Perrone G, Hideshima T, Ikeda H, Okawa Y, Calabrese E, Gorgun G, Santo L, Cirstea D, Raje N, Chauhan D, Baccarani M, Cavo M, Anderson K C
Department of Medical Oncology, LeBow Institute for Myeloma Therapeutics and Jerome Lipper Myeloma Center, Harvard Medical School, Dana-Farber Cancer Institute, Boston, MA 02115, USA.
Leukemia. 2009 Sep;23(9):1679-86. doi: 10.1038/leu.2009.83. Epub 2009 Apr 16.
Earlier studies have shown that ascorbic acid (vitamin C) inhibits bortezomib-induced cytotoxicity against cancer cells in vitro. However, the clinical significance of vitamin C on bortezomib treatment is unclear. In this study, we examined whether daily oral intake of vitamin C inhibits antimultiple myeloma (MM) activities of bortezomib. Vitamin C, at orally achievable concentrations, inhibited in vitro MM cell cytotoxicity of bortezomib and blocked its inhibitory effect on 20S proteasome activity. Specifically, plasma collected from healthy volunteers taking 1 g/day vitamin C reduced bortezomib-induced MM cell death in vitro. This antagonistic effect of vitamin C against proteasome inhibitors is limited to the boronate class of inhibitors (bortezomib and MG262). In vivo activity of this combination treatment was then evaluated using our xenograft model of human MM in SCID (severe combined immune-deficient) mice. Bortezomib (0.1 mg/kg twice a week for 4 weeks) significantly inhibits in vivo MM cell growth, which was blocked by oral vitamin C (40 mg/kg/day). Therefore, our results for the first time show that vitamin C can significantly reduce the activity of bortezomib treatment in vivo; and importantly, suggest that patients receiving treatment with bortezomib should avoid taking vitamin C dietary supplements.
早期研究表明，抗坏血酸（维生素C）在体外可抑制硼替佐米对癌细胞的细胞毒性作用。然而，维生素C对硼替佐米治疗的临床意义尚不清楚。在本研究中，我们检测了每日口服维生素C是否会抑制硼替佐米的抗多发性骨髓瘤（MM）活性。在口服可达到的浓度下，维生素C抑制了硼替佐米在体外对MM细胞的细胞毒性，并阻断了其对20S蛋白酶体活性的抑制作用。具体而言，从每日服用1g维生素C的健康志愿者采集的血浆在体外减少了硼替佐米诱导的MM细胞死亡。维生素C对蛋白酶体抑制剂的这种拮抗作用仅限于硼酸酯类抑制剂（硼替佐米和MG262）。然后，我们使用人MM的SCID（严重联合免疫缺陷）小鼠异种移植模型评估了这种联合治疗的体内活性。硼替佐米（0.1mg/kg，每周两次，共4周）显著抑制体内MM细胞生长，而口服维生素C（40mg/kg/天）可阻断这一作用。因此，我们的结果首次表明，维生素C可显著降低硼替佐米在体内的治疗活性；重要的是，提示接受硼替佐米治疗的患者应避免服用维生素C膳食补充剂。
