Vitamin C inactivates the proteasome inhibitor PS-341 in human cancer cells.
Vitamin C inactivates the proteasome inhibitor PS-341 in human cancer cells.
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DOI：
10.1158/1078-0432.ccr-05-0503
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发表时间：
2006-01-01
影响因子：
11.5
通讯作者：
Sun, SY
中科院分区：
文献类型：
--
作者：
Zou, W;Yue, P;Sun, SY
目的：PS-341（bortezomib，Velcade）是美国食品和药物管理局批准的第一个用于治疗复发性多发性骨髓瘤患者的蛋白酶体抑制剂，可诱导人类癌细胞系凋亡。维生素 C（抗坏血酸）是许多正常生理功能所需的必需水溶性维生素，人类必须通过饮食或补充片剂获取。在这里，我们研究了维生素C对PS-341在人类癌细胞系中的抗癌活性的潜在影响。实验设计：研究了维生素C对PS-341单独和PS-341联合肿瘤坏死因子相关凋亡诱导配体诱导细胞凋亡的影响。此外，还检查了维生素 C 和其他抗氧化剂对 PS-341 介导的蛋白酶体抑制的影响。最后，确定了维生素 C 和 PS-341 之间的直接化学相互作用。结果：维生素 C 消除了 PS-341 在各种人类癌细胞系中诱导细胞凋亡、诱导 G(2)-M 阻滞以及增强肿瘤坏死因子相关凋亡诱导配体诱导的细胞凋亡的能力。此外，维生素 C 还可抑制 PS-341 介导的蛋白酶体活性抑制。 PS-341 本身不会诱导细胞内活性氧的产生，而其他抗氧化剂未能消除其生物活性。重要的是，我们检测到维生素 C 和 PS-341 之间存在直接化学相互作用。结论：维生素 C 直接与 PS-431 结合，从而使 PS-341 失活，而与其抗氧化活性无关。我们的研究结果表明，维生素 C 可能会对 PS-341 介导的抗癌活性产生负面影响。
Purpose: PS-341 (bortezomib,Velcade), the first proteasome inhibitor approved by the Food and Drug Administration for the treatment of patients with relapsed multiple myeloma, induces apoptosis in human cancer cell lines. Vitamin C (ascorbic acid) is an essential water-soluble vitamin required for many normal physiologic functions and has to be obtained through diet or supplemental tablets in humans. Here we studied the potential effect of vitamin C on the anticancer activity of PS-341 in human cancer cell lines.Experimental Design: The effects of vitamin C on apoptosis induction by PS-341 alone and by PS-341 combined with tumor necrosis factor-related apoptosis-inducing ligand were studied. In addition, the effects of vitamin C and other antioxidants on PS-341-mediated proteasome inhibition were also examined. Finally, the direct chemical interaction between vitamin C and PS-341 was determined.Results: Vitamin C abrogated the ability of PS-341 to induce apoptosis in various human cancer cell lines, to induce G(2)-M arrest, and to augment apoptosis induced by tumor necrosis factor-related apoptosis-inducing ligand. Moreover, vitamin C suppressed PS-341-mediated inhibition of proteasome activity. PS-341 itself did not induce generation of intracellular reactive oxygen species whereas other antioxidants failed to abrogate its biological activity. Importantly, we detected a direct chemical interaction between vitamin C and PS-341.Conclusion: Vitamin C directly binds to PS-431, thus inactivating PS-341 independent of its antioxidant activity. Our findings suggest that vitamin C may have a negative effect on PS-341-mediated anticancer activity.