Mechanism Of Sc/D-F9 Anticancer Activity And Its Synergistic Effects With Tamoxifen In Breast Cancer Cell Lines
Loading...
Date
2015
Authors
NIK MOHAMED KAMAL, NIK NUR SYAZNI
Journal Title
Journal ISSN
Volume Title
Publisher
Universiti Sains Malaysia
Abstract
Strobilanthes crispus (S. crispus) or locally known as ‘Pecah beling’ has been regarded as a folkloric remedy against various ailments. Several studies have indicated that extracts of S. crispus have growth inhibitory effects on a number of human cancer cell lines, however, the mechanism underlying the anticancer activity was unclear. In this study, the cytotoxicity of various sub-fractions of dichloromethane extract isolated from the leaves of S. crispus was determined on the human breast cancer cell lines, MCF-7 and MDA-MB-231. The anticancer activity of one of the active sub-fractions, SC/D-F9, was further analysed in these cell lines. Our results demonstrated that SC/D-F9 greatly inhibited MCF-7 and MDA-MB-231 cell growth in a concentration- and time-dependent manner, with EC50 (effective concentration that causes 50 % cell death) of 8.5 g/ml and 10.0 g/ml, respectively. The combined SC/D-F9 and tamoxifen treatment (SC/D-F9+tamoxifen) displayed strong synergistic inhibition of MCF-7 and MDA-MB-231 cell growth at low doses of the antiestrogen. Interestingly, the non-malignant MCF-10A cells displayed no cytotoxicity or DNA damage when treated with either SC/D-F9 or SC/D-F9+tamoxifen. The results showed the cell death action by SC/D-F9 was associated with apoptosis as indicated by an increase in the exposure of phosphatidylserine (PS), mitochondria depolarization and the activation of caspases (3/7, 8 and 9). Furthermore, we also show that SC/D-F9 promoted the tamoxifen-induced apoptosis in both MCF-7 and MDA-MB-231 cell lines. Further analyses showed SC/D-F9 to be equally as potent as SC/D-F9+tamoxifen in inducing cell cycle arrest of MCF-7 and MDA-MB-231 cells at G1 phase. It was associated with post-translational modulation of cyclin D1, p21, p53 and ERα proteins.
Meanwhile, PCR array analysis showed that SC/D-F9 and SC/D-F9+tamoxifen appear to modulate the expression of death receptor, Bcl-2 and caspase genes, which are involved in the control of DNA damage repair, inflammatory response and cell survival. Moreover, protein expression of some apoptosis key regulatory molecules including Bax, tBid, cytochrome c, FADD and TRADD was differently modulated following treatment with SC/D-F9 and SC/D-F9+tamoxifen. Taken together, these results provide further evidence that SC/D-F9 and SC/D-F9+tamoxifen induced apoptosis in MCF-7 and MDA-MB-231 cells via both extrinsic and intrinsic signaling pathways. The anticancer effect of SC/D-F9 and its synergistic effects with tamoxifen in MCF-7 and MDA-MB-231 cell lines, serve as a new, promising approach for breast cancer treatment.
Description
Keywords
Dichloromethane extract isolated , on the human breast cancer cell lines,