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Inhibition of Ras and STAT3 activity of 4-(tert-butyl)-N-carbamoylbenzamide as antiproliferative agent in HER2-expressing breast cancer cells

  • Aguslina Kirtishanti , Siswandono Siswodihardjo EMAIL logo , I Ketut Sudiana , Desak G. A. Suprabawati and Aristika Dinaryanti
Published/Copyright: June 25, 2021
Journal of Basic and Clinical Physiology and Pharmacology
From the journal Journal of Basic and Clinical Physiology and Pharmacology Volume 32 Issue 4

Abstract

Objectives

Human epidermal growth factor receptor type 2 (HER2)-expressing breast cancer patients indicate poor prognosis in disease progression. HER2 overexpression can increase activities of Ras-mitogen activated protein kinase (Ras-MAPK) pathway and Janus Kinase (JAK)-STAT3, increasing breast cancer cell proliferation as demonstrated by marker Ki67. Therapeutic options for HER2-expressing breast cancer are limited and have major side effects, so anticancer development as an antiproliferative is needed. From previous research, synthetic chemical 4-(tert-butyl)-N-carbamoylbenzamide (4TBCB) compound has cytotoxic activity in vitro on HER2-expressing breast cancer cells. This study wanted to determine the mechanism 4TBCB compound in inhibiting HER2 signaling through Rat Sarcoma (Ras) and signal transducer and activator of transcription 3 (STAT3) pathway in HER2-expressing breast cancer cells.

Methods

Breast cancer cells were isolated from the biopsy tissue of breast cancer patients. The isolated cells were cultured and given 4TBCB test compound with three concentrations (0.305, 0.61, and 1.22 mM) and lapatinib 0.05 mM as a comparison compound. Cancer cell cultures were stained with monoclonal antibodies phosphorylated HER2 (pHER2), phosphorylated Ras (pRas), phosphorylated STAT3 (pSTAT3), and Ki67. The expression of pHER2, pRas, pSTAT3, and Ki67 proteins was observed using the immunofluorescence method and the results were compared with control cells, namely cancer cells that were not given 4TBCB and lapatinib but stained with monoclonal antibodies.

Results

4TBCB compounds (0.61 and 1.22 mM) and lapatinib can reduce pHER2, pRas, pSTAT3, and Ki67 expressions compared to control cells.

Conclusions

4TBCB compounds (0.61 and 1.22 mM) can reduce pHER2, pRas, pSTAT3, Ki67 expressions and predicted to inhibit HER2 signaling through the Ras and STAT3 pathways in HER2-expressing breast cancer cells.

Keywords: antiproliferative; breast cancer cells; HER2; Ras; STAT3; 4-(tert-butyl)-N-carbamoylbenzamide
Corresponding author: Siswandono Siswodihardjo, Department of Medicinal Chemistry, Faculty of Pharmacy, University of Airlangga, Surabaya, Indonesia, Phone: +62 8123206328, E-mail:

Funding source: Directorate General of Resources for Science, Technology and Higher Education of Ministry of Research, Technology and Higher Education (KEMENRISTEK DIKTI)

Acknowledgments

We acknowledge Eryk Hendrianto and Aida Ariyanti from the Stem Cell Research Center for supporting the current research.

  1. Research funding: Directorate General of Resources for Science, Technology and Higher Education of Ministry of Research, Technology and Higher Education (KEMRISTEK DIKTI).

  2. Author contributions: All authors have accepted responsibility for the entire content of this manuscript and approved its submission.

  3. Competing interests: Authors state no conflict of interest.

  4. Informed consent: Informed consent was obtained from all individuals included in this study.

  5. Ethical approval: Research involving human subjects complied with all relevant national regulations, institutional policies and is in accordance with the tenets of the Helsinki Declaration (as revised in 2013), and has been approved by Ethical Commission of General Hospital in Surabaya, Indonesia.

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Received: 2020-12-14
Accepted: 2021-03-24
Published Online: 2021-06-25

© 2021 Walter de Gruyter GmbH, Berlin/Boston

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  1. Frontmatter
  2. Original Articles
  3. Cost of illness of diabetes mellitus in Indonesia: a systematic review
  4. Social media health interventions to improve diabetes mellitus patient outcome: a systematic review
  5. Developing pharmacokinetics–pharmacodynamics model of valproic acid syrup based on prediction of population pharmacokinetics parameter and seizure frequency in Indonesian pediatric epilepsy outpatients
  6. Acetylcholinesterase inhibitory activity of extract and fractions from the root of Rauvolfia serpentina(L.) Bth.ex Kurz
  7. Green tea and its active compound epigallocathechin-3-gallate (EGCG) inhibit neuronal apoptosis in a middle cerebral artery occlusion (MCAO) model
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  13. Inhibition of Ras and STAT3 activity of 4-(tert-butyl)-N-carbamoylbenzamide as antiproliferative agent in HER2-expressing breast cancer cells
  14. Predicting the molecular mechanism of glucosamine in accelerating bone defect repair by stimulating osteogenic proteins
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  18. Assessment of patient understanding of their conventional cardiac medicines and herbal prepared/derived products: preliminary survey and interviews with selected community-dwelling elderly patients in the Philippines
  19. The development and validation of the health belief model questionnaire for measuring factors affecting adherence in the elderly with hypertension
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  36. Hepatoprotective effect of ethanolic extract of sugarcane (Saccharum officinarum Linn.) leaves
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https://doi.org/10.1515/jbcpp-2020-0508
Keywords for this article
antiproliferative; breast cancer cells; HER2; Ras; STAT3; 4-(tert-butyl)-N-carbamoylbenzamide

