in vivo. Taken together, we demonstrate that HeLa/ADR cells are less fit and their growth can be inhibited by parental cells in the absence of ADR; therefore, the maintenance of a certain amount of ADR-sensitive cells during treatment may facilitate the control of the development of ADR resistance.

Keywords: adriamycin resistance; cervical cancer; fitness differences; tumor evolution

1 Introduction

Adriamycin (ADR) is a valuable clinical antitumor agent and is routinely used in the treatment of several cancers [1,2]. However, in addition to problems with toxicity, the dominant growth of ADR-resistant cells after treatment is a key factor limiting its use. Multiple studies have indicated the appearance of resistant cells prior to the initiation of therapy [3,4,5,6]. There are findings that even provide evidence that resistant cells can both preexist and evolve from drug-sensitive cells [7,8], and that cancer therapies may eventually select for resistant cells and further promote their clonal expansion [3,9,10]. However, some models suggest that the development of drug-resistant cells may be delayed in the presence of existing dominant clones owing to the limited availability of nutrition and space [11,12,13].

Adaptive therapy was first introduced by Gatenby [11]. The principle of adaptive therapy is to achieve a fixed tumor size by maintaining a certain amount of drug-sensitive cells, which can suppress the growth of less fit, but drug-resistant cells. In this way, adaptive therapy could significantly extend patient progression-free survival in both the mathematical model and various preclinical models of breast cancer [12,14]. Their model found that when resistant cells emerged in an untreated tumor, they are commonly present in small quantities and their growth is inhibited by existing sensitive cells that are more fit because resistance mechanisms need to consume additional resources for growth. Accordingly, drug-resistant cells are less fit, and this has been partially confirmed in a breast cancer cell line [12,14]. Therefore, treatments designed to kill all drug-sensitive cells may abrogate this counterbalancing effect and actually promote more rapid outgrowth of resistant cells.

Currently, few studies have examined the fitness distinctions between ADR-resistant and ADR-sensitive cells. Gatenby et al. reported that ADR-sensitive breast cancer cells are more fit than resistant cells in glucose-restricted conditions, and patient survival could be increased under certain conditions by utilizing the competition between drug-resistant and drug-sensitive cells according to certain computational models [14]. However, more direct experimental evidence about the fitness deficit of ADR-resistant cells may have important future implications and is currently limited.

In this study, we revealed that the proliferation of HeLa cells was substantially faster than that of HeLa/ADR cells both in vitro and in vivo, and HeLa/ADR cells failed to occupy space when introduced at a one-to-one ratio with sensitive cells in vivo. Our data provides a direct evidence that ADR-sensitive HeLa cells are significantly more fit than ADR-resistant HeLa cells, and adaptive strategy may have important implications in the treatment of cervical tumor.

2 Materials and methods

2.1 Cell culture

HeLa cell line was purchased from the Type Culture Collection of the Chinese Academy of Sciences, Shanghai, China. RFP-tagged HeLa cell line was derived via the lentiviral transduction. HeLa/ADR cell line was induced by sustained exposure of HeLa cells to incremental concentrations of ADR (KeyGEN BioTECH). The higher drug concentration was employed after the cells got into a steady growth period. IC50 was calculated by GraphPad Prism. In order to maintain the resistant phenotype, HeLa/ADR cell line was maintained in the presence of 90 ng/mL ADR until 1 week before experiments. All cell lines were cultured in RPMI 1640 (Invitrogen) supplemented with 10% FBS (Biological Industries, BI) under a 5% CO2 environment. All cell lines were authenticated by short tandem repeat profiling analysis.

2.2 Cell proliferation analysis

Cells were seeded onto 12-well plates at 1 × 104 cells per well and incubated with 1 mL of media. Cells were counted daily by Cell Counter (Scepter 2.0, Millipore) for 9 days.

2.3 Cell viability assay

HeLa and HeLa/ADR cell lines were seeded onto 96-well plates at 3 × 103 cells per well. After 24 h, growth media were exchanged for media containing different concentrations of ADR (0, 12.5, 25, 50, 100, 200, and 400 ng/mL). Cell viability was analyzed after 48 h by CCK8 (Dojindo) according to the manufacturer’s instruction.

2.4 Colony-formation assay

Cells were seeded onto 6-well plates at 500–1,000 cells per well and incubated with 2 mL of media with or without 50 ng/mL ADR for 14 days. Cells were fixed with 70% methanol for 10 min and stained with 0.5% crystal violet for 20 min. Colonies of more than 50 cells were counted under a microscope.

2.5 EdU assay

Cells were labeled using the Click-iT® Plus EdU (5-ethynyl-2′-deoxyuridine) Imaging Kit (Invitrogen) according to the manufacturer’s protocols. The ratio of EdU-positive cells was evaluated from three randomly selected sample regions by counting 500–1,000 cells per field using the ImageJ software (1.48 v).

