Department of Molecular Science and Technology, Institute for Medical Sciences, Ajou University School of Medicine, Suwon 443-749, Korea.
Carcinogenesis. 2010 Mar;31(3):367-75. doi: 10.1093/carcin/bgp298. Epub 2009 Nov 25.
Capsaicin, a pungent ingredient of red chili peppers, has been reported to possess antitumor activities. Here, we show that subtoxic doses of capsaicin effectively sensitize multiple malignant glioma cell lines to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis. Although TRAIL alone mediated partial proteolytic processing of procaspase-3 in glioma cells, cotreatment with capsaicin and TRAIL efficiently restored complete activation of caspases. We found that treatment of various gliomas with capsaicin significantly upregulated DR5, a death receptor of TRAIL, and downregulated the caspase inhibitor survivin. The induction of DR5 was mediated by CHOP/GADD153. The reduction in survivin protein level was associated with downregulation of cyclin B and Cdc2 expression, suggesting that inhibition of Cdc2 activity might contribute to capsaicin-induced survivin downregulation. Taken together, these results indicate that the activity of capsaicin toward DR5 and survivin contributes to the amplification of caspase cascades, thereby restoring TRAIL sensitivity in malignant glioma cells. Interestingly, normal astrocytes were resistant to combined treatment with capsaicin and TRAIL. Neither capsaicin-induced DR5 upregulation/survivin downregulation nor the partial processing of procaspase-3 by TRAIL was induced in astrocytes. Thus, a combined regimen using capsaicin and TRAIL may provide a safe and effective strategy for treating malignant gliomas.
辣椒素是红辣椒中的一种辛辣成分，据报道具有抗肿瘤活性。在这里，我们表明，亚毒性剂量的辣椒素能有效地使多种恶性神经胶质瘤细胞系对肿瘤坏死因子相关凋亡诱导配体（TRAIL）诱导的细胞凋亡敏感。虽然 TRAIL 本身能使神经胶质瘤细胞中的 procaspase-3 发生部分蛋白水解处理，但辣椒素与 TRAIL 的共同处理能有效地恢复 caspase 的完全激活。我们发现，用辣椒素处理各种神经胶质瘤能显著上调 DR5，即 TRAIL 的死亡受体，下调 caspase 抑制剂 survivin。DR5 的诱导是由 CHOP/GADD153 介导的。survivin 蛋白水平的降低与细胞周期蛋白 B 和 Cdc2 表达的下调有关，这表明抑制 Cdc2 活性可能有助于辣椒素诱导 survivin 的下调。总之，这些结果表明，辣椒素对 DR5 和 survivin 的活性有助于 caspase 级联的放大，从而恢复恶性神经胶质瘤细胞对 TRAIL 的敏感性。有趣的是，正常星形胶质细胞对辣椒素和 TRAIL 的联合治疗有抗性。星形胶质细胞中既没有诱导出 DR5 的上调/ survivin 的下调，也没有 TRAIL 诱导的 procaspase-3 的部分处理。因此，使用辣椒素和 TRAIL 的联合治疗方案可能为治疗恶性神经胶质瘤提供一种安全有效的策略。
