The Doxorubicin-Induced G2/M Arrest in Breast Cancer Cells Modulated by Natural Compounds Naringenin and Hesperidin
Abstract
Doxorubicin as the common drug for breast cancer has been widely proposed to use in combine with a natural compound in order to overcome its side effects such as cardiotoxicity and resistance. Previously, we reported that naringenin and hesperidin, the abundant flavanons in citrus fruit peel, increased cytotoxic and apoptosis activities of doxorubicin in doxorubicin resistant breast cancer cells (T47D and MCF-7 cells). Since doxorubicin arrests G2/M phase in most cancer cells, both flavanons are speculated to affect the similar phase in breast cancer cells. Cell cycle distributions were determined by flowcytometry using propidium iodide (PI) to stain DNA of the cells. Combination of naringenin or hesperidin with doxorubicin increased accumulation of T47D cells in G2/M phase, while in MCF-7 cells, accumulated cells in G2/M phase were decreased, accompanying with slightly increased in G1 phase. Naringenin itself had no effect on cell cycle of both cells. Whereas, hesperidin arrested G2/M and G1 phases in T47D and MCF-7 cells, respectively. The different effect of naringenin and hesperidin in T47D and MCF-7 cells is most likely caused by difference of p53 status. In p53 mutant, T47D cells, naringenin and hesperidin supported mechanism of doxorubicin to arrest at G2/M that to be considered via p53-independent pathway. Whereas, in p53 wild-type MCF-7 cells, naringenin and hesperidin decreased G2/M arrest, suggesting that both flavanons do not utilize cell cycle arrest for their anticancer activity with doxorucibin. This study revealed that potential co-chemoterapeutic agents, naringenin and hesperidin distinctly modulated cell cycle arrest induced by doxorubicin according to the characteristic of breast cancer cells.
Keywords: naringenin, hesperidin, doxorubicin, cell cycle, breast cancer cells.
Full Text:
PDFReferences
Ahamad, M.S., Siddiqui, S., Jafri, A., Ahmad, S., Afzal, M. and Arshad, M., 2014, Induction of apoptosis and antiproliferative activity of naringenin in human epidermoid carcinoma cell through ROS generation and cell cycle arrest, PLOS ONE, 9(10), e110003. CrossRef
Arul, D. and Subramanian, P., 2013, Naringenin (citrus flavonone) induces growth inhibition, cell cycle arrest and apoptosis in human hepatocellular carcinoma cells, Pathol. Oncol. Res., 19(4), 763–770. CrossRef
Bai, J., Li, Y. and Zhang, G., 2017, Cell cycle regulation and anticancer drug discovery, Cancer Biol. Med., 14(4), 348–362. CrossRef
Barrett-Lee, P.J., Dixon, J.M., Farrell, C., Jones, A., Leonard, R., Murray, N., et al., 2009, Expert opinion on the use of anthracyclines in patients with advanced breast cancer at cardiac risk, Ann. Oncol. Off. J. Eur. Soc. Med. Oncol., 20(5), 816–827. CrossRef
Birt, D.F., Wang, W., Paiva, N., Au, A., Chung, C., Schmitt, L., and Jiang, Y., 2003, Cancer prevention by phytochemicals, modulation of cell cycle, In: Phytochemicals: Mechanisms of Action, CRC Press LLC, pp. 61-77.
Bray, F., Ferlay, J., Soerjomataram, I., Siegel, R.L., Torre, L.A., and Jemal, A., 2018, Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries, Cancer J. Clin., 68(6), 394–424. CrossRef
Christowitz, C., Davis, T., Isaacs, A., van Niekerk, G., Hattingh, S. and Engelbrecht, A.-M., 2019, Mechanisms of doxorubicin-induced drug resistance and drug resistant tumour growth in a murine breast tumour model, BMC Cancer, 19(1), 757-766. CrossRef
Desai, U.N., Shah, K.P., Mirza, S.H., Panchal, D.K., Parikh, S.K. and Rawal, R.M., 2015, Enhancement of the cytotoxic effects of Cytarabine in synergism with Hesperidine and Silibinin in Acute Myeloid Leukemia: An in-vitro approach, J Cancer Res Ther., 11(2),352-357. CrossRef
Drummond, C., 2008, The Mechanism of Anti-Tumour Activity of the DNA Binding Agent SN 28049, Dissertation, The University of Auckland, New Zealand.
Fitriasari, A., Susidarti, R.A. and Meiyanto, E., 2010, Peningkatan efek sitotoksik doxorubicin oleh naringenin melalui pemacuan apoptosis sel kanker payudara MCF-7, J. Bahan Alam Indones., 7, 165–170.
