P53 AND CYCLIN B1 MEDIATE APOPTOTIC EFFECTS OF APIGENIN AND RUTIN IN ERï¡+-BREAST CANCER MCF-7 CELLS
DOI:
https://doi.org/10.11113/jt.v80.10704Keywords:
Apigenin, rutin, tamoxifen, apoptosis, MCF-7Abstract
Tamoxifen is an effective treatment for estrogen receptor alpha positive (ERa+)-breast cancer, however patients who received the treatment for five years have greater mortality risk compared to those who did not receive tamoxifen. Furthermore, patients treated with tamoxifen developed resistance to the drug which mediated through p53 and PTEN. Therefore, the study is undertaken to determine the potential adjuvant properties of flavonoids, apigenin and rutin to promote the anticancer activity induced by tamoxifen using ERa+-breast cancer MCF-7 cell lines. MCF-7 and non-transformed breast MCF-10A cells were treated separately with apigenin, rutin, tamoxifen or the combination of each flavonoids with tamoxifen. Anti-proliferative activity and respective IC50 concentrations were determined using MTT assay. The respective IC50 concentrations obtained were used in the subsequent experiments. The anti-proliferative mechanism was determined using Annexin V-FITC morphological staining and DNA fragmentation assays. The effect on tumor suppressor (p53 and PTEN) and cell cycle related genes (p21, CDK1 and Cyclin B1) were determined by QuantiGene Plex assay. Our results showed that MCF-7 cells were more sensitive to both apigenin and rutin compared to MCF-10A cells. Both cells were sensitive to tamoxifen. Apigenin and rutin synergistically enhanced tamoxifen anti-proliferative effect in MCF-7. Meanwhile rutin protects MCF-10A against the toxicity of tamoxifen. Our results indicate that the anti-proliferative mechanism of apigenin and rutin is mediated by apoptosis signals. In MCF-7 cells, both tumor suppressor (p53 and PTEN) and cell cycle related genes (p21 and CDK1) were up regulated by apigenin and rutin, contrary to tamoxifen. Apigenin and rutin induced G2/M arrest and apoptosis in MCF-7 cells through p53-dependent pathway. Both flavonoids are suggested as potential adjuvant agents to enhance tamoxifen efficacy in ERa+-breast cancer treatment. Â
References
Stewart, B. W., Wild, C. P. 2014. World Cancer Report 2014. Lyon, France: International Agency for Research on Cancer. Publisher International Agency for Research in Cancer. IARC Nonserial Publication, WHO Press.
Lin, A. H. Y., Li, R. W. S., Ho, E. Y. W., Leung, G. P. H., Leung, S. W. S., Vanhoutte, P. M., et al. 2013. Differential Ligand Binding Affinities of Human Estrogen Receptor-ï¡ Isoforms. PLoS ONE. 8(4): e63199.
Karn, A., Jha, A. K., Shresta, S., Acharya, B., Poudel, S., Bhandari, R. B. 2010. Tamoxifen for Breast Cancer. J Nepal Med Asoc. 49(177): 62-67.
Housman, G., Byler, S., Heerboth, S., Lapinska, K., Longacre, M., Snyder, N., Sarkar, S. 2014. Drug Resistance in Cancer: An Overview. Cancers (Basel). 6(3): 1769-1792.
Dixon, J. M. 2014. Endocrine Resistance in Breast Cancer. New Journal of Science. 2014: 1-27.
Fernandez-Cuesta, L., Anaganti, S., Hainaut, P., Olivier, M. 2011. p53 Status Influences Response to Tamoxifen But Not to Fulvestrant in Breast Cancer Cell Lines. Int J Cancer. 128(8): 1813-21.
Tanic, N., Milovanovic, Z., Dzodic, R., Juranic, Z., Susnjar, S., Plesinac-Karapandzic, V., Titas, S., Dramicanin, T., Davidovic, R., Dimitrijevic, B. 2012. The Impact of PTEN Tumor Suppressor Gene on Acquiring Resistance to Tamoxifen Treatment in Breast Cancer Patients. Cancer Biol Ther. 13(12): 1165-1174.
