Synergistic Cytotoxic Effects of Tamoxifen and 5-Fluorouracil in Gastric Cancer MKN-45 Cells
Iranian Journal of Pharmaceutical Sciences,
Vol. 22 No. 1 (2026),
26 January 2026
,
Page 272-279
https://doi.org/10.22037/ijps.v22i1.47983
Abstract
Gastric cancer is a major global health concern, and identifsying agents that inhibit cancer cell growth can improve treatment outcomes. Tamoxifen and 5-Fluorouracil (5-FU) have demonstrated antitumor effects, and their combination may enhance therapeutic efficacy. In this study, the MKN-45 gastric cancer cell line was cultured in DMEM/F12 medium with 10% FBS and antibiotics. Cytotoxicity of Tamoxifen, 5-FU, and their combination was assessed using the MTT assay, and synergism was analyzed with Compusyn software (P ≤ 0.05). Tamoxifen and 5-FU reduced cell viability in a dose-dependent manner, with IC₅₀ values of 7 µg/ml and 0.9 µg/ml, respectively. Their combination further decreased the IC₅₀ to 0.7 µg/ml. Combination index (CI) analysis showed synergism, with CI values <0.7 at Fa = 0.25 and ≈0.7 at Fa = 0.5 and 0.75. Dose-reduction index (DRI) values for both drugs were >1, indicating reduced doses required in combination. These results suggest that combining 5-FU with Tamoxifen may be a promising strategy to enhance gastric cancer treatment.
- 5-Fluorouracil (5-FU)
- Cytotoxicity
- Gastric cancer
- MTT assay
- Synergistic effects
- Tamoxifen
How to Cite
References
1. Wong, M.C., et al., Global incidence and mortality of gastric cancer, 1980-2018. JAMA network open, 2021. 4(7): p. e2118457-e2118457.
2. Huang, J., et al., Updated epidemiology of gastrointestinal cancers in East Asia. Nature Reviews Gastroenterology & Hepatology, 2023: p. 1-17.
3. Amoori, N., S. Mahdavi, and M. Enayatrad, Epidemiology and trend of stomach cancer mortality in Iran. Epidemiology and Health System Journal, 2016. 3(3): p. 268-275.
4. González, C.A. and L. López-Carrillo, Helicobacter pylori, nutrition and smoking interactions: their impact in gastric carcinogenesis. Scandinavian journal of gastroenterology, 2010. 45(1): p. 6-14.
5. Li, H., M. Shen, and S. Wang, Current therapies and progress in the treatment of advanced gastric cancer. Frontiers in Oncology, 2024. 14: p. 1327055.
6. Mokhtari, R.B., et al., Combination therapy in combating cancer. Oncotarget, 2017. 8(23): p. 38022.
7. Correia, A., et al., Study of new therapeutic strategies to combat breast cancer using drug combinations. Biomolecules, 2018. 8(4): p. 175.
8. Yao, J.C., et al. Combined‐modality therapy for gastric cancer. in Seminars in surgical Oncology. 2003. Wiley Online Library.
9. Sisodiya, S., et al., Impact of combinatorial immunotherapies in breast cancer: a systematic review and meta-analysis. Frontiers in Immunology, 2024. 15: p. 1469441.
10. Koirala, M. and M. DiPaola, Overcoming cancer resistance: Strategies and modalities for effective treatment. Biomedicines, 2024. 12(8): p. 1801.
11. Aldea, M., et al., Overcoming resistance to tumor-targeted and immune-targeted therapies. Cancer Discovery, 2021. 11(4): p. 874-899.
12. Gumusay, O., et al. Strategic Combinations to Prevent and Overcome Resistance to Targeted Therapies in Oncology. in American Society of Clinical Oncology Educational book. American Society of Clinical Oncology. Annual Meeting. 2020.
13. Vodenkova, S., et al., 5-fluorouracil and other fluoropyrimidines in colorectal cancer: Past, present and future. Pharmacology & therapeutics, 2020. 206: p. 107447.
14. Longley, D.B., D.P. Harkin, and P.G. Johnston, 5-fluorouracil: mechanisms of action and clinical strategies. Nature reviews cancer, 2003. 3(5): p. 330-338.
15. Wagner, A.D., et al., Chemotherapy for advanced gastric cancer. Cochrane database of systematic reviews, 2017(8).
16. Cavanna, L., et al., Oxaliplatin in combination with 5-fluorouracil (5-FU) and leucovorin (LV) in patients with metastatic gastric cancer (MGC). American journal of clinical oncology, 2006. 29(4): p. 371-375.
