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Bufalin Induces Apoptotic Cell Death in Human Nasopharyngeal Carcinoma Cells through Mitochondrial ROS and TRAIL Pathways

    https://doi.org/10.1142/S0192415X19500125Cited by:17
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    Abstract

    The aim of this study was to investigate the effects of bufalin on human nasopharyngeal carcinoma NPC-TW 076 cells in vitro. Bufalin is a cardiotonic steroid and a key active ingredient of the Chinese medicine ChanSu. The extracts of Chansu are used for various cancer treatments in China. In the present study, bufalin induced cell morphological changes, decreased total cell viability and induced G2/M phase arrest of cell cycle in NPC-TW 076 cells. Results also indicated that bufalin induced chromatin condensation (cell apoptosis) and DNA damage by DAPI staining and comet assay, respectively. The induced apoptotic cell death was further confirmed by annexin-V/PI staining assay. In addition, bufalin also increased ROS and Ca2+ production and decreased the levels of ΔΨm. Furthermore, the alterations of ROS, ER stress and apoptosis associated protein expressions were investigated by Western blotting. Results demonstrated that bufalin increased the expressions of ROS associated proteins, including SOD (Cu/Zn), SOD2 (Mn) and GST but decreased that of catalase. Bufalin increased ER stress associated proteins (GRP78, IRE-1α, IRE-1β, caspase-4, ATF-6α, Calpain 1, and GADD153). Bufalin increased the pro-apoptotic proteins Bax, and apoptotic associated proteins (cytochrome c, caspase-3, -8 and -9, AIF and Endo G) but reduced anti-apoptotic protein Bcl-2 in NPC-TW 076 cells. Furthermore, bufalin elevated the expressions of TRAIL-pathway associated proteins (TRAIL, DR4, DR5, and FADD). Based on these findings, we suggest bufalin induced apoptotic cell death via caspase-dependent, mitochondria-dependent and TRAIL pathways in human nasopharyngeal carcinoma NPC-TW 076 cells.

    References

    • Bianchi, K., A. Rimessi, A. Prandini, G. Szabadkai and R. Rizzuto. Calcium and mitochondria: Mechanisms and functions of a troubled relationship. Biochim. Biophys. Acta. 1742: 119–131, 2004. Crossref, Medline, Google Scholar
    • Chen, Y., M.B. Azad and S.B. Gibson. Superoxide is the major reactive oxygen species regulating autophagy. Cell Death Differ. 16: 1040–1052, 2009. Crossref, Medline, Google Scholar
    • Chien, Y.C. and C.J. Chen. Epidemiology and etiology of nasopharyngeal carcinoma: Gene-environment interaction. Cancer Rev.: Asia-Pacific 1: 19, 2003. Link, Google Scholar
    • Chou, H.Y., F.S. Chueh, Y.S. Ma, R.S. Wu, C.L. Liao, Y.L. Chu, M.J. Fan, W.W. Huang and J.G. Chung. Bufalin induced apoptosis in SCC4 human tongue cancer cells by decreasing Bcl2 and increasing Bax expression via the mitochondriadependent pathway. Mol. Med. Rep. 16: 7959–7966, 2017. Crossref, Medline, Google Scholar
    • Dewaele, M., H. Maes and P. Agostinis. ROS-mediated mechanisms of autophagy stimulation and their relevance in cancer therapy. Autophagy 6: 838–854, 2010. Crossref, Medline, Google Scholar
    • Ding, Y., K. Ren, H. Dong, F. Song, J. Chen, Y. Guo, Y. Liu, W. Tao and Y. Zhang. Flavonoids from persimmon (Diospyros kaki L.) leaves inhibit proliferation and induce apoptosis in PC-3 cells by activation of oxidative stress and mitochondrial apoptosis. Chem. Biol. Interact. 275: 210–217, 2017. Crossref, Medline, Google Scholar