Articles in the same Issue

  1. Frontmatter
  2. Original Articles
  3. Cost of illness of diabetes mellitus in Indonesia: a systematic review
  4. Social media health interventions to improve diabetes mellitus patient outcome: a systematic review
  5. Developing pharmacokinetics–pharmacodynamics model of valproic acid syrup based on prediction of population pharmacokinetics parameter and seizure frequency in Indonesian pediatric epilepsy outpatients
  6. Acetylcholinesterase inhibitory activity of extract and fractions from the root of Rauvolfia serpentina(L.) Bth.ex Kurz
  7. Green tea and its active compound epigallocathechin-3-gallate (EGCG) inhibit neuronal apoptosis in a middle cerebral artery occlusion (MCAO) model
  8. The effects of quercetin on nicotine-induced reward effects in mice
  9. Resveratrol ameliorates physical and psychological stress-induced depressive-like behavior
  10. Translation and cross-cultural adaption of an instrument measuring patient’s well-being under treatment for schizophrenia
  11. Quercetin promotes behavioral recovery and biomolecular changes of melanocortin-4 receptor in mice with ischemic stroke
  12. Knowledge and attitudes of healthcare professionals on prescribing errors
  13. Inhibition of Ras and STAT3 activity of 4-(tert-butyl)-N-carbamoylbenzamide as antiproliferative agent in HER2-expressing breast cancer cells
  14. Predicting the molecular mechanism of glucosamine in accelerating bone defect repair by stimulating osteogenic proteins
  15. Larvicidal toxicity and parasporal inclusion of native Bacillus thuringiensis BK5.2 against Aedes aegypti
  16. Synthesis, ADMET predictions, molecular docking studies, and in-vitro anticancer activity of some benzoxazines against A549 human lung cancer cells
  17. Thymoquinone and its derivatives against breast cancer with HER2 positive: in silico studies of ADMET, docking and QSPR
  18. Assessment of patient understanding of their conventional cardiac medicines and herbal prepared/derived products: preliminary survey and interviews with selected community-dwelling elderly patients in the Philippines
  19. The development and validation of the health belief model questionnaire for measuring factors affecting adherence in the elderly with hypertension
  20. Analysis of the side effect of QTc interval prolongation in the bedaquiline regimen in drug resistant tuberculosis patients
  21. Shallot skin profilling, computational evaluation of physicochemical properties, ADMET, and molecular docking of its components against P2Y12 receptor
  22. Analysis of HMGB-1 level before and after providing atorvastatin standard therapy in coronary artery disease patients with type-2 diabetes mellitus compared to without type-2 diabetes mellitus
  23. Analysis of matrix metalloproteinase-9 levels among acute heart failure patients with ACE inhibitor therapy (Dr. Soetomo Regional General Hospital, Surabaya)
  24. The correlation between self-related adherence, asthma-related quality of life and control of asthma in adult patients
  25. Providing counseling through home pharmacy care (HPC) for hemodialysis patients with hypertension in lowering blood pressure
  26. Community knowledge and attitude in recognizing asthma symptoms and using medication for asthma attacks: a cross-sectional study
  27. A study of anticoagulant therapy in patients with coronary artery disease
  28. The association of FKBP5 polymorphism with asthma susceptibility in asthmatic patients
  29. Gastroprotective effect of fluvoxamine and ondansetron on stress-induced gastric ulcers in mice
  30. Osteoblast iron genes: real time PCR and microarray hybridization approach under hyperoxia
  31. Attenuation of hyperplasia in lung parenchymal and colonic epithelial cells in DMBA-induced cancer by administering Andrographis paniculata Nees extract using animal model
  32. N-nitrosodiethylamine induces inflammation of liver in mice
  33. AST/ALT levels, MDA, and liver histopathology of Echinometra mathaei ethanol extract on paracetamol-induced hepatotoxicity in rats
  34. Development, characterization, molecular docking, and in vivo skin penetration of coenzyme Q10 nanostructured lipid carriers using tristearin and stearyl alcohol for dermal delivery
  35. The effect of Camellia sinensis (green tea) with its active compound EGCG on neuronal cell necroptosis in Rattus norvegicus middle cerebral artery occlusion (MCAO) model
  36. Hepatoprotective effect of ethanolic extract of sugarcane (Saccharum officinarum Linn.) leaves
  37. Correlation between the exposure time to mobile devices and the prevalence of evaporative dry eyes as one of the symptoms of computer vision syndrome among Senior High School students in East Java, Indonesia