17. Lewis, J.S. and V.C. Jordan, Selective estrogen receptor modulators (SERMs): mechanisms of anticarcinogenesis and drug resistance. Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis, 2005. 591(1-2): p. 247-263.
18. Tokunaga, A., et al., Hormone receptors in gastric cancer. European journal of cancer & clinical oncology, 1983. 19(5): p. 687-689.
19. Stedman, K.E., G.E. Moore, and R.T. Morgan, Estrogen receptor proteins in diverse human tumors. Archives of Surgery, 1980. 115(3): p. 244-248.
20. Muralidharan, K.G., Biological and Therapeutic Aspects of Breast Cancer Progression. 2017, Karolinska Institutet (Sweden).
21. Osborne, C.K. and R. Schiff, Mechanisms of endocrine resistance in breast cancer. Annual review of medicine, 2011. 62(1): p. 233-247.
22. Khanipouyani, F. and H. Akrami, Tamoxifen downregulates the expression of Notch1 and DLL1 genes in MKN-45 gastric cancer cells. Journal of Gastrointestinal Cancer, 2021. 52: p. 922-927.
23. Chou, T.-C., Drug combination studies and their synergy quantification using the Chou-Talalay method. Cancer research, 2010. 70(2): p. 440-446.
24. Yang, L., et al., Gastric cancer: Epidemiology, risk factors and prevention strategies. Chinese Journal of Cancer Research, 2020. 32(6): p. 695.
25. Joshi, S.S. and B.D. Badgwell, Current treatment and recent progress in gastric cancer. CA: a cancer journal for clinicians, 2021. 71(3): p. 264-279.
26. Nawara, H.M., et al., Paclitaxel-based chemotherapy targeting cancer stem cells from mono-to combination therapy. Biomedicines, 2021. 9(5): p. 500.
27. Bottino, D.C., et al., Dose optimization for anticancer drug combinations: maximizing therapeutic index via clinical exposure-toxicity/preclinical exposure-efficacy modeling. Clinical Cancer Research, 2019. 25(22): p. 6633-6643.
28. Zhang, L., et al., Effects of glabridin combined with 5-fluorouracil on the proliferation and apoptosis of gastric cancer cells. Oncology letters, 2018. 15(5): p. 7037-7045.
29. Khakbaz, P., et al., Allicin reduces 5-fluorouracil-resistance in gastric cancer cells through modulating MDR1, DKK1, and WNT5A expression. Drug Research, 2021. 71(08): p. 448-454.
30. Hosoya, Y., et al., Combination effects of tamoxifen plus 5-fluorouracil on gastric cancer cell lines in vitro. Cancer letters, 1999. 140(1-2): p. 139-143.
31. Osaki, M., et al., 5-Fluorouracil (5-FU) induced apoptosis in gastric cancer cell lines: role of the p53 gene. Apoptosis, 1997. 2: p. 221-226.
32. Matsuoka, T. and M. Yashiro, The role of PI3K/Akt/mTOR signaling in gastric carcinoma. Cancers, 2014. 6(3): p. 1441-1463.
33. Del Principe, M.I., et al., Clinical significance of bax/bcl-2 ratio in chronic lymphocytic leukemia. haematologica, 2016. 101(1): p. 77.
34. Mandlekar, S., et al., Activation of caspase-3 and c-Jun NH2-terminal kinase-1 signaling pathways in tamoxifen-induced apoptosis of human breast cancer cells. Cancer Research, 2000. 60(21): p. 5995-6000.
35. Du, B., et al., Synergistic inhibitory effects of curcumin and 5-fluorouracil on the growth of the human colon cancer cell line HT-29. Chemotherapy, 2005. 52(1): p. 23-28.
36. Xu, T., et al., Synergistic effects of curcumin and 5-fluorouracil on the hepatocellular carcinoma in vivo and vitro through regulating the expression of COX-2 and NF-κB. Journal of Cancer, 2020. 11(13): p. 3955.
37. Liu, X., et al., Combining data from TCGA and GEO databases and reverse transcription quantitative PCR validation to identify gene prognostic markers in lung cancer. OncoTargets and therapy, 2019: p. 709-720.
38. Zamanian-Azodi, M., et al., Proteomics analysis of MKN45 cell line before and after treatment with Lavender aqueous extract. Gastroenterology and Hepatology from bed to bench, 2012. 5(1): p. 35.
- Abstract Viewed: 31 times
- IJPS_Volume22_Issue1_Pages272-279 Downloaded: 26 times