2.6 Analysis of cell cycle distribution and apoptosis

Cell cycle analysis was performed using the Cycletest™ Plus DNA Reagent Kit (BD Bioscience) based on manufacturer’s instruction; then cells were analyzed by flow cytometry. Apoptosis rate in vitro was performed using the Annexin V-FITC apoptosis detection kit (BD Bioscience) based on manufacturer’s instruction; then cells were analyzed by flow cytometry.

2.7 Xenograft experiments

Male Nu/Nu mice of 4 weeks old were purchased from Vital River Laboratories. 106 cells (total cell number was 2 × 106 for the group which contained both RFP-tagged HeLa cells and HeLa/ADR cells) were suspended in 0.2 mL of RPMI 1640 supplemented with 50% Matrigel (BD Biosciences) before subcutaneous implantation into the flank region of each mice. n = 5 for HeLa group, n = 6 for mixed group, and n = 12 for HeLa/ADR group; HeLa/ADR cells were implanted into each flank of the six mice. Tumor volumes were monitored using electronic calipers twice a week; when the tumor volume reached 1,000–2,000 mm3, the mice were sacrificed. Tumor volumes were calculated using the following formula: 1/2 × length × width2. Length indicated the longest diameter of tumor.

  1. Ethical approval: The research related to animal use has been complied with all the relevant national regulations and institutional policies for the care and use of animals and has been approved by the Medical Ethics Review Committee of the First People’s Hospital of Yunnan Province (Kunming, China).

2.8 Immunohistochemistry

Tumor tissues were fixed in 10% formalin (Sigma) at room temperature and embedded in paraffin. Paraffin-embedded samples were then processed for immunohistochemistry; Ki67 (1:100, 0.2 mg/mL, ab8191; Abcam) was used as a measure of cell proliferation. Scoring for the expression of Ki67 was performed as follows: the percentage of Ki67+ cells was calculated from three randomly selected regions of the samples by counting an average of 1,600–2,000 cells per slide using the ImageJ software.

2.9 RFP ratio analyses and terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) assay

Tumor samples were frozen in liquid nitrogen for RFP ratio assay. 5 µm sections of frozen samples were prepared by freezing microtome, and cell nucleus was stained with DAPI. TUNEL assay was determined by the in situ cell death detection kit (Roche) according to the manufacturer’s protocols. The percentages of RFP-positive and TUNEL-positive cells were calculated from three randomly selected regions of the xenografts by counting an average of 1,600–2,000 cells per slide using the ImageJ software.

2.10 Statistical analyses

All the statistical analyses were performed using GraphPad Prism 6.0. All the experiments were repeated at least three times. Unless otherwise indicated, all experiments data were expressed as mean ± SD of triplicate wells of a representative experiment. Difference in tumor formation rate was evaluated by the Chi-square test. Differences between treatments were evaluated by Student’s t test. Differences were considered statistically significant when P < 0.05 (*P < 0.05, **P < 0.01, and ***P < 0.001).

3 Results

3.1 The development of HeLa cells is significantly faster than that of HeLa/ADR cells in vitro

The IC50 values for ADR of both cell lines were evaluated, and the IC50 value of HeLa/ADR cells was almost ten times higher than that of HeLa cells (Figure 1a). Next, we evaluated the growth of both cell lines in vitro (Figure 1b). The growth rate of the HeLa cell line was faster than that of the HeLa/ADR cell line. In the colony-formation assay, more colonies formed in the HeLa cell line than the HeLa/ADR cell line, but the clonogenic growth of HeLa cell line was completely suppressed by ADR (Figure 1c); however, the clonogenic growth of HeLa/ADR cell line was not impacted. These results showed that the growth of the HeLa/ADR cell line was apparently slower than that of its parental cell line without drug treatment.

Figure 1 The growth of ADR-sensitive cells is substantially faster than that of ADR-resistant cells in vitro. (a) The IC50 values for HeLa and HeLa/ADR. (b) Growth curve of both cell lines in the absence of ADR. (c) The colony-formation assay was performed in HeLa and HeLa/ADR under conditions indicated. ADR (50 ng/mL) was added to the medium after 24 h. The clonogenic growth of HeLa/ADR cell line was not impacted by ADR, whereas the clonogenic growth of HeLa cell line was completely suppressed (*P < 0.05, **P < 0.01, and ***P < 0.001).
Figure 1

The growth of ADR-sensitive cells is substantially faster than that of ADR-resistant cells in vitro. (a) The IC50 values for HeLa and HeLa/ADR. (b) Growth curve of both cell lines in the absence of ADR. (c) The colony-formation assay was performed in HeLa and HeLa/ADR under conditions indicated. ADR (50 ng/mL) was added to the medium after 24 h. The clonogenic growth of HeLa/ADR cell line was not impacted by ADR, whereas the clonogenic growth of HeLa cell line was completely suppressed (*P < 0.05, **P < 0.01, and ***P < 0.001).

