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

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.

Combination of salinomycin and silver nanoparticles enhances apoptosis and autophagy in human ovarian cancer cells: an effective anticancer therapy

“…105 Several studies confirmed that Sal could potentiate anticancer activity with several DNA damage-causing chemotherapeutic drugs. 27 In line with previous studies, our results show that Sal enhances the cytotoxic effect of AgNPs in human ovarian cancer cells. AgNPs have been shown to induce DNA fragmentation in AgNPs-treated Dalton's lymphoma ascites cells.…”

“…It also induces cell death by overcoming ABC transporter-mediated multidrug and apoptosis resistance in MDR cancer cells. 21,27,28 Sal causes concentration-and time-dependent reduction in the viability of LNM35 and A549 cells through a caspase-3/7-associated cell death pathway. Similarly, Sal treatment at a concentration of 2.5-5 µM for 7 days significantly decreases the growth of human lung cancer cell lines, LNM35 and A549 colonies, in soft agar.…”

“…12 The activation of apoptotic pathways by Sal is independent of p53 and caspase activation, and it has been shown that Sal can sensitize cancer cells by reducing p21 levels. 18,27 Sal induces apoptosis in various cancer cell lines through cell cycle arrest and reactive oxygen species (ROS)-mediated mitochondrial pathways. It also induces cell death by overcoming ABC transporter-mediated multidrug and apoptosis resistance in MDR cancer cells.…”

Impact of Salinomycin on human cholangiocarcinoma: induction of apoptosis and impairment of tumor cell proliferation in vitro

“…The impact of Salinomycin on human CC cells is reflected by cell cycle accumulation in the G2-phase. This finding is noticeable because others have demonstrated that treatment with Salinomycin in equal concentrations is associated with accumulation in the pre-G1-phase, indicating increased apoptosis [17] Furthermore, in pre-treated human breast cancer with antimitotic drugs, Salinomycin abolishes G2-arrest and aneuploid cell formation [17,40]. In contrast, radiationtreated breast cancer cells accumulate in the G2-phase after treatment with Salinomycin [41].…”

“…First, the effects of Salinomycin were described in the treatment of cancer stem cells in vitro and in vivo [16]. Later, the efficacy of Salinomycin against tumor cells has been demonstrated in several cancer cell lines from different origin, including solid and non-solid malignancies [17][18][19][20]. Nevertheless, the precise mode of action of Salinomycin as an anti-cancer agent remains unclear.…”