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.