Involvement of peroxynitrite in capsaicin-induced apoptosis of C6 glioma cells

Qiao, Shanlou; Li, Weihua; Tsubouchi, Ryoko; Haneda, Miyako; Murakami, Keiko; Yoshino, Masataka

doi:10.1016/j.neures.2004.10.006

Cited by 46 publications

(28 citation statements)

References 43 publications

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“…4A). Our results agree with previous findings that capsaicin and resveratrol modulate the processes of apoptosis in tumor cells through caspase activation accelerated by the decreased level of Bcl-2 (15,30,31). We also found the activation of caspase 9 together with caspase 3, indicating that these compounds induce apoptosis via the mitochondrial pathway.…”

Section: Discussionsupporting

confidence: 93%

Nitric oxide triggers apoptosis in A375 human melanoma cells treated with capsaicin and resveratrol

Kim

2011

Mol Med Report

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Abstract. Capsaicin and resveratrol are strong chemopreventive agents with promising human consumption safety records and anticarcinogenic activities. However, the mechanism by which they induce apoptosis in tumor cells remains to be defined. In this study, we examined the role of nitric oxide (NO • ) during apoptosis induced by these agents in A375 human melanoma cells. Capsaicin and resveratrol, alone or in combination, inhibited cell growth and promoted apoptosis by the elevation of NO• in A375 cells. Increased NO • production following treatment stimulated p53 and triggered mitochondrial apoptotic events by inducing conformational changes in Bax and Bcl-2 with subsequent release of cytochrome c and activation of caspase 9 and 3. Caspase 8 activation concurrently appeared to be mediated by death receptor processing and downstream caspases. Collectively, our data suggest that capsaicin and resveratrol activate the mitochondrial and death receptor pathways, working together to induce apoptosis in A375 cells, and indicate that NO• could be considered a potential target for improvement of the effectiveness of melanoma treatment. IntroductionMelanoma, a solid tumor that arises from pigment-producing melanocytes, is the most aggressive and lethal type of cutaneous cancer and is notoriously resistant to all current modalities of cancer therapy (1,2). Melanoma represents only 4% of all skin cancers, but almost 80% of skin cancer mortality (1,3,4). Alternative options for patients with malignancies include natural compound treatments that have been used for a number of years throughout the world (5-9). Among natural compounds, capsaicin (N-vanilly-8-methyl-1-nonenamide) and resveratrol (trans-3,5,4'-trihydroxystilbene) have experienced increasing attention from the scientific and medical field due to their substantial antimutagenic and anticarcinogenic potentials (6,10-12). However, the molecular mechanism by which they selectively induce apoptosis in cancer cells has not yet been fully elucidated.Nitric oxide (NO • ), a product synthesized endogenously via arginine metabolism by various isoforms of nitric oxide synthase (NOS), is a pleiotropic signaling molecule that facilitates a wide variety of basic cellular functions and manifests itself pathophysiologically (13). The effects of capsaicin-induced NO• production have been reported in rat pheochromocytoma, PC-12 (14) and C6 glioma (15) cells. Some in vitro studies have shown that resveratrol is capable of inducing apoptosis through the elevation of NO• concentration in the human breast cancer cell line MCF-7 (16) and exerts antiproliferative action on HepG2 hepatocellular carcinoma cells by NOS activation (17).Based on the collective evidence that capsaicin and resveratrol share the ability to stimulate NO• production in certain cell types, we hypothesized that they may act synergistically in the induction of apoptosis via this pathway. To test this hypothe sis, we examined mechanisms of death signaling induced by capsaicin and resveratrol with special emphasis on ...

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Section: Discussionsupporting

confidence: 93%

Nitric oxide triggers apoptosis in A375 human melanoma cells treated with capsaicin and resveratrol

Kim

2011

Mol Med Report

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“…The mechanism by which this vanilloid mediates its anticarcinogenic effects is not understood but has been shown to alter the metabolism of carcinogens such as aflatoxin B1 (11) and the tobacco-specific nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (12,13). In culture, capsaicin has been found to selectively suppress the growth of various human tumor cells (14,15), including leukemic (16 -18), gastric (19), hepatic (20), glioma (21), and prostate cells (9). How capsaicin mediates its anticancer effects is not fully understood, but the roles of NADH oxidase activity (14), proteasome (9), cyclooxygenases (22), c-Jun NH 2 -terminal kinase (23), nuclear factor-nB (24), peroxisome proliferator-activated receptor g (25,26), peroxynitrite (21), and mitochondrial respiration (27) have been implicated.…”

