Research Institute, National Cancer Center, 809 Madu 1-dong, Ilsan-gu, Goyang-si, Gyeonggi-do 411-764, Republic of Korea.
Invest New Drugs. 2012 Aug;30(4):1311-8. doi: 10.1007/s10637-011-9685-6. Epub 2011 May 15.
Salinomycin (Sal) is potentially useful for the treatment of cancer. The present study examined a novel mechanism of Sal sensitization in cancer cells. Sal sensitized radiation-treated cancer cells by inducing G2 arrest and causing DNA damage. Sal treatment also reduced p21 levels in radiation-treated cells. Considering that Sal sensitizes doxorubicin (DOX)- or etoposide (ETO)-treated cancer cells by causing DNA damage and reducing p21 expression, the results from our study suggest that the mechanism underlying Sal sensitization is conserved in both chemo- and radiation-treated cells. We also tested the ability of Sal to inhibit p-glycoprotein (P-gp), which plays a role in the efflux of anti-cancer drugs to reduce cellular damage. In particular, we compared Sal to verapamil (Ver), a well-known P-gp inhibitor. Sal inhibits P-gp with a different substrate distinct from that of Ver. In addition, Sal sensitized Ver-resistant cells, indicating that this compound is more effective for sensitizing than Ver. Taken together, the results from our study may contribute to the development of Sal-based therapy for cancer patients treated with P-gp-inhibiting drugs or radiation therapy.
沙利霉素（Sal）在癌症治疗方面具有潜在的应用价值。本研究探讨了 Sal 增强癌细胞对辐射敏感性的新机制。Sal 通过诱导 G2 期阻滞和造成 DNA 损伤来增强辐射处理的癌细胞对辐射的敏感性。Sal 处理还降低了辐射处理细胞中的 p21 水平。鉴于 Sal 通过造成 DNA 损伤和降低 p21 表达来增强阿霉素（DOX）或依托泊苷（ETO）处理的癌细胞对化疗药物的敏感性，我们的研究结果表明，Sal 增强敏感性的机制在化疗和放疗处理的细胞中是保守的。我们还测试了 Sal 抑制 p-糖蛋白（P-gp）的能力，P-gp 在抗癌药物外排中起作用，可减少细胞损伤。具体而言，我们将 Sal 与维拉帕米（Ver）进行了比较，Ver 是一种众所周知的 P-gp 抑制剂。Sal 以不同于 Ver 的不同底物抑制 P-gp。此外，Sal 增强了 Ver 耐药细胞的敏感性，表明该化合物比 Ver 更有效增强敏感性。总之，我们的研究结果可能有助于开发基于 Sal 的治疗方案，用于接受 P-gp 抑制药物或放射治疗的癌症患者。