3.2 The slower growth rate of HeLa/ADR cells is due to reduced proliferation

Next, we further investigated the reasons for the slower growth rate of the HeLa/ADR cells compared with HeLa cells. First, we revealed that the apoptosis rate was similar in both cell lines (Figure 2a), but a significant increase in G1 arrest was observed in HeLa/ADR cells compared with HeLa cells (Figure 2b). Consistent with the cell cycle distribution results, an EdU proliferation assay showed that HeLa/ADR cells had significantly reduced DNA synthesis compared with that of HeLa cells (Figure 2c). These results demonstrated that the lower growth rate of HeLa/ADR cells was caused by a reduced proliferation rate and not by an increased apoptosis rate.

Figure 2 The slower growth rate of HeLa/ADR cells is owing to reduced proliferation. (a) Apoptosis of HeLa and HeLa/ADR cells under different conditions. The medium was exchanged after 24 h. Apoptosis analysis was performed 72 h after medium substitution. (b) Cell cycle analysis of HeLa and HeLa/ADR cells. The medium was exchanged after 24 h. The cell cycle analysis of both cell lines was performed 48 h after medium substitution. (c) EdU assay of HeLa and HeLa/ADR cells. The medium was replaced after 24 h. The EdU-positive cells were analyzed 48 h after medium substitution (*P < 0.05, **P < 0.01, and ***P < 0.001).
Figure 2

The slower growth rate of HeLa/ADR cells is owing to reduced proliferation. (a) Apoptosis of HeLa and HeLa/ADR cells under different conditions. The medium was exchanged after 24 h. Apoptosis analysis was performed 72 h after medium substitution. (b) Cell cycle analysis of HeLa and HeLa/ADR cells. The medium was exchanged after 24 h. The cell cycle analysis of both cell lines was performed 48 h after medium substitution. (c) EdU assay of HeLa and HeLa/ADR cells. The medium was replaced after 24 h. The EdU-positive cells were analyzed 48 h after medium substitution (*P < 0.05, **P < 0.01, and ***P < 0.001).

3.3 HeLa cells are more fit than HeLa/ADR cells in vivo

To verify the fitness differences between HeLa cells and HeLa/ADR cells under microenvironmental constraints, HeLa cells were implanted in the right flank of Nu/Nu mice (n = 5) and HeLa/ADR cells were implanted in each flank of Nu/Nu mice (n = 6). Initially, we observed that significantly fewer HeLa/ADR cells grew in mice compared with their parental cells (Figure 3a), and the progression of HeLa tumors was apparently faster than that of HeLa/ADR tumors (Figure 3b and c). Further study demonstrated that HeLa/ADR tumor cells had a much slower proliferation rate than the parental tumor cells based on Ki67 staining (Figure 3d and e). There was no significant difference in apoptotic cells between HeLa/ADR tumor cells and HeLa tumor cells based on a TUNEL assay (Figure 3d and e). These results demonstrated that HeLa/ADR cell lines exhibited remarkably reduced proliferation in vivo.

Figure 3 ADR-resistant cells exhibit poor adaptability compared with parental cells in vivo. (a) Both cell lines were grafted and monitored for tumor formation over 1 month; n = 5 for HeLa group and n = 12 for HeLa/ADR group. HeLa/ADR cells were implanted into each flank of the six mice. (b) Representative images of tumors. (c) Tumor growth curve, n = 5 per group; the error bars represent SEM (d) Immunohistochemistry analysis of Ki67 expression and quantification of TUNEL+ cell per field in tumor tissues (n = 3 mice per group). (e) Representative images of indicated staining in (d). (f) Mice body weights of HeLa and HeLa/ADR groups. (*P < 0.05, **P < 0.01, and ***P < 0.001).
Figure 3

ADR-resistant cells exhibit poor adaptability compared with parental cells in vivo. (a) Both cell lines were grafted and monitored for tumor formation over 1 month; n = 5 for HeLa group and n = 12 for HeLa/ADR group. HeLa/ADR cells were implanted into each flank of the six mice. (b) Representative images of tumors. (c) Tumor growth curve, n = 5 per group; the error bars represent SEM (d) Immunohistochemistry analysis of Ki67 expression and quantification of TUNEL+ cell per field in tumor tissues (n = 3 mice per group). (e) Representative images of indicated staining in (d). (f) Mice body weights of HeLa and HeLa/ADR groups. (*P < 0.05, **P < 0.01, and ***P < 0.001).

