Abstract
Previous studies have observed that Paris saponin I (PSI) exerts a wide range of pharmacological activities, including cytotoxic activity against a number of malignancies, such as non-small cell lung cancers. The present study aimed to investigate the radiosensitization of PSI treatment on a gefitinib-resistant lung adenocarcinoma cell line, PC-9-ZD, and its possible mechanism. A 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-tetrazolium bromide assay was used to determine the growth inhibition effect of PSI. A clonogenic assay was performed to determine the radiosensitizing effect of PSI treatment on the PC-9-ZD cell line. A single-hit multi-target model was used to plot survival curves and calculate sensitizing enhancement ratios. The cell cycle was analyzed by flow cytometry and cell apoptosis was analyzed with fluorescein-isothiocyanate-Annexin V/propidium iodide and Hoechst staining. The expression levels of the proteins were detected by western blotting. There was a significant reduction observed in the proliferation of the PC-9-ZD cell lines that were treated with PSI. PSI enhanced the radiosensitivity of the PC-9-ZD cells with a sensitization enhancement ratio of 1.77. Furthermore, PSI induced G2/M arrest and apoptosis of the irradiated PC-9-ZD cells. Notably, B-cell lymphoma 2 (Bcl-2) was downregulated, and caspase-3, Bcl-2-like protein 4 (Bax) and cyclin-dependent kinase inhibitor 1 (P21waf1/cip1) were upregulated by the PSI treatment. The present study showed that PSI treatment exhibited potent radiosensitivity against gefitinib-resistant PC-9-ZD cells in vitro. This radiosensitivity was associated with cell cycle arrest at the G2/M phase, and apoptosis via an increase in caspase-3, Bax and P21waf1/cip1 as well as a decrease in Bcl-2 production.
Highlights
Lung cancer has become one of the leading causes of cancer‐related mortality worldwide and non‐small cell lung cancer (NSCLC) represents 80% of lung cancers (1,2)
The radiosensitivity effect of Paris saponin I (PSI) treatment is increased in the PC‐9‐ZD cells, the average lethal dosage is decreased with irradiation, the decrease of shoulder is more significant and the repair ability of cell sublethal injury is clearly decreased
The results from assessing the cell cycle and apoptosis in the present study indicate that PSI predominantly induces G2/M phase arrest and apoptosis
Summary
Lung cancer has become one of the leading causes of cancer‐related mortality worldwide and non‐small cell lung cancer (NSCLC) represents 80% of lung cancers (1,2). The epidermal growth factor (EGFR) is a significant therapeutic target in NSCLC (3). Radiotherapy with increased irradiation dosage may delay tumor development, it leads to serious side‐effects, including irradiation pneumonitis and a repressed hemopoietic system. It is significant to use radiosensitizers to raise the therapeutic effect at a normal irradiation dosage. In the last few decades, increased attention has been focused on identifying biologically active cancer therapeutic agents derived from natural resources (7). Chinensis (Franch) Hara and Paris polyphylla Smith var. Preclinical studies have shown that Paris saponins (PS) have emerged as promising anticancer agents (8‐12), and PSI exerts a wide range of pharmacological activities, including cytotoxic activity against certain malignancies, such as NSCLC (13‐17). The present study focused on examining the radiosensitization effects of PSI on NSCLCs with acquired gefitinib resistance in vitro and to further verify the possible mechanisms
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