Zhang Ruifen, Humphreys Ian, Sahu Ravi P, Shi Yan, Srivastava Sanjay K
Department of Pharmacology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
Apoptosis. 2008 Dec;13(12):1465-78. doi: 10.1007/s10495-008-0278-6.
Pancreatic cancer is one of the most common invasive malignancies and the fourth leading cause of cancer related mortality in U.S., thus developing new strategies to control pancreatic cancer is an important mission. We investigated the mechanism of capsaicin, the major pungent ingredient of red-chili pepper, in inducing apoptosis in pancreatic cancer cells. Treatment of AsPC-1 and BxPC-3 cells with capsaicin resulted in a dose-dependent inhibition of cell-viability and induction of apoptosis which was associated with the generation of ROS and persistent disruption of mitochondrial membrane potential. These effects were significantly blocked when the cells were pretreated with a general antioxidant N-acetyl cysteine (NAC). Exposure of AsPC-1 and BxPC-3 cells to capsaicin was also associated with increased expression of Bax, down-regulation of bcl-2, survivin and significant release of cytochrome c and AIF in the cytosol. On the contrary, above-mentioned effects were not observed in the normal acinar cells in response to capsaicin-treatment. Capsaicin-treatment resulted in the activation of JNK and JNK inhibitor SP600125 afforded protection against capsaicin-induced apoptosis. Furthermore, capsaicin when given orally markedly suppressed the growth of AsPC-1 pancreatic tumor xenografts in athymic nude mice, without side effects. Tumors from capsaicin treated mice demonstrated increased apoptosis, which was related to the activation of JNK and increased cytosolic protein expression of Bax, cytochrome c, AIF and cleaved caspase-3, as compared with controls. Taken together, these results show that capsaicin is an effective inhibitor of in vitro and in vivo growth of pancreatic cancer cells. These findings provide the rationale for further clinical investigation of capsaicin against pancreatic cancer.
胰腺癌是最常见的侵袭性恶性肿瘤之一，也是美国癌症相关死亡的第四大主要原因，因此开发控制胰腺癌的新策略是一项重要任务。我们研究了红辣椒的主要辛辣成分辣椒素诱导胰腺癌细胞凋亡的机制。用辣椒素处理AsPC-1和BxPC-3细胞导致细胞活力呈剂量依赖性抑制和凋亡诱导，这与活性氧的产生以及线粒体膜电位的持续破坏有关。当细胞用一般抗氧化剂N-乙酰半胱氨酸（NAC）预处理时，这些效应被显著阻断。AsPC-1和BxPC-3细胞暴露于辣椒素还与Bax表达增加、bcl-2、survivin下调以及细胞溶质中细胞色素c和AIF的显著释放有关。相反，在正常腺泡细胞中，对辣椒素处理未观察到上述效应。辣椒素处理导致JNK激活，JNK抑制剂SP600125可提供针对辣椒素诱导凋亡的保护作用。此外，辣椒素口服给药可显著抑制无胸腺裸鼠中AsPC-1胰腺肿瘤异种移植物的生长，且无副作用。与对照组相比，辣椒素处理小鼠的肿瘤显示凋亡增加，这与JNK激活以及Bax、细胞色素c、AIF和裂解的caspase-3的细胞溶质蛋白表达增加有关。综上所述，这些结果表明辣椒素是胰腺癌细胞体外和体内生长的有效抑制剂。这些发现为进一步对辣椒素抗胰腺癌进行临床研究提供了理论依据。
