Pomalidomide enhanced gemcitabine and nab-paclitaxel on pancreatic cancer both in vitro and in vivo

BACKGROUND: Chemotherapy with gemcitabine and nab-paclitaxel (gemcitabine/nab-paclitaxel) is recommended for unresectable pancreatic cancer. However, the therapeutic efficacy is attenuated by the antitumor agent-induced activation of nuclear factor-κB (NF-κB). Thalidomide inhibits NF-κB activation, therefore, we hypothesized that pomalidomide, a third-generation IMiD, would also inhibit NF-κB activation and enhance the antitumor effects of gemcitabine/nab-paclitaxel. METHODS: In vitro, we assessed NF-κB activity and apoptosis in response to pomalidomide alone, gemcitabine/nab-paclitaxel, or combination of pomalidomide and gemcitabine/nab-paclitaxel in human pancreatic cancer cell lines (PANC-1 and MIA PaCa-2). In vivo, we established orthotopic model and the animals were treated with oral pomalidomide and injection of gemcitabine/nab-paclitaxel. RESULTS: In pomalidomide and gemcitabine/nab-paclitaxel group, gemcitabine/nab-paclitaxel-induced NF-κB activation was inhibited and apoptosis was enhanced in comparison with those in the other groups both in vitro and in vivo. Especially, this study revealed for the first time that pomalidomide enhances p53 on pancreatic cancer cells. The tumor growth in the pomalidomide and gemcitabine/nab-paclitaxel group was significantly slower than that in the gemcitabine/nab-paclitaxel group. Moreover, pomalidomide induced G0/G1 cell cycle arrest and suppressed angiogenesis. CONCLUSIONS: Pomalidomide enhanced the antitumor effect of gemcitabine/nab-paclitaxel by inhibition of NF-κB activation. This combination regimen would be a novel strategy for treating pancreatic cancer.