Triptolide induces pancreatic cancer cell death via inhibition of heat shock protein 70
Triptolide induces pancreatic cancer cell death via inhibition of heat shock protein 70
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DOI：
10.1158/0008-5472.can-07-1077
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发表时间：
2007-10-01
期刊：
影响因子：
11.2
通讯作者：
Saluja, Ashok K.
中科院分区：
文献类型：
--
作者：
Phillips, Phoebe A.;Dudeja, Vikas;Saluja, Ashok K.
胰腺癌对目前的化疗药物具有高度耐药性。因此，我们使用胰腺癌原位模型研究了雷公藤甲素（一种二萜三氧化物）对胰腺癌生长和局部肿瘤扩散的影响。我们最近的研究表明，胰腺癌细胞中HSP70水平的升高赋予细胞凋亡抗性，抑制HSP70可诱导细胞凋亡。此外，雷公藤甲素最近被确定为小分子筛选的一部分，作为人类热休克反应的调节剂。因此，我们的目的是通过评估胰腺癌细胞的活力和凋亡来研究雷公藤甲素对(a)胰腺癌细胞的影响，(b)胰腺癌在体内的生长和局部侵袭，以及(c)胰腺癌细胞中的HSP70水平。用雷公藤甲素（50-200 nmol/L）孵育PANC-1和MiaPaCa-2细胞可显著降低细胞活力，但对正常胰腺导管细胞活力无影响。雷公藤甲素在两种细胞系中诱导细胞凋亡（通过Annexin V、caspase-3和末端核苷酸转移酶介导的缺口末端标记来评估），并降低HSP70 mRNA和蛋白水平。体内给药雷公藤甲素（0.2 mg/kg/d，持续60天）可降低胰腺癌生长，并显著降低局部肿瘤扩散。对照组小鼠有广泛的局部侵入邻近器官，包括脾、肝、肾和小肠。雷公藤甲素在体外和体内通过诱导细胞凋亡导致胰腺癌细胞死亡，其作用机制是通过抑制HSP70介导的。雷公藤甲素是一种潜在的治疗药物，可用于预防胰腺癌的进展和转移。
Pancreatic cancer is highly resistant to current chemotherapy agents. We therefore examined the effects of triptolide (a diterpenoid triepoxide) on pancreatic cancer growth and local-regional tumor spread using an orthotopic model of pancreatic cancer. We have recently shown that an increased level of HSP70 in pancreatic cancer cells confers resistance to apoptosis and that inhibiting HSP70 induces apoptosis in these cells. In addition, triptolide was recently identified as part of a small molecule screen, as a regulator of the human heat shock response. Therefore, our aims were to examine the effects of triptolide on (a) pancreatic cancer cells by assessing viability and apoptosis, (b) pancreatic cancer growth and local invasion in vivo, and (c) HSP70 levels in pancreatic cancer cells. Incubation of PANC-1 and MiaPaCa-2 cells with triptolide (50-200 nmol/L) significantly reduced cell viability, but had no effect on the viability of normal pancreatic ductal cells. Triptolide induced apoptosis (assessed by Annexin V, caspase-3, and terminal nucleotidyl transferase-mediated nick end labeling) and decreased HSP70 mRNA and protein levels in both cell lines. Triptolide (0.2 mg/kg/d for 60 days) administered in vivo decreased pancreatic cancer growth and significantly decreased local-regional tumor spread. The control group of mice had extensive local invasion into adjacent organs, including the spleen, liver, kidney, and small intestine. Triptolide causes pancreatic cancer cell death in vitro and in vivo by induction of apoptosis and its mechanism of action is mediated via the inhibition of HSP70. Triptolide is a potential therapeutic agent that can be used to prevent the progression and metastases of pancreatic cancer.