  38. The effect of various high-fat diet on liver histology in the development of NAFLD models in mice
  39. Fabrication and characterization of bovine hydroxyapatite-gelatin-alendronate scaffold cross-linked by glutaraldehyde for bone regeneration
  40. Health related quality of life among postmenopausal woman with hormone responsive HER2− breast cancer in Indonesia
  41. Gender differences in the blood glucose type 2 diabetes patients with combination rapid and long acting insulin therapy
  42. Correlation of dietary iron intake and serum iron with thyroid stimulating hormone (TSH) and free thyroxine (FT4) levels in adult hyperthyroid patients
  43. The effect of pillbox use and education by pharmacist toward medication adherence in diabetes mellitus patients in a Primary Health Care Center in Mataram
  44. Variation concentration effect of propyleneglycol, glycerin, and polyethyleneglycol 400 to physical properties and dissolution rate of loratadine liquisolid tablet
  45. Role of Centella asiatica and ceramide in skin barrier improvement: a double blind clinical trial of Indonesian batik workers
  46. Secondary metabolite and antipyretic effects of Maja (Crescentia cujete L.) in fever-induced mice
  47. Hydration effect on kidney function and serum electrolyte in children with tumor lysis syndrome (TLS) and risk of TLS
  48. Drug utilization study and cost analysis of adult β-thalassemia major patient therapy at Dr. Soetomo General Hospital Surabaya
  49. The role of hyperbaric oxygen to platelet aggregation in noninsulin-dependent diabetes mellitus (NIDDM)
  50. Cocrystal formation of loratadine-succinic acid and its improved solubility
  51. The role of chondroitin sulfate to bone healing indicators and compressive strength
  52. The effects of quercetin on the expression of SREBP-1c mRNA in high-fat diet-induced NAFLD in mice
  53. Analysis of stress ulcer prophylaxis drug regimentation in surgical patients
  54. The stability and irritability study of the chitosan–Aloe vera spray gel as wound healing
  55. Effectiveness of citicoline in pediatric patients with refractive amblyopia in Surabaya, East Java, Indonesia
  56. The thermodynamic study of p-methoxycinnamic acid inclusion complex formation, using β-cyclodextrin and hydroxypropyl-β-cyclodextrin
  57. The effect of chitosan type and drug-chitosan ratio on physical characteristics and release profile of ketoprofen microparticles prepared by spray drying
  58. The maximum dose and duration in the therapy single use methotrexate to achieve remission by rheumatoid arthritis patients through disease activity score 28 (DAS28)
  59. Knowledge, attitudes, and practices (KAP) towards COVID-19 among university students in Pakistan: a cross-sectional study
  60. The impact of glutaraldehyde on the characteristics of bovine hydroxyapatite-gelatin based bone scaffold as gentamicin delivery system
  61. Analysis of the use of antibiotics profile and factors of surgical site infections study on digestive and oncology surgeries
  62. Second internal transcribed spacer (ITS-2) as genetic marker for molecular characterization of Sarcoptes scabiei in rabbits from several areas of East Java, Indonesia
  63. Design of gossypetin derivatives based on naturally occurring flavonoid in Hibiscus sabdariffa and the molecular docking as antibacterial agents
  64. Discovery of new targeting agents against GAPDH receptor for antituberculosis drug delivery
  65. The effect of red passion fruit (Passiflora edulis Sims.) fermentation time on its activity against Extended Strain Methicillin-Resistant (ESBL) Escherichia coli and Methicillin-Resistant Staphylococcus aureus (MRSA)
  66. Antibiotic use on acute respiratory tract infection nonpneumonia and nonspecific diarrhea in Primary Health Care Centre in Banjarbaru City, South Kalimantan, Indonesia
  67. Screening of anti-HIV activities in ethanol extract and fractions from Ficus fistulosa leaves
  68. The characteristics of lactic acid bacteria isolated from fermented food as potential probiotics
  69. Profile of gyrA gene mutation in clinical isolate of levofloxacin resistant Escherichia coli
  70. Antimicrobial activity of Centella asiatica and Gigantochloa apus
  71. Drug-related problems of antibiotic use in gastroenteritis related to patient therapy outcomes at Universitas Gadjah Mada Hospital
  72. The impact of suitability of empirical antibiotics use on therapeutic outcome of respiratory tract infection patients at inpatient wards of Universitas Gadjah Mada Academic Hospital
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