邻硝基苯基靛红查尔酮单用或与抗癌药或抑制剂联用的抗癌活性

The anticancer activity of o-nitrobenzyl-isatinyl chalcone used alone or in combinations with anticancer drugs or inhibitors

目的研究邻硝基苯基靛红查尔酮(ONIC)单独和联合用药的抗癌效果并分析其机制。方法检测ONIC对体外培养癌细胞的增殖抑制。用Chou氏法和金氏法探讨ONIC与10种抗癌药或通路抑制剂的联用效果。结果 ONIC对8种癌细胞系均有显著抗癌活性。与ONIC有协同作用的药物有5种:HSP90抑制剂17-AAG、Arf抑制剂布雷菲德菌素A、蛋白酶体抑制剂硼替佐米、mTOR抑制剂雷帕霉素、ERK1/2抑制剂U0126。与ONIC拮抗的药物有3种:RhoA抑制剂法舒地尔、PI3K抑制剂LY294002、LKB1-AMPK激动剂甲福明。微管稳定剂紫杉醇和Rac1抑制剂NSC23766与ONIC有叠加作用。结论 ONIC不仅自身有强抗癌活性,而且与不同药物联用具有特异的协同或拮抗效果,提示其机制可能与ONIC作用于RhoA和mTOR的上、下游通路有关。

Objective Investigate anticancer effects and mechanisms of o-nitrobenzyl-isatinyl chalcone （ONIC） used alone or in drug combination. Method Detection of proliferation inhibition on cultured cancer cells treated with ONIC. Using Chou’s and Jin’s methods to evaluate drug combination effects among ONIC and ten anticancer drugs or pathway inhibitors. Result ONIC had potent in vitro anticancer activity against eight cancer cell lines. Five drugs were shown to have synergetic effects with ONIC： HSP 90 inhibitor 17-AAG, Arf inhibitor brefeldin A, proteasome inhibitor bortezomib, mTOR inhibitor rapamycin, and ERK1/2 inhibitor U0126. Antagonistic effects were revealed among ONIC and three drugs： RhoA inhibitor fasudil, PI3K inhibitor LY294002, and LKB1-AMPK agonist metformin. Both the microtubule stabilizer paclitaxel and Rac1 inhibitor NSC23766 showed additive effects with ONIC. Conclusion ONIC not only itself has potent anticancer activity, but also has specific synergetic or antagonistic effects in combination with other drugs, suggesting that the RhoA pathway and the up- and downstream elements in mTOR pathway were closely related with the anticancer mechanisms of ONIC.