Muller, P. A. J., Vousden, K. H. 2014. Mutant p53 in Cancer: New Functions and Therapeutic Opportunities. Cancer Cell March. 25(3): 304-317.
Kandoth, C., McLellan, M. D., Vandin, F., Ye, K., Niu, B., Lu, C., Xie, M., Zhang, Q., McMichael, J. F., Wyczalkowski, M. A., Leiserson, M. D., Miller, C. A., Welch, J. S., Walter, M. J., Wendl, M. C., Ley, T. J., Wilson, R. K., Raphael, B. J., Ding, L. 2013. Mutational Landscape and Significance Across 12 Major Cancer Types. Nature Oct. 502(7471): 333-339.
Lo Nigro, C., Vivenza, D., Monteverde, M., Lattanzio, L., Gojis, O., Garrone, O., Comino, A., Merlano, M., Quinlan, P. R., Syed, N., Purdie, C. A., Thompson, A., Palmieri, C., Crook, T. 2012. High Frequency of Complex TP53 Mutations in CNS Metastases from Breast Cancer. British Journal of Cancer. 106: 397-404.
Yang, P., Du, C. W., Kwan, M., Liang, S. X., Zhang, G. J. 2013. The Impact of p53 in Predicting Clinical Outcome of Breast Cancer Patients with Visceral Metastasis. Scientific Reports. 3: 2246-2251.
Arafa, E. A., Zhu, Q., Shah, Z. I., Wani, G., Barakat, B. M., Racoma, I., El-Mahdy, M. A., Wani, A. A. 2011. Thymoquinone Up-regulates PTEN Expression and Induces Apoptosis in Doxorubicin-resistant Human Breast Cancer Cells. Mutat Res. 706(1-2): 28-35.
Nakanishi, A., Kitagishi, Y., Ogura, Y., Matsuda, S. 2014. The Tumor Suppressor PTEN Interacts with p53 in Hereditary Cancer (Review). International Journal of Oncology. 44(6): 1813-1819.
Lu, X. X., Cao, L. Y., Chen, X., Xiao, J., Zou, Y., Q. Chen. 2016. PTEN Inhibits Cell Proliferation, Promotes Cell Apoptosis, and Induces Cell Cycle Arrest via Downregulating the PI3K/AKT/hTERT Pathway in Lung Adenocarcinoma A549 Cells. Biomed Res Int. 2016: 1-8.
Zhang, H. Y., Liang, F., Jia, Z. L., Song, S. T, Jiang, Z. F. 2013. PTEN Mutation, Methylation and Expression in Breast Cancer Patients. Oncol Lett. 6(1): 161-168.
Bai, H., Jin, H., Yang, F., Zhu, H., Cai, J. 2014. Apigenin Induced MCF-7 Cell Apoptosis-associated Reactive Oxygen Species. Scanning Nov-Dec. 36(6): 622-631.
Batra, P., Sharma, A. K. 2013. Anti-cancer Potential of Flavonoids: Recent Trends and Future Perspectives. Biotech. 3(6): 439-459.
Long, X., Fan, M., Bigsby, R. M., Nephew, K. P. 2008. Apigenin Inhibits Antiestrogen-resistant Breast Cancer Cell Growth through Estrogen Receptor-alpha-dependent and Estrogen Receptor-aalpha-independent Mechanisms. Mol Cancer Ther. 7: 2096-2108.
Chen, H., Miao, Q., Geng, M., Liu, J., Hu, Y., Tian, L., Pan, J., Yang, Y. 2013. Anti-tumor Effect of Rutin on Human Neuroblastoma Cell Lines Through Inducing G2/M Cell Cycle Arrest and Promoting Apoptosis. The Scientific World Journal. 2013: 1-8.
Parrish, A. B., Freel, C. D., Kornbluth, S. 2013. Cellular Mechanisms Controlling Caspase Activation and Function. Cold Spring Harb Perspect Biol. 5(6): 1-24.
Zhao E, Mu Q. 2011. Phytoestrogen Biological Actions on Mammalian Reproductive System and Cancer Growth. Sci Pharm. 79(1): 1-20.