3.4 HeLa cells can completely suppress the growth of HeLa/ADR cells in vivo

To evaluate the interaction between HeLa and HeLa/ADR cell lines when they coexist in vivo, we formed tumors that consisted of RFP-tagged HeLa cells and HeLa/ADR cells at an equal initial proportion to promote cooperation or competition. Although mixed groups had double the number of initial cells, no significant difference in tumor growth was observed between these two groups (Figure 4a and b), indicating that neither HeLa cells nor HeLa/ADR cells increased the growth of mixed tumors. Then, we analyzed the percentages of RFP-positive cells in these two groups when the mice were killed, and there was no significant difference in the proportion of RFP-positive cells between mixed groups and HeLa cell groups (Figure 4c), demonstrating that the development of HeLa/ADR cells was fully suppressed by the growth of HeLa cells. Together, our results implied that the development of HeLa/ADR cells was significantly slower than that of HeLa cells and was fully inhibited when HeLa/ADR cells coexisted with HeLa cells in vivo.

Figure 4 The growth of ADR-resistant cells is significantly inhibited by ADR-sensitive cells in vivo. (a) Images of tumors. (b) Tumor growth curve, n = 5 for HeLa group and n = 6 for mixed group; the error bars represent SEM (c) Analysis of RFP-positive cell per field; each dot indicates a tumor. (*P < 0.05, **P < 0.01, and ***P < 0.001).
Figure 4

The growth of ADR-resistant cells is significantly inhibited by ADR-sensitive cells in vivo. (a) Images of tumors. (b) Tumor growth curve, n = 5 for HeLa group and n = 6 for mixed group; the error bars represent SEM (c) Analysis of RFP-positive cell per field; each dot indicates a tumor. (*P < 0.05, **P < 0.01, and ***P < 0.001).

4 Discussion

The solid tumor microenvironment has a dramatic effect on tumor development. Limited resources and architecture of the microenvironment restrict the volume of solid tumors at every period of their progression [10]. Tumor growth will slow down as it becomes larger following the Gompertzian growth. The tumor cell doubling time (approximately 1–2 days) is substantially faster than the tumor volume doubling time (approximately 60–200 days) [15], indicating that most tumor cells either die before they can divide or remain dormant within the tumor microenvironment. Thus, natural selection in tumors occurs through competition for nutrition and space [10], and the most-fit clone will defeat other clones.

Intratumor heterogeneity is a common feature of advanced cancers because of genomic instability within tumors [16,17,18,19], and a diverse cell population will be generated during tumor progression in this context [20]. The aim of current antitumor therapy strategies is to eradicate the maximum number of tumor cells, but variable responses of tumor subclones to different environmental pressures during various phases of tumor development produce tumors with potential ability to adapt to cytotoxic treatment, complicating tumor eradication [21]. However, adaptive therapy can significantly prolong patients’ overall survival by utilizing competitive relationships among different subclones, instead of maximizing cell killing [11,12]. Adaptive therapy is based on the theory that drug-sensitive cells are more fit than drug-resistant cells without drug treatment because resistant cells need to maintain the resistance mechanism to continue functioning, even in the absence of the drug pressure [22]. For example, resistance mechanisms involve a series of biosynthetic processes that require NADPH consumption, including the suppression of apoptosis in toxic conditions and enhanced antioxidant capacity. Meanwhile, cell proliferation also includes a series of processes that require NADPH consumption, including the biosynthesis of amino acids, fatty acids, and nucleotides. However, NADPH availability is limited for these processes, and if NADPH is increasingly used to maintain resistance mechanisms, the activity of anabolic processes will be restricted, further hindering proliferation [23,24]. In our study, we noticed that ADR-sensitive cells’ growth was significantly faster than that of ADR-resistant cells, even when nutrients were abundant, indicating that ADR-resistant cells require many resources for drug resistance processes, impacting proliferation. Additionally, our results demonstrated that ADR-sensitive cells could completely inhibit the development of ADR-resistant cells in vivo. We inferred that if certain quantities of ADR-sensitive cells are maintained during ADR treatment in cervical cancer, sensitive cells may inhibit the development of ADR-resistant cells by competition for nutrition and space, and accordingly, may delay the development of ADR resistance.

In the previous study, ADR-resistant breast cancer cells did not display apparent defect in the abundance of glucose, but showed fitness deficits under energy-restricted conditions compared with sensitive cells, and patient survival time could be extended by adaptive therapy based on a computational model [14]. In our study, the HeLa/ADR cell line exhibited a significant fitness deficit, even in optimum conditions, and had notably slower growth in vivo, indicating that the ADR-resistant mechanism has diverse impact on the growth of various tumors. Accordingly, adaptive therapy may have specific efficacies depending on tumor type. Additional studies are needed to identify the types of tumors susceptible to ADR-resistant mechanisms to develop more precise, individualized adaptive therapies.

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  1. Funding: This work was supported by Joint Foundation of Kunming Medical University and Yunnan Provincial Science and Technology Department (No. 2019FE001(-159)), Yunnan Provincial Medical Reserve Personnel (No. H-2018043), and Yunnan Provincial Innovation Group of Science and Technology (No. 2018HC006).

