Salinomycin sensitizes cancer cells to the effects of doxorubicin and etoposide treatment by increasing DNA damage and reducing p21 protein
Salinomycin sensitizes cancer cells to the effects of doxorubicin and etoposide treatment by increasing DNA damage and reducing p21 protein
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DOI：
10.1111/j.1476-5381.2010.01089.x
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发表时间：
2011-02-01
影响因子：
7.3
通讯作者：
Yoon, Sungpil
中科院分区：
文献类型：
--
作者：
Kim, Ju-Hwa;Chae, Minji;Yoon, Sungpil
背景和方法盐霉素（Salinomycin，Sal）最近被证明能抑制多种癌症干细胞.实验方法采用彗星试验、免疫细胞化学和Western blot分析，研究了Sal是否能增强肿瘤细胞对阿霉素（DOX）或依托泊苷（ETO）的敏感性。我们进行了细胞增殖测定以确定细胞活力、细胞脱离、增加的前G1区、Annexin V染色和TUNEL测定以测量Sal增加凋亡的能力。Sal还诱导pH2AX和53BP1的DNA灶的形成。此外，Sal增加了癌细胞对DOX或ETO的凋亡作用的敏感性。我们发现，在Sal与DOX或ETO共同处理后，pH2AX、pBRCA 1、p53BP 1和pChk 1的水平显著升高。抗凋亡p21蛋白的水平增加DOX或ETO，但下降由Sal，这增加了蛋白酶体activity.CONCLUSIONS AND IMPLICATIONS这是第一个研究报告，Sal增加DNA损伤，这种影响起着重要作用，在增加Sal引起的细胞凋亡。总之，我们证明了Sal使癌细胞对DOX或ETO的作用敏感的能力与DNA损伤的增加和抗凋亡蛋白p21水平的降低相关。这些结果可能有助于开发用于接受DOX或ETO治疗的癌症患者的基于Sal的化疗。
BACKGROUND AND PURPOSESalinomycin (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 APPROACHUsing 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 RESULTSSal 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 IMPLICATIONSThis 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.