    • Doan, P., T. Nguyen, O. Yli-Harja, N.R. Candeias and M. Kandhavelu. Effect of alkylaminophenols on growth inhibition and apoptosis of bone cancer cells. Eur. J. Pharm. Sci. 107: 208–216, 2017. Crossref, Medline, Google Scholar
    • Ferlay, J., I. Soerjomataram, R. Dikshit, S. Eser, C. Mathers, M. Rebelo, D.M. Parkin, D. Forman and F. Bray. Cancer incidence and mortality worldwide: Sources, methods and major patterns in GLOBOCAN 2012. Int. J. Cancer. 136: E359–E386, 2015. Crossref, Medline, ISI, Google Scholar
    • Han, K.Q., G. Huang, W. Gu, Y.H. Su, X.Q. Huang and C.Q. Ling. Anti-tumor activities and apoptosis-regulated mechanisms of bufalin on the orthotopic transplantation tumor model of human hepatocellular carcinoma in nude mice. World J. Gastroenterol. 13: 3374–3379, 2007. Crossref, Medline, ISI, Google Scholar
    • Hashimoto, S., Y. Jing, N. Kawazoe, Y. Masuda, S. Nakajo, T. Yoshida, Y. Kuroiwa and K. Nakaya. Bufalin reduces the level of topoisomerase II in human leukemia cells and affects the cytotoxicity of anticancer drugs. Leuk. Res. 21: 875–883, 1997. Crossref, Medline, Google Scholar
    • Heinzelmann, S and G. Bauer. Multiple protective functions of catalase against intercellular apoptosis-inducing ROS signaling of human tumor cells. Biol. Chem. 391: 675–693, 2010. Crossref, Medline, Google Scholar
    • Hsiao, Y.T., C.L. Kuo, F.S. Chueh, K.C. Liu, D.T. Bau and J.G. Chung. Curcuminoids induce reactive oxygen species and autophagy to enhance apoptosis in human oral cancer cells. Am. J. Chin. Med. 46: 1145–1168, 2018a. Link, ISI, Google Scholar
    • Hsiao, Y.T., M.J. Fan, A.C. Huang, J.C. Lien, J.J. Lin, J.C. Chen, T.C. Hsia, R.S. Wu and J.G. Chung. Deguelin impairs cell adhesion, migration and invasion of human lung cancer cells through the NF-κB signaling pathways. Am. J. Chin. Med. 46: 209–229, 2018b. Link, Google Scholar
    • Hsu, W.L., K.J. Yu, Y.C. Chien, C.J. Chiang, Y.J. Cheng, J.Y. Chen, M.Y. Liu, S.P. Chou, S.L. You, M.M. Hsu, P.J. Lou, C.P. Wang, J.H. Hong, Y.S. Leu, M.H. Tsai, M.C. Su, S.T. Tsai, W.Y. Chao, L.P. Ger, P.R. Chen, C.S. Yang, A. Hildesheim, S.R. Diehl and C.J. Chen. Familial tendency and risk of nasopharyngeal carcinoma in taiwan: Effects of covariates on risk. Am. J. Epidemiol. 173: 292–299, 2011. Crossref, Medline, Google Scholar
    • Hu, P. and N. Tirelli. Scavenging ROS: Superoxide dismutase/catalase mimetics by the use of an oxidation-sensitive nanocarrier/enzyme conjugate. Bioconjug. Chem. 23: 438–449, 2012. Crossref, Medline, Google Scholar
    • Huang, H., M. Hu, R. Zhao, P. Li and M. Li. Dihydromyricetin suppresses the proliferation of hepatocellular carcinoma cells by inducing G2/M arrest through the Chk1/Chk2/Cdc25C pathway. Oncol. Rep. 30: 2467–2475, 2013. Crossref, Medline, Google Scholar
    • Huang, W.W., J.S. Yang, S.J. Pai, P.P. Wu, S.J. Chang, F.S. Chueh, M.J. Fan, S.M. Chiou, H.M. Kuo, C.C. Yeh, P.Y. Chen, M. Tsuzuki and J.G. Chung. Bufalin induces G0/G1 phase arrest through inhibiting the levels of cyclin D, cyclin E, CDK2 and CDK4, and triggers apoptosis via mitochondrial signaling pathway in T24 human bladder cancer cells. Mutat. Res. 732: 26–33, 2012. Crossref, Medline, ISI, Google Scholar