  2. Author contributions: Conception and design: M.Q., G.D.; development of methodology: M.Q., L.X.; acquisition of data: M.Q., L.X.; analysis and interpretation of data: M.Q., L.X.; writing, revision of the manuscript: M.Q., G.D.; administrative, technical, or material support: M.Q., G.D.; study supervision: M.Q., G.D.; all authors read and approved the final manuscript.

  3. Conflict of interest: The authors state no conflict of interest.

  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: 2020-03-27
Revised: 2020-08-11
Accepted: 2020-08-13
Published Online: 2021-01-20

© 2021 Min Qi et al., published by De Gruyter

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

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  49. Silencing of LINC00707 suppresses cell proliferation, migration, and invasion of osteosarcoma cells by modulating miR-338-3p/AHSA1 axis
  50. Successful extracorporeal membrane oxygenation resuscitation of patient with cardiogenic shock induced by phaeochromocytoma crisis mimicking hyperthyroidism: A case report
  51. Effects of miR-185-5p on replication of hepatitis C virus
  52. Lidocaine has antitumor effect on hepatocellular carcinoma via the circ_DYNC1H1/miR-520a-3p/USP14 axis
  53. Primary localized cutaneous nodular amyloidosis presenting as lymphatic malformation: A case report
  54. Multimodal magnetic resonance imaging analysis in the characteristics of Wilson’s disease: A case report and literature review
  55. Therapeutic potential of anticoagulant therapy in association with cytokine storm inhibition in severe cases of COVID-19: A case report
  56. Neoadjuvant immunotherapy combined with chemotherapy for locally advanced squamous cell lung carcinoma: A case report and literature review
  57. Rufinamide (RUF) suppresses inflammation and maintains the integrity of the blood–brain barrier during kainic acid-induced brain damage
  58. Inhibition of ADAM10 ameliorates doxorubicin-induced cardiac remodeling by suppressing N-cadherin cleavage
  59. Invasive ductal carcinoma and small lymphocytic lymphoma/chronic lymphocytic leukemia manifesting as a collision breast tumor: A case report and literature review
  60. Clonal diversity of the B cell receptor repertoire in patients with coronary in-stent restenosis and type 2 diabetes
  61. CTLA-4 promotes lymphoma progression through tumor stem cell enrichment and immunosuppression
  62. WDR74 promotes proliferation and metastasis in colorectal cancer cells through regulating the Wnt/β-catenin signaling pathway
  63. Down-regulation of IGHG1 enhances Protoporphyrin IX accumulation and inhibits hemin biosynthesis in colorectal cancer by suppressing the MEK-FECH axis
  64. Curcumin suppresses the progression of gastric cancer by regulating circ_0056618/miR-194-5p axis
  65. Scutellarin-induced A549 cell apoptosis depends on activation of the transforming growth factor-β1/smad2/ROS/caspase-3 pathway
  66. lncRNA NEAT1 regulates CYP1A2 and influences steroid-induced necrosis
  67. A two-microRNA signature predicts the progression of male thyroid cancer
  68. Isolation of microglia from retinas of chronic ocular hypertensive rats
  69. Changes of immune cells in patients with hepatocellular carcinoma treated by radiofrequency ablation and hepatectomy, a pilot study
  70. Calcineurin Aβ gene knockdown inhibits transient outward potassium current ion channel remodeling in hypertrophic ventricular myocyte
  71. Aberrant expression of PI3K/AKT signaling is involved in apoptosis resistance of hepatocellular carcinoma
  72. Clinical significance of activated Wnt/β-catenin signaling in apoptosis inhibition of oral cancer
  73. circ_CHFR regulates ox-LDL-mediated cell proliferation, apoptosis, and EndoMT by miR-15a-5p/EGFR axis in human brain microvessel endothelial cells
  74. Resveratrol pretreatment mitigates LPS-induced acute lung injury by regulating conventional dendritic cells’ maturation and function
  75. Ubiquitin-conjugating enzyme E2T promotes tumor stem cell characteristics and migration of cervical cancer cells by regulating the GRP78/FAK pathway
  76. Carriage of HLA-DRB1*11 and 1*12 alleles and risk factors in patients with breast cancer in Burkina Faso
  77. Protective effect of Lactobacillus-containing probiotics on intestinal mucosa of rats experiencing traumatic hemorrhagic shock
  78. Glucocorticoids induce osteonecrosis of the femoral head through the Hippo signaling pathway
  79. Endothelial cell-derived SSAO can increase MLC20 phosphorylation in VSMCs
  80. Downregulation of STOX1 is a novel prognostic biomarker for glioma patients
  81. miR-378a-3p regulates glioma cell chemosensitivity to cisplatin through IGF1R
  82. The molecular mechanisms underlying arecoline-induced cardiac fibrosis in rats
  83. TGF-β1-overexpressing mesenchymal stem cells reciprocally regulate Th17/Treg cells by regulating the expression of IFN-γ
  84. The influence of MTHFR genetic polymorphisms on methotrexate therapy in pediatric acute lymphoblastic leukemia
  85. Red blood cell distribution width-standard deviation but not red blood cell distribution width-coefficient of variation as a potential index for the diagnosis of iron-deficiency anemia in mid-pregnancy women
  86. Small cell neuroendocrine carcinoma expressing alpha fetoprotein in the endometrium
  87. Superoxide dismutase and the sigma1 receptor as key elements of the antioxidant system in human gastrointestinal tract cancers
  88. Molecular characterization and phylogenetic studies of Echinococcus granulosus and Taenia multiceps coenurus cysts in slaughtered sheep in Saudi Arabia
  89. ITGB5 mutation discovered in a Chinese family with blepharophimosis-ptosis-epicanthus inversus syndrome
  90. ACTB and GAPDH appear at multiple SDS-PAGE positions, thus not suitable as reference genes for determining protein loading in techniques like Western blotting
  91. Facilitation of mouse skin-derived precursor growth and yield by optimizing plating density
  92. 3,4-Dihydroxyphenylethanol ameliorates lipopolysaccharide-induced septic cardiac injury in a murine model
