Paris Saponins enhance radiosensitivity in a gefitinib-resistant lung adenocarcinoma cell line by inducing apoptosis and G(2)/M cell cycle phase arrest

摘要

Acquired resistance to epidermal growth factor inhibitors has been reported to be associated with cross-resistance to radiation. Paris Saponins (PSs) exert a wide range of pharmacological activities, including cell apoptosis induction, multidrug resistance inhibition, angiogenesis inhibition and tumor cell migration by modulating various signaling pathways. The present study aimed to investigate the radiosensitization effects of PSII, PSVI and PSVII in a gefitinib-resistant PC-9-ZD lung adenocarcinoma cell line, and the possible mechanism underlying their function. A clonogenic assay was performed to determine the effects of PS radiosensitization on the PC-9-ZD cell line. The cell cycle was analyzed by flow cytometry, and cell apoptosis was analyzed with Annexin V/propidium iodide and Hoechst staining. Protein expression levels were detected by western blotting. The results of the present study revealed a significant increase in PC-9-ZD cell line radiosensitivity following treatment with PSs. PSs induced G(2)/M cell cycle phase arrest and apoptosis of the irradiated PC-9-ZD cells. Notably, the expression levels of B cell lymphoma 2 (Bcl-2) were downregulated, and those of caspase-3, Bcl-2-associated X protein (Bax) and p21/Waf1/Cip1 were upregulated following treatment with PSs. The present results demonstrated that PSs induced radiosensitivity in gefitinib-resistant cells by inducing G(2)/M phase arrest and by enhancing the apoptotic response via the modulation of caspase-3, Bax, Bcl-2 and p21/Waf1/Cip1 expression.