Saito Nobuhiro, Shirai Yoshihiro, Uwagawa Tadashi, Horiuchi Takashi, Sugano Hiroshi, Haruki Koichiro, Shiba Hiroaki, Ohashi Toya, Yanaga Katsuhiko
Department of Surgery, The Jikei University School of Medicine, Tokyo, Japan.
Division of Gene Therapy, Research Center for Medical Science, The Jikei University School of Medicine, Tokyo, Japan.
Oncotarget. 2018 Mar 2;9(21):15780-15791. doi: 10.18632/oncotarget.24608. eCollection 2018 Mar 20.
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.
, 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). , we established orthotopic model and the animals were treated with oral pomalidomide and injection of gemcitabine/nab-paclitaxel.
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 and . 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.
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.
吉西他滨与白蛋白结合型紫杉醇（吉西他滨/白蛋白结合型紫杉醇）联合化疗被推荐用于不可切除的胰腺癌。然而，抗肿瘤药物诱导的核因子-κB（NF-κB）激活会削弱治疗效果。沙利度胺可抑制NF-κB激活，因此，我们推测第三代免疫调节药物泊马度胺也会抑制NF-κB激活并增强吉西他滨/白蛋白结合型紫杉醇的抗肿瘤作用。
我们评估了在人胰腺癌细胞系（PANC-1和MIA PaCa-2）中，单独使用泊马度胺、吉西他滨/白蛋白结合型紫杉醇或泊马度胺与吉西他滨/白蛋白结合型紫杉醇联合使用时的NF-κB活性和细胞凋亡情况。我们建立了原位模型，动物接受口服泊马度胺并注射吉西他滨/白蛋白结合型紫杉醇治疗。
在泊马度胺与吉西他滨/白蛋白结合型紫杉醇联合治疗组中，与其他组相比，吉西他滨/白蛋白结合型紫杉醇诱导的NF-κB激活受到抑制，细胞凋亡增强，体内和体外实验均如此。特别是，本研究首次揭示泊马度胺可增强胰腺癌细胞上的p53。泊马度胺与吉西他滨/白蛋白结合型紫杉醇联合治疗组的肿瘤生长明显慢于吉西他滨/白蛋白结合型紫杉醇组。此外，泊马度胺诱导G0/G1期细胞周期阻滞并抑制血管生成。
泊马度胺通过抑制NF-κB激活增强了吉西他滨/白蛋白结合型紫杉醇的抗肿瘤作用。这种联合治疗方案将是治疗胰腺癌的一种新策略。
