Cells were stained with DHE (C) or CM-H2DCFDA (D) 30 min before collecting cells and then analyzed Hydroxychloroquine by flow cytometer. Figure 5 ROS accumulation contributes to the synergistic cytotoxicity induced by saikosaponins plus cisplatin in Siha cells, A549 cells, and SKOV3 cells. Siha cells (A), A549 cells (B), and SKOV3 cells (C) were pretreated with NAC (1 mM) for 30 min or remained untreated and then treated with saikosaponin-a
(10 μM) or saikosaponin-d (2 μM) or cisplatin individually or combination of saikosaponin and cisplatin for 48 h. The dose of cisplatin is 30 μM for Siha, 8 μM for A549 and SKOV3, respectively. Cell death was measured as described in Fig. 1A. Discussion In this study we demonstrated that both SSa and SSd potently sensitize a number of human cancer cells to cisplatin-induced apoptosis through ROS accumulation. First, the chemosensitization effect of SSa and SSd appeared to be general in solid cancer cells, including those derived from cervix, ovary, and lung. Second, the enhanced cell death in saikosaponin and cisplatin-cotreated cells was mainly apoptotic this website because the co-treated cells showed typical apoptotic morphology, increased early apopototic and late apoptotic
cell population, and activation of caspases. Furthermore, the chemosensitization effect of saikosaponins could be efficiently blocked by the pan-caspase inhibitor zVAD-fmk. Third, both SSa and SSd induced.O2 – and H2O2 accumulation in cancer cells and pretreatment of cells with ROS scavengers effectively inhibited the potentiated cytotoxicity. To our knowledge, this is the first report showing that saikosaponins sensitize cisplatin-induced cell Cediranib (AZD2171) death through modulation of redox status in cancer cells. The combination of saikosaponins and cisplatin could greatly improve the sensitivity of cancer cells to cisplatin. Combination with agents that sensitize cancer cell to chemotherapeutics has been recognized
as an efficient strategy to overcome chemoresistance. Naturally occurring compounds from diets or medicinal plants are generally safe and associated with low toxicity, making them ideal candidates for increasing anticancer drugs’ activity. Saikosaponin-a and -d, two major triterpene saponins derived from Bupleurum radix, have been reported previously to have anticancer property [6, 8]. However, the effect of combination of saikosaponins and chemotherapeutics has never been addressed. In the present study we found that non-toxic dose of either SSa or SSd could sensitize a panel of cancer cells to cisplatin-induced cell death. It is unlikely that p53 is involved in the synergistic cytotoxicity of saikosaponins and cisplatin, because this anticancer effect was detected in cancer cell lines with both wild-type p53 (A549), inactivated p53 (HeLa) and mutated p53 (SKOV3).
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