Polydatin, a potential NOX5 agonist, synergistically enhances antitumor activity of cisplatin by stimulating oxidative stress in non­small cell lung cancer.

Non­small cell lung cancer (NSCLC) is one of the major causes of cancer­related death worldwide. Cisplatin is a front­line chemotherapeutic agent in NSCLC. Nevertheless, subsequent harsh side effects and drug resistance limit its further clinical application. Polydatin (PD) induces apoptosis in various cancer cells by generating reactive oxygen species (ROS). However, underlying molecular mechanisms of PD and its effects on cisplatin­mediated antitumor activity in NSCLC remains unknown. MTT, colony formation, wound healing analyses and flow cytometry was employed to investigate the cell phenotypic changes and ROS generation. Relative gene and protein expressions were evaluated by reverse transcription­quantitative PCR and western blot analyses. The antitumor effects of PD, cisplatin and their combination were evaluated by mouse xenograft model. In the present study, it was found that PD in combination with cisplatin synergistically enhances the antitumor activity in NSCLC by stimulating ROS­mediated endoplasmic reticulum stress, and the C­Jun­amino­terminal kinase and p38 mitogen­activated protein kinase signaling pathways. PD treatment elevated ROS generation by promoting expression of NADPH oxidase 5 (NOX5), and NOX5 knockdown attenuated ROS­mediated cytotoxicity of PD in NSCLC cells. Mice xenograft model further confirmed the synergistic antitumor efficacy of combined therapy with PD and cisplatin. The present study exhibited a superior therapeutic strategy for some patients with NSCLC by combining PD and cisplatin.

Regorafenib activates oxidative stress by inhibiting SELENOS and potentiates oxaliplatin-induced cell death in colon cancer cells.

Colorectal cancer (CRC) is the third most common cancer, and is one of the leading causes of cancer-related death worldwide. At the time of diagnosis, about 20% of patients with CRC present metastatic disease. Regorafenib, an oral multi-kinase inhibitor, has been demonstrated the efficacy and tolerability in patients with metastatic CRC. Oxaliplatin is a frontline treatment regimen for CRC, and combination treatments with oxaliplatin and other chemotherapeutic agents exert superior therapeutic effects. However, side effects and drug resistance limited their further clinical application. Here, we found that combined treatment with regorafenib and oxaliplatin synergistically enhanced anti-tumor activities in CRC by activating reactive oxygen species (ROS) mediated endoplasmic reticulum (ER) stress, C-Jun-amino-terminal kinase (JNK) and p38 signaling pathways. Regorafenib promoted ROS production by suppressing the expression of selenoprotein S (SELENOS). Knocking down SELENOS sensitized ROS-mediated anti-tumor effects of regorafenib in CRC cells. Furthermore, mouse xenograft models demonstrated that synergistic anti-tumor effects of combined treatment with regorafenib and oxaliplatin. This study provided solid experimental evidences for the combined treatment with regorafenib and oxaliplatin in CRC.