Chen Ping, Lamson Davis, Anderson Paul, Drisko Jeanne, Chen Qi
Department of Pharmacology, Toxicology, and Therapeutics, University of Kansas School of Medicine, Kansas City, KS, USA.
School of Naturopathic Medicine, Bastyr University, Kenmore, WA, USA.
Clin Med Insights Oncol. 2024 Oct 31;18:11795549241283421. doi: 10.1177/11795549241283421. eCollection 2024.
Intravenous vitamin C (IVC, ascorbate [Asc]) and alpha-lipoic acid (ALA) are frequently coadministered in integrative oncology clinics, with limited understanding of combination effects or drug-drug interactions. As high-dose IVC has anticancer activity through peroxide (HO), it is hypothesized that IV ALA, a thiol antioxidant, might have untoward effects when combined with IVC.
In vitro combination index (CI) was investigated in 6 types of human cancer cells, using clinically relevant concentrations of Asc (0.625-20 mM) and ALA (0.25, 0.5, and 1 mM) evaluated by nonconstant ratio metrics. Cellular HO was measured using HeLa cells expressing a fluorescent probe HyPer. Mouse xenografts of the metastatic breast cancer MDA-MB-231 were treated with intraperitoneal injections of ALA (10, 20, and 50 mg/kg) and Asc (0.2, 0.5, and 4 g/kg) at various dose levels.
Cancer cell lines were sensitive to Asc treatment but not to ALA. There is no evidence ALA becomes a prooxidant at higher doses. The CIs showed a mixture of synergistic and antagonistic effects with different ALA and Asc combination ratios, with a "U" shape response to Asc concentrations. The ALA concentrations did not influence the CIs or cellular HO formation. Adding ALA to Asc dampened the increase of HO. Toxicity was observed in mice receiving prolonged treatment of ALA at all doses. The Asc at all doses was nontoxic. The combination of ALA and Asc increased toxicity. The ALA at all doses did not inhibit tumor growth. The Asc at 4 g/kg inhibited tumor growth. Adding ALA 50 mg/kg to Asc 4 g/kg did not enhance the effect, but lower doses of ALA (10 or 20 mg/kg) dampened the inhibitory effect of Asc.
These data do not support the concurrent or relative concurrent use of high-dose intravenous ALA with prooxidative high-dose IVC in clinical oncology care with potentially increased toxicity.
在综合肿瘤诊所中，静脉注射维生素C（IVC，抗坏血酸盐[Asc]）和α-硫辛酸（ALA）经常联合使用，但对联合效果或药物相互作用的了解有限。由于高剂量IVC通过过氧化物（HO）具有抗癌活性，因此推测作为硫醇抗氧化剂的静脉注射ALA与IVC联合使用时可能会产生不良影响。
使用临床相关浓度的Asc（0.625 - 20 mM）和ALA（0.25、0.5和1 mM），通过非恒定比例指标在6种人类癌细胞中研究体外联合指数（CI）。使用表达荧光探针HyPer的HeLa细胞测量细胞内HO。转移性乳腺癌MDA-MB-231的小鼠异种移植瘤在不同剂量水平下接受腹腔注射ALA（10、20和50 mg/kg）和Asc（0.2、0.5和4 g/kg）治疗。
癌细胞系对Asc治疗敏感，但对ALA不敏感。没有证据表明高剂量的ALA会成为促氧化剂。CI显示不同ALA和Asc组合比例具有协同和拮抗作用的混合，对Asc浓度呈“U”形反应。ALA浓度不影响CI或细胞内HO的形成。在Asc中添加ALA可抑制HO的增加。在接受所有剂量ALA长期治疗的小鼠中观察到毒性。所有剂量的Asc均无毒。ALA和Asc的组合增加了毒性。所有剂量的ALA均未抑制肿瘤生长。4 g/kg的Asc抑制肿瘤生长。在4 g/kg的Asc中添加50 mg/kg的ALA并未增强效果，但较低剂量的ALA（10或20 mg/kg）会减弱Asc的抑制作用。
这些数据不支持在临床肿瘤治疗中同时或相对同时使用高剂量静脉注射ALA和具有促氧化作用的高剂量IVC，因为这可能会增加毒性。