  93. Downregulation of PITX2 inhibits the proliferation and migration of liver cancer cells and induces cell apoptosis
  94. Expression of CDK9 in endometrial cancer tissues and its effect on the proliferation of HEC-1B
  95. Novel predictor of the occurrence of DKA in T1DM patients without infection: A combination of neutrophil/lymphocyte ratio and white blood cells
  96. Investigation of molecular regulation mechanism under the pathophysiology of subarachnoid hemorrhage
  97. miR-25-3p protects renal tubular epithelial cells from apoptosis induced by renal IRI by targeting DKK3
  98. Bioengineering and Biotechnology
  99. Green fabrication of Co and Co3O4 nanoparticles and their biomedical applications: A review
  100. Agriculture
  101. Effects of inorganic and organic selenium sources on the growth performance of broilers in China: A meta-analysis
  102. Crop-livestock integration practices, knowledge, and attitudes among smallholder farmers: Hedging against climate change-induced shocks in semi-arid Zimbabwe
  103. Food Science and Nutrition
  104. Effect of food processing on the antioxidant activity of flavones from Polygonatum odoratum (Mill.) Druce
  105. Vitamin D and iodine status was associated with the risk and complication of type 2 diabetes mellitus in China
  106. Diversity of microbiota in Slovak summer ewes’ cheese “Bryndza”
  107. Comparison between voltammetric detection methods for abalone-flavoring liquid
  108. Composition of low-molecular-weight glutenin subunits in common wheat (Triticum aestivum L.) and their effects on the rheological properties of dough
  109. Application of culture, PCR, and PacBio sequencing for determination of microbial composition of milk from subclinical mastitis dairy cows of smallholder farms
  110. Investigating microplastics and potentially toxic elements contamination in canned Tuna, Salmon, and Sardine fishes from Taif markets, KSA
  111. From bench to bar side: Evaluating the red wine storage lesion
  112. Establishment of an iodine model for prevention of iodine-excess-induced thyroid dysfunction in pregnant women
  113. Plant Sciences
  114. Characterization of GMPP from Dendrobium huoshanense yielding GDP-D-mannose
  115. Comparative analysis of the SPL gene family in five Rosaceae species: Fragaria vesca, Malus domestica, Prunus persica, Rubus occidentalis, and Pyrus pyrifolia
  116. Identification of leaf rust resistance genes Lr34 and Lr46 in common wheat (Triticum aestivum L. ssp. aestivum) lines of different origin using multiplex PCR
  117. Investigation of bioactivities of Taxus chinensis, Taxus cuspidata, and Taxus × media by gas chromatography-mass spectrometry
  118. Morphological structures and histochemistry of roots and shoots in Myricaria laxiflora (Tamaricaceae)
  119. Transcriptome analysis of resistance mechanism to potato wart disease
  120. In silico analysis of glycosyltransferase 2 family genes in duckweed (Spirodela polyrhiza) and its role in salt stress tolerance
  121. Comparative study on growth traits and ions regulation of zoysiagrasses under varied salinity treatments
  122. Role of MS1 homolog Ntms1 gene of tobacco infertility
  123. Biological characteristics and fungicide sensitivity of Pyricularia variabilis
  124. In silico/computational analysis of mevalonate pyrophosphate decarboxylase gene families in Campanulids
  125. Identification of novel drought-responsive miRNA regulatory network of drought stress response in common vetch (Vicia sativa)
  126. How photoautotrophy, photomixotrophy, and ventilation affect the stomata and fluorescence emission of pistachios rootstock?
  127. Apoplastic histochemical features of plant root walls that may facilitate ion uptake and retention
  128. Ecology and Environmental Sciences
  129. The impact of sewage sludge on the fungal communities in the rhizosphere and roots of barley and on barley yield
  130. Domestication of wild animals may provide a springboard for rapid variation of coronavirus
  131. Response of benthic invertebrate assemblages to seasonal and habitat condition in the Wewe River, Ashanti region (Ghana)
  132. Molecular record for the first authentication of Isaria cicadae from Vietnam
  133. Twig biomass allocation of Betula platyphylla in different habitats in Wudalianchi Volcano, northeast China
  134. Animal Sciences
  135. Supplementation of probiotics in water beneficial growth performance, carcass traits, immune function, and antioxidant capacity in broiler chickens
  136. Predators of the giant pine scale, Marchalina hellenica (Gennadius 1883; Hemiptera: Marchalinidae), out of its natural range in Turkey
  137. Honey in wound healing: An updated review
  138. NONMMUT140591.1 may serve as a ceRNA to regulate Gata5 in UT-B knockout-induced cardiac conduction block
  139. Radiotherapy for the treatment of pulmonary hydatidosis in sheep
  140. Retraction
  141. Retraction of “Long non-coding RNA TUG1 knockdown hinders the tumorigenesis of multiple myeloma by regulating microRNA-34a-5p/NOTCH1 signaling pathway”
  142. Special Issue on Reuse of Agro-Industrial By-Products
  143. An effect of positional isomerism of benzoic acid derivatives on antibacterial activity against Escherichia coli
  144. Special Issue on Computing and Artificial Techniques for Life Science Applications - Part II
  145. Relationship of Gensini score with retinal vessel diameter and arteriovenous ratio in senile CHD
  146. Effects of different enantiomers of amlodipine on lipid profiles and vasomotor factors in atherosclerotic rabbits
  147. Establishment of the New Zealand white rabbit animal model of fatty keratopathy associated with corneal neovascularization
  148. lncRNA MALAT1/miR-143 axis is a potential biomarker for in-stent restenosis and is involved in the multiplication of vascular smooth muscle cells
https://doi.org/10.1515/biol-2021-0004
Keywords for this article
adriamycin resistance; cervical cancer; fitness differences; tumor evolution
Creative Commons
BY 4.0

