Department of Pharmacology, Shenyang Pharmaceutical University, Shenyang, 110016, People's Republic of China.
Curr Cancer Drug Targets. 2014;14(1):91-103. doi: 10.2174/1568009613666131113100634.
Gambogic acid (GA) has been approved by the Chinese Food and Drug Administration for the treatment of lung cancer in clinical trials. However, whether GA has chemosensitizing properties when combined with other chemotherapy agents in the treatment of lung cancer is not known. Here we investigated the effects of GA combined with adriamycin (ADM), a common chemotherapy agent, in regard to their activities and the possible mechanisms against lung cancer in vitro and in vivo. Cell viability results showed that sequential GA-ADM treatment was synergistic, while the reverse sequence and simultaneous treatments were antagonistic or additive, in lung cancer cells and ADM resistant cells, but not in normal cells. The combined use of GA and ADM synergistically displayed apoptosis-inducing activities in lung cancer cells. Moreover, GA in combination with ADM could promote PARP cleavage, enhance caspases activation and decrease the expression of anti-apoptotic proteins in lung cancer cells. The combined use of GA and ADM decreased the expression of P-glycoprotein and increased the accumulation of ADM in lung cancer cells. Furthermore, it was found that, prior to ADM treatment, GA could inhibit NF-κB signaling pathways, which have been validated to confer ADM resistance. The critical role of NF-κB was further confirmed by using PDTC, a NF-κB inhibitor, which significantly increased apoptosis induction by the combination of GA and ADM and inhibited ADM-induced ABCB1 upregulation. Importantly, our results indicated that the combination of GA and ADM exerted enhanced anti-tumor effects on A549 xenograft models through inhibiting NF-κB and P-glycoprotein, and attenuated ADM-induced cardiotoxicity. Collectively, these findings indicate that GA sensitizes lung cancer cells to ADM in vitro and in vivo, providing a rationale for the combined use of GA and ADM in lung cancer chemotherapy.
藤黄酸（GA）已被中国食品药品监督管理局批准用于临床试验治疗肺癌。然而，GA 与其他化疗药物联合治疗肺癌时是否具有化疗增敏作用尚不清楚。在这里，我们研究了 GA 与阿霉素（ADM）联合使用在体外和体内对肺癌的作用及其可能的机制，ADM 是一种常用的化疗药物。细胞活力结果表明，GA-ADM 序贯治疗具有协同作用，而相反顺序和同时治疗则具有拮抗或相加作用，无论是在肺癌细胞和 ADM 耐药细胞中，还是在正常细胞中均如此。GA 与 ADM 联合使用可协同诱导肺癌细胞凋亡。此外，GA 与 ADM 联合使用可促进 PARP 裂解，增强半胱天冬酶激活，并降低肺癌细胞中抗凋亡蛋白的表达。GA 与 ADM 联合使用可降低 P-糖蛋白的表达并增加肺癌细胞中 ADM 的积累。此外，研究发现，在 ADM 治疗之前，GA 可以抑制 NF-κB 信号通路，该通路已被证实可赋予 ADM 耐药性。使用 NF-κB 抑制剂 PDTC 进一步证实了 NF-κB 的关键作用，其显著增加了 GA 和 ADM 联合诱导的细胞凋亡，并抑制了 ADM 诱导的 ABCB1 上调。重要的是，我们的结果表明，GA 与 ADM 的联合使用通过抑制 NF-κB 和 P-糖蛋白对 A549 异种移植模型发挥了增强的抗肿瘤作用，并减轻了 ADM 引起的心脏毒性。总之，这些发现表明，GA 在体外和体内使肺癌细胞对 ADM 敏感，为 GA 与 ADM 联合用于肺癌化疗提供了理论依据。
