Abstract
Flavokawain B (FKB) possesses strong anti-neoplastic activity against many cancer cells. Here we assessed its antitumor activity and molecular mechanisms in lung cancer H460 cells in vitro. FKB significantly inhibited cell proliferation and caused arrest of the cell cycle G2-M of H460 cells in a dose-dependent manner. FKB also inducted apoptosis, which was associated with cytochrome c release, caspase-7 and caspase-9 activation and Bcl-xL/Bax dys-regulation. FKB significantly down-regulated survivin and XIAP, and the inhibitory effect induced by FKB was greatly attenuated by through over-expression of survivin or Bax−/− MEFs. Furthermore, FKB activated the mitogen-activated protein kinases and the JNK inhibitor SP600125 significantly decreased the growth-inhibitory and apoptotic effects of FKB. Together, these results suggest the anti-lung cancer potential of flavokawain B for the prevention and treatment of lung cancer.
Similar content being viewed by others
References
Altieri DC (2008) Survivin, cancer networks and pathway-directed drug discovery. Nat Rev Cancer 8(1):61–70
Bressenot A, Marchal S, Bezdetnaya L (2009) Assessment of apoptosis by immunohistochemistry to active caspase-3, active caspase-7, or cleaved PARP in monolayer cells and spheroid and subcutaneous xenografts of human carcinoma. J Histochem Cytochem 57:289–300
Church DN, Talbot DC (2012) Survivin in solid tumors: rationale for development of inhibitors. Curr Oncol Rep 14(2):120–128
Dhanasekaran DN, Reddy EP (2008) JNK signaling in apoptosis. Oncogene 27(48):6245–6251
Dohi T, Okada K, Xia F, Wilford CE, Samuel T, Welsh K et al (2004) An IAP–IAP complex inhibits apoptosis. J Biol Chem 279:34087–34090
Marusawa H, Matsuzawa S, Welsh K, Zou H, Armstrong R, Tamm I et al (2003) HBXIP functions as a cofactor of survivin in apoptosis suppression. EMBO J 22:2729–2740
Shin S, Sung BJ, Cho YS, Kim HJ, Ha NC, Hwang JI et al (2001) An anti-apoptotic protein human survivin is a direct inhibitor of caspase-3 and -7. Biochemistry 40:1117–1123
Stone AA, Chambers TC (2000) Microtubule inhibitors elicit differential effects on MAP kinase (JNK, ERK, and p38) signaling pathways in human KB-3 carcinoma cells. Cell Res 254:110–119
Tabudravu JN, Jaspars M (2005) Anticancer activities of constituents of kava (Piper methysticum). The South Pac J Natural Sci 23:26–29
Tang Y, Simoneau AR, Xie J, Shahandeh B, Zi X (2008) Effects of the kava chalcone flavokawain A differ in bladder cancer cells with wild-type versus mutant p53. Cancer Prev Res 1:439–451
Tang Y, Li X, Liu Z, Simoneau AR, Xie J, Zi X (2010) Flavokawain B, a kava chalcone, exhibits robust apoptotic mechanisms on androgen receptor-negative, hormone-refractory prostate cancer cell lines and reduces tumor growth in a preclinical model. Int J Cancer 127(8):1758–1768
Wagner EF, Nebreda AR (2009) Signal integration by JNK and p38 MAPK pathways in cancer development. Nat Rev Cancer 9(8):537–549
Zhao X, Chao Y, Wan Q, Chen X, Su P, Sun J, Tang Y (2011) Flavokawain B induces apoptosis of human oral adenoid cystic cancer ACC-2 cells via up-regulation of Bim and down-regulation of Bcl-2 gene expression. Can J Physiol Pharmacol 89(12):875–882
Zi X, Simoneau AR (2005) Flavokawain, a novel chaclone from kava extract, induces apoptosis in bladder cancer cells by involvement of Bax protein-dependent and mitochondria-dependent apoptotic pathways and suppresses tumor growth in mice. Cancer Res 65:3479–3486
Acknowledgments
This work was financially supported by the National Natural Science Foundation of China #81173095 and the International Cooperation Program of Sichuan, China #2011HH0012 (Yaxiong Tang) and by the Major Research plan of the National Natural Science Foundation of China #91013006 (Jian Sun).
Author information
Authors and Affiliations
Corresponding authors
Additional information
JunXia An and YaRong Gao contributed equally to this study.
Rights and permissions
About this article
Cite this article
An, J., Gao, Y., Wang, J. et al. Flavokawain B induces apoptosis of non-small cell lung cancer H460 cells via Bax-initiated mitochondrial and JNK pathway. Biotechnol Lett 34, 1781–1788 (2012). https://doi.org/10.1007/s10529-012-0976-6
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s10529-012-0976-6