Synergistic effects of a novel lipid-soluble extract from Pinellia pedatisecta Schott and cisplatin on human cervical carcinoma cell lines through the regulation of DNA damage response signaling pathway

摘要

Herbal medicines have been recognized as an attractive approach for cancer therapy with minimal side effects. The present study investigated the type of interaction between a novel lipid-soluble extract from Pinellia pedatisecta Schott (PE) and cisplatin (CDDP) on human cervical cancer SiHa and CaSki cell lines in vitro. The mechanism of this combination was studied using cell proliferation, invasion and apoptosis assays, and by analyzing cell cycle distribution and protein expression, with a focus on DNA damage response (DDR) activation. Equipotent combinations of PE and CDDP were determined by isobologram analysis, in order to evaluate potential synergy. The combination index for SiHa cells was 0.43, and the index for CaSki cells was 0.68, indicating synergy. Treatment with PE and CDDP combined resulted in a significantly greater inhibition of invasion in the two cells, compared with either drug alone (SiHa, P<0.01; CaSki, P<0.001). This co-treatment induced significantly more apoptosis in the two cell lines, and arrested cells at the G0/G1 phase and G2/M phase in SiHa and CaSki, respectively, with a significant decrease (P<0.01) in S phase cells in the two cell lines. Combined PE and CDDP targeting synergistically enhanced the expression of markers of DDR (phosphorylation of ataxia-telangiectasia mutated, checkpoint kinase (Chk)-1, Chk-2, and γ-H2A histone family member X) in cells. These results suggest that PE and cisplatin act synergistically in cervical cancer cells with high DDR activation. The approach presented in the present study may have important implications for the pharmacological mechanism of Pinellia pedatisecta Schott and cervical cancer therapeutic strategies.