Hermawan, A., Meiyanto, E. and Susidarti, R.A., 2010, Hesperidine increases cytotoxic effect of doxorubicin on MCF-7 Cells, Maj. Farm. Indones., 21, 8–17. CrossRef
Jin, C.Y., Park, C., Hwang, H.J., Kim, G.Y., Choi, B.T., Kim, W.J. and Choi, Y.H., 2011, Naringenin up-regulates the expression of death receptor 5 and enhances TRAIL-induced apoptosis in human lung cancer A549 cells, Mol. Nutr. Food Res., 55(2), 300-309. CrossRef
Junedi, S., Susidarti, R.A. and Meiyanto, E., 2010, Naringenin meningkatkan efek sitotoksik doxorubicin pada sel kanker payudara T47D melalui induksi apoptosis, Ind. J. Pharm. Sci., 8, 85–90.
Kanno, S., Tomizawa, A., Hiura, T., Osanai, Y., Shouji, A., Ujibe, M., et al., 2005, Inhibitory effects of naringenin on tumor growth in human cancer cell lines and sarcoma S-180-implanted mice, Biol. Pharm. Bull., 28(3), 527-530. CrossRef
Lim, W., Park, S., Bazer, F.W. and Song, G., 2017, Naringenin-induced apoptotic cell death in prostate cancer cells is mediated via the PI3K/AKT and MAPK Signaling Pathways, J. Cell Biochem., 118(5), 1118-1131. CrossRef
Pandey, P., Sayyed, U., Tiwari, R.K., Siddiqui, M.H., Pathak, N. and Bajpai, P., 2019, Hesperidin induces ROS-mediated apoptosis along with cell cycle arrest at G2/M phase in human gall bladder carcinoma, Nutr. Cancer, 71, 676–687. CrossRef
Park, H.J., Choi, Y.J., Lee, J.H. and Nam, M.J., 2017, Naringenin causes ASK1-induced apoptosis via reactive oxygen species in human pancreatic cancer cells, Food Chem. Toxicol., 99, 1-8. CrossRef
Setiawati, A., Susidarti, R.A. and Meiyanto, E., 2011, Peningkatan efek sitotoksik doxorubicin oleh hesperidin pada sel kanker T47D, Bionatura, 13(2), 85-92. CrossRef
Siddiqi, A., Hasan, S.K., Nafees, S., Rashid, S., Saidullah, B. and Sultana, S., 2015, Chemopreventive efficacy of hesperidin against chemically induced nephrotoxicity and renal carcinogenesis via amelioration of oxidative stress and modulation of multiple molecular pathways, Exp. Mol. Pathol., 99(3), 641-653. CrossRef
Wang, X., Zhang, H. and Chen, X., 2019, Drug resistance and combating drug resistance in cancer, Cancer Drug Resist., 2, 141–160. CrossRef
Wang, Y., Yu, H., Zhang, J., Gao, J., Ge, X. and Lou, G., 2015, Hesperidin inhibits HeLa cell proliferation through apoptosis mediated by endoplasmic reticulum stress pathways and cell cycle arrest, BMC Cancer, 15, 682-692. CrossRef
Ye, L., Chan, F.L., Chen, S. and Leung, L.K., 2012, The citrus flavonone hesperetin inhibits growth of aromatase-expressing MCF-7 tumor in ovariectomized athymic mice, J. Nutr. Biochem., 23(10), 1230-1237. CrossRef
Yumnam, S., Hong, G.E., Raha, S., Saralamma, V.V., Lee, H.J., Lee, W.S., et al., 2016, Mitochondrial dysfunction and Ca(2+) overload contributes to hesperidin induced paraptosis in hepatoblastoma cells, HepG2, J. Cell Physiol., 231(6), 1261-1268. CrossRef
Zhang, H., Zhong, X., Zhang, X., Shang, D., Zhou, Y.I. and Zhang, C., 2016, Enhanced anticancer effect of ABT-737 in combination with naringenin on gastric cancer cells, Exp. Ther. Med., 11(2), 669-673. CrossRef
Zohny, S.F., Al-Malki, A.L., Zamzami, M.A. and Choudhry, H., 2019, p21 Waf1/Cip1: Its paradoxical effect in the regulation of breast cancer, Breast Cancer, 6(2), 131-137. CrossRef
DOI: http://dx.doi.org/10.14499/indonesianjcanchemoprev12iss2pp83-89
Copyright (c) 2021 Indonesian Journal of Cancer Chemoprevention
Indexed by:
Indonesian Society for Cancer Chemoprevention
