The PhD Program for Cancer Biology and Drug Discovery, China Medical University, Taichung, Taiwan.
J Cell Physiol. 2012 Jan;227(1):213-22. doi: 10.1002/jcp.22719.
Drug resistance frequently develops in tumors during chemotherapy. Therefore, to improve the clinical outcome, more effective and tolerable combination treatment strategies are needed. Here, we show that isochaihulactone (K8) enhanced paclitaxel-induced apoptotic death in human lung cancer cells, and the enhancing effect was related to increased NSAID-activated gene-1 (NAG-1) expression. CalcuSyn software was used to evaluate the synergistic interaction of K8 and paclitaxel on human lung cancer cells; the synergistic effect of K8 in combination with paclitaxel was increased more than either of these drugs alone. Furthermore, the activity of ERK1/2 was enhanced by the combination of K8 and paclitaxel, and an ERK1/2 inhibitor dramatically inhibited NAG-1 expression in human lung cancer cells. Therefore, this synergistic apoptotic effect in human lung cancer cells may be directly associated with K8-induced NAG-1 expression through ERK1/2 activation. Moreover, over-expression of NAG-1 enhanced K8/paclitaxel-induced apoptosis in human lung cancer cells. In addition, treatment of nude mice with K8 combined with paclitaxel induced phospho-ERK1/2 and NAG-1 expression in vivo. Targeting of NAG-1 signaling could enhance therapeutic efficacy in lung cancer. Our results reveal that activation of NAG-1 by K8 enhanced the therapeutic efficacy of paclitaxel in human lung cancer cells via the ERK1/2 signaling pathway.
肿瘤在化疗过程中经常会产生耐药性。因此，为了改善临床疗效，需要更有效和耐受的联合治疗策略。在这里，我们表明异土木香内酯（K8）增强了紫杉醇诱导的人肺癌细胞凋亡，这种增强作用与 NSAID 激活基因-1（NAG-1）表达增加有关。CalcuSyn 软件用于评估 K8 和紫杉醇对人肺癌细胞的协同作用；K8 与紫杉醇联合的协同作用大于这些药物单独使用的效果。此外，K8 和紫杉醇联合增强了 ERK1/2 的活性，ERK1/2 抑制剂显著抑制了人肺癌细胞中 NAG-1 的表达。因此，这种人肺癌细胞中的协同凋亡作用可能与 K8 诱导的 NAG-1 表达通过 ERK1/2 激活直接相关。此外，NAG-1 的过表达增强了 K8/紫杉醇诱导的人肺癌细胞凋亡。此外，K8 联合紫杉醇治疗裸鼠在体内诱导磷酸化 ERK1/2 和 NAG-1 的表达。靶向 NAG-1 信号通路可以增强肺癌的治疗效果。我们的结果表明，K8 通过激活 NAG-1 增强了 ERK1/2 信号通路在人肺癌细胞中紫杉醇的治疗效果。