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confidence: 99%

Capsaicin Is a Novel Blocker of Constitutive and Interleukin-6–Inducible STAT3 Activation

Bhutani

Pathak

Nair

et al. 2007

Clinical Cancer Research

179

102

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Purpose: Capsaicin, a constituent of green and red peppers, has been linked with suppression of tumorigenesis through a mechanism that is not well understood. Because the transcription factor signal transducer and activator of transcription 3 (STAT3) has been closely linked with tumorigenesis, we investigated the effect of this vanilloid on the STAT3 pathway in human multiple myeloma cells. Experimental Design: The effect of capsaicin on both constitutive and interleukin-6^induced STAT3 activation, associated protein kinases, and STAT3-regulated gene products involved in proliferation, survival and angiogenesis, cellular proliferation, and apoptosis in multiple myeloma cells was investigated. Results: We found that capsaicin inhibited constitutive activation of STAT3 in multiple myeloma cells in a dose-and time-dependent manner, with minimum effect on STAT5. Capsaicin also inhibited the interleukin-6^induced STAT3 activation. The activation of Janus-activated kinase 1 and c-Src, implicated in STAT3 activation, was also inhibited by the vanilloid, with no effect on extracellular signal-regulated kinase 1/2 activation. Pervanadate reversed the capsaicin-induced down-regulation of STAT3, suggesting the involvement of a protein tyrosine phosphatase. Capsaicin down-regulated the expression of the STAT3-regulated gene products, such as cyclin D1, Bcl-2, Bcl-xL, survivin, and vascular endothelial growth factor. Finally, capsaicin induced the accumulation of cells in G 1 phase, inhibited proliferation, and induced apoptosis, as indicated by caspase activation. Capsaicin also significantly potentiated the apoptotic effects of Velcade and thalidomide in multiple myeloma cells. When administered i.p., capsaicin inhibited the growth of human multiple myeloma xenograft tumors in male athymic nu/nu mice. Conclusion: Overall, these results suggest that capsaicin is a novel blocker of the STAT3 activation pathway, with a potential role in the prevention and treatment of multiple myeloma and other cancers.

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“…Consistent with the relative insensitivity of normal cells, which do not express TRPV1 to capsaicin, capsaicin (even at 300 mM for 5 days) failed to initiate ROS production, apoptosis or Ca 2þ mobilization in resting T cells. In contrast, other laboratories have reported that the anticancer activities of capsaicin are due to a reduction of ROS levels Qiao et al 2005). For instance, Brar et al (2001) found that capsaicin inhibited the growth of melanoma and other malignant cell lines.…”

Section: Direct Effects On Cancerous Cellsmentioning

confidence: 90%

A Comprehensive Review of the Carcinogenic and Anticarcinogenic Potential of Capsaicin

et al. 2012

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Human exposure to capsaicin, the most abundant pungent chili pepper component, is ubiquitous. Evaluation of capsaicin's carcinogenic potential has produced variable results in in vitro and in vivo genotoxicity and carcinogenicity assays. The capsaicin tested in older studies was often from pepper plant extracts and included other capsaicinoids and diverse impurities. Recent studies utilizing high-purity capsaicin and standardized protocols provide evidence that the genotoxic and carcinogenic potential of capsaicin is quite low and that the purity of capsaicin is important. Several small epidemiological studies suggest a link between capsaicin consumption and stomach or gall bladder cancer, but contamination of capsaicin-containing foods with known carcinogens renders their interpretation problematic. The postulated ability of capsaicin metabolites to damage DNA and promote carcinogenesis remains unsupported. Anticancer activities of capsaicin have been widely reported, as it inhibits the activity of carcinogens and induces apoptosis in numerous cancer cell lines in vitro and explanted into rodents. Diverse mechanisms have been postulated for capsaicin's anticancer properties. One hypothesis is that inhibition of cytochrome P450 enzymes-particularly CYP2E1-retards carcinogen activation but is contradicted by the low potency of capsaicin for CYP inhibition. The potential for dietary capsaicin to act as a chemopreventative is now widely postulated.

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Involvement of peroxynitrite in capsaicin-induced apoptosis of C6 glioma cells

Cited by 46 publications

References 43 publications

Nitric oxide triggers apoptosis in A375 human melanoma cells treated with capsaicin and resveratrol

Nitric oxide triggers apoptosis in A375 human melanoma cells treated with capsaicin and resveratrol

Capsaicin Is a Novel Blocker of Constitutive and Interleukin-6–Inducible STAT3 Activation

A Comprehensive Review of the Carcinogenic and Anticarcinogenic Potential of Capsaicin

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