In vitro and in vivo induction of apoptosis by capsaicin in pancreatic cancer cells is mediated through ROS generation and mitochondrial death pathway
In vitro and in vivo induction of apoptosis by capsaicin in pancreatic cancer cells is mediated through ROS generation and mitochondrial death pathway
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DOI：
10.1007/s10495-008-0278-6
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发表时间：
2008-12-01
期刊：
影响因子：
7.2
通讯作者：
Srivastava, Sanjay K.
中科院分区：
文献类型：
--
作者：
Zhang, Ruifen;Humphreys, Ian;Srivastava, Sanjay K.
胰腺癌是美国最常见的浸润性恶性肿瘤之一，也是美国癌症相关死亡的第四大原因，因此开发控制胰腺癌的新策略是一项重要的任务。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。辣椒素处理ASPC-1和BxPC-3细胞后，细胞活力呈剂量依赖性抑制，并诱导细胞凋亡，这与ROS的产生和线粒体膜电位的持续破坏有关。当用普通抗氧化剂N-乙酰半胱氨酸(NAC)处理细胞时，这些作用被显著阻断。辣椒素对ASPC-1和BxPC-3细胞的作用也与Bax表达增加、bcl2、Survivin表达下调以及胞浆中细胞色素c和AIF的显著释放有关。反之，辣椒素对正常腺泡细胞的上述作用不明显。辣椒素处理可激活JNK，JNK抑制剂SP600125可拮抗辣椒素诱导的细胞凋亡。此外，口服辣椒素可显著抑制裸鼠ASPC-1胰腺癌移植瘤的生长，且无副作用。辣椒素处理组小鼠肿瘤细胞凋亡率增加，与JNK活化及Bax、细胞色素c、AIF和裂解caspase-3的胞浆蛋白表达增加有关。综上所述，这些结果表明辣椒素是一种有效的抑制胰腺癌细胞体外和体内生长的药物。这些发现为辣椒素抗胰腺癌的进一步临床研究提供了理论基础。
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.