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  70. Calcineurin Aβ gene knockdown inhibits transient outward potassium current ion channel remodeling in hypertrophic ventricular myocyte
  71. Aberrant expression of PI3K/AKT signaling is involved in apoptosis resistance of hepatocellular carcinoma
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  76. Carriage of HLA-DRB1*11 and 1*12 alleles and risk factors in patients with breast cancer in Burkina Faso
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  78. Glucocorticoids induce osteonecrosis of the femoral head through the Hippo signaling pathway
  79. Endothelial cell-derived SSAO can increase MLC20 phosphorylation in VSMCs
  80. Downregulation of STOX1 is a novel prognostic biomarker for glioma patients
  81. miR-378a-3p regulates glioma cell chemosensitivity to cisplatin through IGF1R
  82. The molecular mechanisms underlying arecoline-induced cardiac fibrosis in rats
  83. TGF-β1-overexpressing mesenchymal stem cells reciprocally regulate Th17/Treg cells by regulating the expression of IFN-γ
  84. The influence of MTHFR genetic polymorphisms on methotrexate therapy in pediatric acute lymphoblastic leukemia
  85. Red blood cell distribution width-standard deviation but not red blood cell distribution width-coefficient of variation as a potential index for the diagnosis of iron-deficiency anemia in mid-pregnancy women
  86. Small cell neuroendocrine carcinoma expressing alpha fetoprotein in the endometrium
  87. Superoxide dismutase and the sigma1 receptor as key elements of the antioxidant system in human gastrointestinal tract cancers
  88. Molecular characterization and phylogenetic studies of Echinococcus granulosus and Taenia multiceps coenurus cysts in slaughtered sheep in Saudi Arabia
  89. ITGB5 mutation discovered in a Chinese family with blepharophimosis-ptosis-epicanthus inversus syndrome
  90. ACTB and GAPDH appear at multiple SDS-PAGE positions, thus not suitable as reference genes for determining protein loading in techniques like Western blotting
  91. Facilitation of mouse skin-derived precursor growth and yield by optimizing plating density
  92. 3,4-Dihydroxyphenylethanol ameliorates lipopolysaccharide-induced septic cardiac injury in a murine model
  93. Downregulation of PITX2 inhibits the proliferation and migration of liver cancer cells and induces cell apoptosis
  94. Expression of CDK9 in endometrial cancer tissues and its effect on the proliferation of HEC-1B
  95. Novel predictor of the occurrence of DKA in T1DM patients without infection: A combination of neutrophil/lymphocyte ratio and white blood cells
  96. Investigation of molecular regulation mechanism under the pathophysiology of subarachnoid hemorrhage
  97. miR-25-3p protects renal tubular epithelial cells from apoptosis induced by renal IRI by targeting DKK3
  98. Bioengineering and Biotechnology
  99. Green fabrication of Co and Co3O4 nanoparticles and their biomedical applications: A review
  100. Agriculture
  101. Effects of inorganic and organic selenium sources on the growth performance of broilers in China: A meta-analysis
  102. Crop-livestock integration practices, knowledge, and attitudes among smallholder farmers: Hedging against climate change-induced shocks in semi-arid Zimbabwe
  103. Food Science and Nutrition
  104. Effect of food processing on the antioxidant activity of flavones from Polygonatum odoratum (Mill.) Druce
  105. Vitamin D and iodine status was associated with the risk and complication of type 2 diabetes mellitus in China
  106. Diversity of microbiota in Slovak summer ewes’ cheese “Bryndza”
  107. Comparison between voltammetric detection methods for abalone-flavoring liquid
  108. Composition of low-molecular-weight glutenin subunits in common wheat (Triticum aestivum L.) and their effects on the rheological properties of dough
  109. Application of culture, PCR, and PacBio sequencing for determination of microbial composition of milk from subclinical mastitis dairy cows of smallholder farms