    • Jaudan, A., S. Sharma, S.N.A. Malek and A. Dixit. Induction of apoptosis by pinostrobin in human cervical cancer cells: Possible mechanism of action. PLoS One 13: e0191523, 2018. Crossref, Medline, Google Scholar
    • Jiang, Y., Y. Zhang, J. Luan, H. Duan, F. Zhang, K. Yagasaki and G. Zhang. Effects of bufalin on the proliferation of human lung cancer cells and its molecular mechanisms of action. Cytotechnology 62: 573–583, 2010. Crossref, Medline, Google Scholar
    • Karkucinska-Wieckowska, A., M. Lebiedzinska, E. Jurkiewicz, M. Pajdowska, J. Trubicka, T. Szymanska-Debinska, J. Suski, P. Pinton, J. Duszynski, M. Pronicki, M.R. Wieckowski and E. Pronicka. Increased reactive oxygen species (ROS) production and low catalase level in fibroblasts of a girl with MEGDEL association (Leigh syndrome, deafness, 3-methylglutaconic aciduria). Folia Neuropathol. 49: 56–63, 2011. Medline, Google Scholar
    • Karnell, L.H., A.J. Christensen, E.L. Rosenthal, J.S. Magnuson and G.F. Funk. Influence of social support on health-related quality of life outcomes in head and neck cancer. Head Neck 29: 143–146, 2007. Crossref, Medline, Google Scholar
    • Kawazoe, N., T. Aiuchi, Y. Masuda, S. Nakajo and K. Nakaya. Induction of apoptosis by bufalin in human tumor cells is associated with a change of intracellular concentration of Na+ ions. J. Biochem. 126: 278–286, 1999. Crossref, Medline, Google Scholar
    • Knox, R.J., F. Friedlos, D.A. Lydall and J.J. Roberts. Mechanism of cytotoxicity of anticancer platinum drugs: Evidence that cis-diamminedichloroplatinum(II) and cis-diammine-(1,1-cyclobutanedicarboxylato)platinum(II) differ only in the kinetics of their interaction with DNA. Cancer Res. 46: 1972–1979, 1986. Medline, Google Scholar
    • Krenn, L. and B. Kopp. Bufadienolides from animal and plant sources. Phytochemistry 48: 1–29, 1998. Crossref, Medline, Google Scholar
    • Lee, A.W., J.C. Lin and W.T. Ng. Current management of nasopharyngeal cancer. Semin. Radiat. Oncol. 22: 233–244, 2012. Crossref, Medline, Google Scholar
    • Li, C.C., M.C. Yu and B.E. Henderson. Some epidemiologic observations of nasopharyngeal carcinoma in Guangdong, People’s Republic of China. Natl. Cancer Inst. Monogr. 69: 49–52, 1985. Medline, Google Scholar
    • Li, D., X. Qu, K. Hou, Y. Zhang, Q. Dong, Y. Teng, J. Zhang and Y. Liu. PI3K/Akt is involved in bufalin-induced apoptosis in gastric cancer cells. Anticancer Drugs 20: 59–64, 2009. Crossref, Medline, Google Scholar
    • Lin, Y.J., S.F. Peng, M.L. Lin, C.L. Kuo, K.W. Lu, C.L. Liao, Y.S. Ma, F.S. Chueh, K.C. Liu, F.S. Yu and J.G. Chung. Tetrandrine induces apoptosis of human nasopharyngeal carcinoma NPC-TW 076 cells through reactive oxygen species accompanied by an endoplasmic reticulum stress signaling pathway. Molecules 21: 1353, 2016. Crossref, Google Scholar
    • Liu, K.C., T.Y. Shih, C.L. Kuo, Y.S. Ma, J.L. Yang, P.P. Wu, Y.P. Huang, K.C. Lai and J.G. Chung. Sulforaphane induces cell death through G2/M phase arrest and triggers apoptosis in HCT 116 human colon cancer cells. Am. J. Chin. Med. 44: 1289–1310, 2016. Link, ISI, Google Scholar
    • Liu, T., C. Wu, G. Weng, Z. Zhao, X. He, C. Fu, Z. Sui and S.X. Huang. Bufalin inhibits cellular proliferation and cancer stem cell-like phenotypes via upregulation of MiR-203 in glioma. Cell Physiol. Biochem. 44: 671–681, 2017. Crossref, Medline, Google Scholar
