Shirai Yoshihiro, Saito Nobuhiro, Uwagawa Tadashi, Shiba Hiroaki, Horiuchi Takashi, Iwase Ryota, Haruki Koichiro, Ohashi Toya, Yanaga Katsuhiko
Department of Surgery, The Jikei University School of Medicine, Tokyo, Japan.
Division of Gene Therapy, Research Center for Medical Sciences, The Jikei University School of Medicine, Tokyo, Japan.
Oncotarget. 2018 Feb 26;9(20):15292-15301. doi: 10.18632/oncotarget.24577. eCollection 2018 Mar 16.
Nuclear factor κB (NF-κB) plays an important role in cancer progression and causes therapeutic resistance to chemotherapy. Pomalidomide, a third-generation immunomodulating drug derived from thalidomide, has been approved for uncontrolled multiple myeloma. We hypothesized that pomalidomide may inhibit the anticancer agent-induced NF-κB activity and enhance chemosensitization of combination chemotherapy with gemcitabine and S1 (Gem/S1) in pancreatic cancer.
, we assessed NF-κB activity, induction of caspase cascade, cell apoptosis and cell proliferation using human pancreatic cancer cell lines (MIA PaCa-2 and PANC-1). , we established an orthotopic xenograft mouse model for human pancreatic cancer by injection of PANC-1 cells. At 5 weeks after injection, the animals were randomly divided into four groups and treated with Gem (100 mg/kg) /S1 (10 mg/kg), with oral administration of pomalidomide (0.5 mg/kg), with combination of gemcitabine, S1, and pomalidomide or vehicle only.
Although chemotherapeutic agents induced NF-κB activation in pancreatic cancer cells, pomalidomide inhibited anticancer agent-induced NF-κB activation ( < 0.01). Of the four groups tested for the apoptosis-related caspase signals and apoptosis under both and conditions, Gem/S1/Pomalidomide group demonstrated the strongest activation of the caspase signals and proapoptotic effect. In Gem/S1/Pomalidomide group, cell proliferation and tumor growth were slower than those in other groups both and ( < 0.01). There were no obvious adverse effects except for thrombocytosis by using pomalidomide.
Pomalidomide promotes chemosensitization of pancreatic cancer by inhibiting chemotherapeutic agents-induced NF-κB activation.
核因子κB（NF-κB）在癌症进展中起重要作用，并导致对化疗的治疗抗性。泊马度胺是一种源自沙利度胺的第三代免疫调节药物，已被批准用于治疗难治性多发性骨髓瘤。我们假设泊马度胺可能抑制抗癌药物诱导的NF-κB活性，并增强吉西他滨和S1（Gem/S1）联合化疗对胰腺癌的化学增敏作用。
我们使用人胰腺癌细胞系（MIA PaCa-2和PANC-1）评估NF-κB活性、半胱天冬酶级联反应的诱导、细胞凋亡和细胞增殖。我们通过注射PANC-1细胞建立了人胰腺癌原位异种移植小鼠模型。注射后5周，将动物随机分为四组，分别用Gem（100 mg/kg）/S1（10 mg/kg）、口服泊马度胺（0.5 mg/kg）、吉西他滨、S1和泊马度胺联合治疗或仅用赋形剂治疗。
尽管化疗药物在胰腺癌细胞中诱导NF-κB激活，但泊马度胺抑制了抗癌药物诱导的NF-κB激活（P<0.01）。在检测的四组中，在体外和体内条件下，Gem/S1/泊马度胺组的凋亡相关半胱天冬酶信号激活最强，促凋亡作用最明显。在Gem/S1/泊马度胺组中，体外和体内的细胞增殖和肿瘤生长均比其他组慢（P<0.01）。除使用泊马度胺导致血小板增多外，没有明显的不良反应。
泊马度胺通过抑制化疗药物诱导的NF-κB激活促进胰腺癌的化学增敏作用。