  110. Investigating microplastics and potentially toxic elements contamination in canned Tuna, Salmon, and Sardine fishes from Taif markets, KSA
  111. From bench to bar side: Evaluating the red wine storage lesion
  112. Establishment of an iodine model for prevention of iodine-excess-induced thyroid dysfunction in pregnant women
  113. Plant Sciences
  114. Characterization of GMPP from Dendrobium huoshanense yielding GDP-D-mannose
  115. Comparative analysis of the SPL gene family in five Rosaceae species: Fragaria vesca, Malus domestica, Prunus persica, Rubus occidentalis, and Pyrus pyrifolia
  116. Identification of leaf rust resistance genes Lr34 and Lr46 in common wheat (Triticum aestivum L. ssp. aestivum) lines of different origin using multiplex PCR
  117. Investigation of bioactivities of Taxus chinensis, Taxus cuspidata, and Taxus × media by gas chromatography-mass spectrometry
  118. Morphological structures and histochemistry of roots and shoots in Myricaria laxiflora (Tamaricaceae)
  119. Transcriptome analysis of resistance mechanism to potato wart disease
  120. In silico analysis of glycosyltransferase 2 family genes in duckweed (Spirodela polyrhiza) and its role in salt stress tolerance
  121. Comparative study on growth traits and ions regulation of zoysiagrasses under varied salinity treatments
  122. Role of MS1 homolog Ntms1 gene of tobacco infertility
  123. Biological characteristics and fungicide sensitivity of Pyricularia variabilis
  124. In silico/computational analysis of mevalonate pyrophosphate decarboxylase gene families in Campanulids
  125. Identification of novel drought-responsive miRNA regulatory network of drought stress response in common vetch (Vicia sativa)
  126. How photoautotrophy, photomixotrophy, and ventilation affect the stomata and fluorescence emission of pistachios rootstock?
  127. Apoplastic histochemical features of plant root walls that may facilitate ion uptake and retention
  128. Ecology and Environmental Sciences
  129. The impact of sewage sludge on the fungal communities in the rhizosphere and roots of barley and on barley yield
  130. Domestication of wild animals may provide a springboard for rapid variation of coronavirus
  131. Response of benthic invertebrate assemblages to seasonal and habitat condition in the Wewe River, Ashanti region (Ghana)
  132. Molecular record for the first authentication of Isaria cicadae from Vietnam
  133. Twig biomass allocation of Betula platyphylla in different habitats in Wudalianchi Volcano, northeast China
  134. Animal Sciences
  135. Supplementation of probiotics in water beneficial growth performance, carcass traits, immune function, and antioxidant capacity in broiler chickens
  136. Predators of the giant pine scale, Marchalina hellenica (Gennadius 1883; Hemiptera: Marchalinidae), out of its natural range in Turkey
  137. Honey in wound healing: An updated review
  138. NONMMUT140591.1 may serve as a ceRNA to regulate Gata5 in UT-B knockout-induced cardiac conduction block
  139. Radiotherapy for the treatment of pulmonary hydatidosis in sheep
  140. Retraction
  141. Retraction of “Long non-coding RNA TUG1 knockdown hinders the tumorigenesis of multiple myeloma by regulating microRNA-34a-5p/NOTCH1 signaling pathway”
  142. Special Issue on Reuse of Agro-Industrial By-Products
  143. An effect of positional isomerism of benzoic acid derivatives on antibacterial activity against Escherichia coli
  144. Special Issue on Computing and Artificial Techniques for Life Science Applications - Part II
  145. Relationship of Gensini score with retinal vessel diameter and arteriovenous ratio in senile CHD
  146. Effects of different enantiomers of amlodipine on lipid profiles and vasomotor factors in atherosclerotic rabbits
  147. Establishment of the New Zealand white rabbit animal model of fatty keratopathy associated with corneal neovascularization
  148. lncRNA MALAT1/miR-143 axis is a potential biomarker for in-stent restenosis and is involved in the multiplication of vascular smooth muscle cells
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