Salinomycin sensitizes cancer cells to the effects of doxorubicin and etoposide treatment by increasing DNA damage and reducing p21 protein

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Abstract
BACKGROUND AND PURPOSE Salinomycin (Sal) has recently been shown to inhibit various cancer stem cells. Here, we investigated whether Sal could sensitize cancer cells to the effects of doxorubicin (DOX) or etoposide (ETO). EXPERIMENTAL APPROACH Using the Comet assay, immunocytochemistry and Western blot analysis, we assessed the ability of Sal to increase DNA breakage. We performed a cell proliferation assay to determine cell viability, cellular detachment, increased pre-G1 region, Annexin V staining and TUNEL assay to measure the ability of Sal to increase apoptosis. KEY RESULTS Sal increased DNA breakage and phosphorylated levels of p53 and H2AX. Sal also induced the formation of DNA foci with pH2AX and 53BP1. Furthermore, Sal increased the sensitivity of cancer cells to the apoptotic effects of DOX or ETO. We found that pH2AX, pBRCA1, p53BP1 and pChk1 levels were greatly increased after co-treatment of Sal with DOX or ETO. The level of anti-apoptotic p21 protein was increased by DOX or ETO but decreased by Sal, which increased proteasome activity. CONCLUSIONS AND IMPLICATIONS This is the first study to report that Sal increases DNA damage, and this effect plays an important role in the increased apoptosis caused by Sal. Overall, we demonstrated that the ability of Sal to sensitize cancer cells to the effects of DOX or ETO is associated with an increase in DNA damage and a decrease in anti-apoptotic protein p21 levels. These results may contribute to the development of Sal-based chemotherapy for cancer patients receiving DOX or ETO treatment.