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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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Abstract

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.

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Acknowledgements

This investigation was supported in part by USPHS RO1 grant CA106953 (to SKS) awarded by the National Cancer Institute. Funds from Texas Tech University Health Sciences Center, School of Pharmacy and Hillman Foundation (to SKS) are also acknowledged. The authors thank Dr. Massimo Trucco, University of Pittsburgh for providing acinar cells isolated from normal human pancreas and Shephalie Lahiri for technical assistance.

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Authors and Affiliations

  1. Department of Pharmacology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA

    Ruifen Zhang & Sanjay K. Srivastava

  2. University of Pittsburgh Cancer Institute, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA

    Ruifen Zhang, Ian Humphreys & Sanjay K. Srivastava

  3. Department of Pharmaceutical Sciences and Cancer Biology Center, School of Pharmacy, Texas Tech University Health Sciences Center, Suite 404, 1300 S Coulter, Amarillo, TX, USA

    Ravi P. Sahu, Yan Shi & Sanjay K. Srivastava

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  1. Ruifen Zhang
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  2. Ian Humphreys
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Correspondence to Sanjay K. Srivastava.

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Ruifen Zhang and Ian Humphreys contributed equally to this work.

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Zhang, R., Humphreys, I., Sahu, R.P. et al. In vitro and in vivo induction of apoptosis by capsaicin in pancreatic cancer cells is mediated through ROS generation and mitochondrial death pathway. Apoptosis 13, 1465–1478 (2008). https://doi.org/10.1007/s10495-008-0278-6

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