Lecomte, S., Demay, F., Ferrière, F., Pakdel, F. 2017. Review Phytochemicals Targeting Estrogen Receptors: Beneï¬cial Rather than Adverse Effects? Int J Mol Sci.18: 1381-1399.
Vidya Priyadarsini, R., Senthil Murugan, R., Maitreyi, S., Ramalingam, K., Karunagaran, D., Nagini, S. 2010. The Flavonoid Quercetin Induces Cell Cycle Arrest and Mitochondria-mediated Apoptosis in Human Cervical Cancer (HeLa) Cells through p53 Induction and NF-ï‹B Inhibition. Eu J Pharmacol. 649(1): 84-91.
Batra, P., Sharma, A. K. 2013. Anti-cancer Potential of Flavonoids: Recent Trends and Future Perspectives. Biotech. 3(6): 439-459.
Sak, K. 2014. Cytotoxicity of Dietary Flavonoids on Different Human Cancer Types. Pharmacogn Rev. 8(16): 122-146.
Sahin, K., Tuzcu, M., Basak, N., Caglayan, B., Kilic, U., Sahin, F., Kucuk, O. 2012. Sensitization of Cervical Cancer Cells to Cisplatin by Genistein: The Role of NFκB and Akt/mTOR Signaling Pathways. Journal of Oncology. 2012: 1-6.
Choi, E. J., Kim, G. H. 20095. Fluorouracil Combined with Apigenin Enhances Anticancer Activity through Induction of Apoptosis in Human Breast Cancer MDA-MB-453 Cells. Oncol Rep. 22(6): 1533-1537.
Yellepeddi, V. K., Vangara, K. K., Kumar, A., Palakurthi, S. 2012. Comparative Evaluation of Small-molecule Chemosensitizers in Reversal of Cisplatin Resistance in Ovarian Cancer Cells. Anticancer Res Sep. 32(9): 3651-3658.
Wlodkowic, D., Telford, W., Skommer, J., Darzynkiewicz, Z. 2011. Apoptosis and Beyond: Cytometry in Studies of Programmed Cell Death. Methods Cell Biol. 103: 55-98.
Morrissey, C., O'Neill, A., Spengler, B., Christoffel, V., Fitzpatrick, J. M., Watson, R. W. 2005. Apigenin Drives the Production of Reactive Oxygen Species and Initiates a Mitochondrial Mediated Cell Death Pathway in Prostate Epithelial Cells. Prostate. 63: 131-142.
Zheng, P. W., Chiang, L. C., Lin, C. C. 2005. Apigenin Induced Apoptosis through p53-dependent Pathway in Human Cervical Carcinoma Cells. Life Sci. 76: 1367-1379.
Yaacob, N. S. and Ismail N. F. 2014. Comparison of Cytotoxicity and Genotoxicity of 4-hydroxytamoxifen in Combination with Tualang Honey in MCF-7 and MCF-10A Cells. BMC Complementary and Alternative Medicine. 14: 106-113.
Wang, Y., Xu, S. L., Wu, Y. Z., Zhao, M. S., Xu, W. J., Yang, H. Y., Li, Y. X. 2013. Simvastatin Induces Caspase-Dependent Apoptosis and Activates P53 in OCM-1 Cells. Exp Eye Res. 113: 128-134.
Iizumi, Y., Oishi, M., Taniguchi, T., Goi, W., Sowa, Y., Sakai, T. 2013. The Flavonoid Apigenin Downregulates CDK1 by Directly Targeting Ribosomal Protein S9. PLoS ONE. 8(8): e73219.
Khan RA, Khan MR and Sahreen S. CCl4-induced hepatotoxicity: protective effect of rutin on p53, CYP2E1 and the antioxidative status in rat. BMC Complementary and Alternative Medicine 2012; 12:178-183.
Downloads
Published
Issue
Section
License
Copyright of articles that appear in Jurnal Teknologi belongs exclusively to Penerbit Universiti Teknologi Malaysia (Penerbit UTM Press). This copyright covers the rights to reproduce the article, including reprints, electronic reproductions, or any other reproductions of similar nature.