    • Liu, Y., X. Wang, Y. Jia and Y. Liu. Effects of bufalin on the mTOR/p70S6K pathway and apoptosis in esophageal squamous cell carcinoma in nude mice. Int. J. Mol. Med. 40: 357–366, 2017. Crossref, Medline, Google Scholar
    • McDermott, A.L., S.N. Dutt and J.C. Watkinson. The aetiology of nasopharyngeal carcinoma. Clin. Otolaryngol. Allied Sci. 26: 82–92, 2001. Crossref, Medline, Google Scholar
    • Meng, Z., P. Yang, Y. Shen, W. Bei, Y. Zhang, Y. Ge, R.A. Newman, L. Cohen, L. Liu, B. Thornton, D.Z. Chang, Z. Liao and R. Kurzrock. Pilot study of huachansu in patients with hepatocellular carcinoma, nonsmall-cell lung cancer, or pancreatic cancer. Cancer 115: 5309–5318, 2009. Crossref, Medline, ISI, Google Scholar
    • Ren, Q.G., S.L. Yang, J.L. Hu, P.D. Li, Y.S. Chen and Q.S. Wang. Evaluation of HO-1 expression, cellular ROS production, cellular proliferation and cellular apoptosis in human esophageal squamous cell carcinoma tumors and cell lines. Oncol. Rep. 35: 2270–2276, 2016. Crossref, Medline, Google Scholar
    • Shen, S., Y. Zhang, Z. Wang, R. Liu and X. Gong. Bufalin induces the interplay between apoptosis and autophagy in glioma cells through endoplasmic reticulum stress. Int. J. Biol. Sci. 10: 212–224, 2014. Crossref, Medline, ISI, Google Scholar
    • Siegel, R.L., K.D. Miller and A. Jemal. Cancer statistics, 2017. CA Cancer J. Clin. 67: 7–30, 2017. Crossref, Medline, ISI, Google Scholar
    • Tischlerova, V., M. Kello, M. Budovska and J. Mojzis. Indole phytoalexin derivatives induce mitochondrial-mediated apoptosis in human colorectal carcinoma cells. World J. Gastroenterol. 23: 4341–4353, 2017. Crossref, Medline, Google Scholar
    • Watabe, M., K. Ito, Y. Masuda, S. Nakajo and K. Nakaya. Activation of AP-1 is required for bufalin-induced apoptosis in human leukemia U937 cells. Oncogene 16: 779–787, 1998. Crossref, Medline, Google Scholar
    • Wei, W.I. and J.S. Sham. Nasopharyngeal carcinoma. Lancet 365: 2041–2054, 2005. Crossref, Medline, ISI, Google Scholar
    • Weis, S., T. Bielow, I. Sommerer, J. Iovanna, C. Malicet, J. Mossner and A. Hoffmeister. P8 deficiency increases cellular ROS and induces HO-1. Arch. Biochem. Biophys. 565: 89–94, 2015. Crossref, Medline, Google Scholar
    • Yom, S.S. and J. Wee. Nasopharyngeal carcinoma: Management strategies. In Nasopharyngeal Carcinoma: Management Strategies. Future Medicine, 2014, pp. 2–4. Crossref, Google Scholar
    • Yu, C.H., S.F. Kan, H.F. Pu, E. Jea Chien and P.S. Wang. Apoptotic signaling in bufalin- and cinobufagin-treated androgen-dependent and -independent human prostate cancer cells. Cancer Sci. 99: 2467–2476, 2008. Crossref, Medline, Google Scholar
    • Zhao, H., Q. Li, J. Pang, H. Jin, H. Li and X. Yang. Blocking autophagy enhances the pro-apoptotic effect of bufalin on human gastric cancer cells through endoplasmic reticulum stress. Biol. Open 6: 1416–1422, 2017. Crossref, Medline, Google Scholar
    • Zhu, Z., E. Li, Y. Liu, Y. Gao, H. Sun, G. Ma, Z. Wang, X. Liu, Q. Wang, X. Qu, Y. Liu and Y. Yu. Inhibition of Jak-STAT3 pathway enhances bufalin-induced apoptosis in colon cancer SW620 cells. World J. Surg. Oncol. 10: 228, 2012. Crossref, Medline, Google Scholar
    Published: 7 January 2019
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