Pomalidomide enhanced gemcitabine and nab-paclitaxel on pancreatic cancer both in vitro and in vivo
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Nobuhiro Saito1,2, Yoshihiro Shirai1,2,*, Tadashi Uwagawa1,3, Takashi Horiuchi1,2, Hiroshi Sugano1,2, Koichiro Haruki1, Hiroaki Shiba1, Toya Ohashi2 and Katsuhiko Yanaga1
1Department of Surgery, The Jikei University School of Medicine, Tokyo, Japan
2Division of Gene Therapy, Research Center for Medical Science, The Jikei University School of Medicine, Tokyo, Japan
3Division of Clinical Oncology and Hematology, Department of Internal Medicine, The Jikei University School of Medicine, Tokyo, Japan
*This author contributed equally to this work
Nobuhiro Saito, email: [email protected]
Keywords: IMiDs; pancreatic cancer; gemcitabine/nab-paclitaxel; NF-κB; p53
Received: December 29, 2017 Accepted: February 25, 2018 Epub: March 02, 2018 Published: March 20, 2018
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.
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