Service de Radiothérapie Hôpital Pitié-Salpétrière, bd. de l'Hôpital, 75013 Paris, France.
Oncol Rep. 2010 May;23(5):1407-16. doi: 10.3892/or_00000778.
The impact of metabolic dysregulation on tumor development has long been established. We have targeted two enzymes that are altered during carcinogenesis: pyruvate dehydrogenase (PDH), which is down-regulated, and ATP citrate lyase, which is overexpressed in cancer cells. Alpha lipoic acid is a cofactor of PDH, while hydroxycitrate is a known inhibitor of ATP citrate lyase. Our hypothesis is that a combination of these drugs may have antitumoral potential. The efficacy of these molecules was screened in vitro by treatment of different human cancer and murine cell lines. Lipoic acid reduced the cell number by 10-50% depending on concentrations (0.1-10 microM) and cell types. Calcium hydroxycitrate reduced the cell number by 5-60% at different concentrations (10-500 microM). When hydroxycitrate and lipoic acid were used together, there was a major cytotoxic effect: complete cell death was seen following 8 microM lipoic acid and 300 microM hydroxycitrate treatment for 72 h. The combination of alpha lipoic acid and hydroxycitrate was administered to healthy mice, at doses currently utilized for other indications than cancer; no demonstrable toxicity was observed. The combination was used to treat mouse syngenic cancer models: MBT-2 bladder transitional cell carcinoma, B16-F10 melanoma and LL/2 Lewis lung carcinoma. The efficacy of this combination appears similar to conventional chemotherapy (cisplatin or 5-fluorouracil) as it resulted in significant tumor growth retardation and enhanced survival. This preliminary study suggests that this combination of drugs is efficient against cancer cell proliferation both in vitro and in vivo. A clinical trial is warranted.
代谢失调对肿瘤发展的影响早已确立。我们针对两种在癌变过程中发生改变的酶：丙酮酸脱氢酶（PDH），其表达下调，以及三磷酸柠檬酸裂解酶，其在癌细胞中过表达。α-硫辛酸是 PDH 的辅助因子，而羟基柠檬酸是三磷酸柠檬酸裂解酶的已知抑制剂。我们的假设是，这些药物的组合可能具有抗肿瘤潜力。这些分子的疗效通过不同的人类癌症和鼠细胞系的体外治疗进行筛选。根据浓度（0.1-10 μM）和细胞类型的不同，硫辛酸使细胞数量减少 10-50%。在不同浓度（10-500 μM）下，羟基柠檬酸使细胞数量减少 5-60%。当羟基柠檬酸和硫辛酸一起使用时，会产生主要的细胞毒性作用：在用 8 μM 硫辛酸和 300 μM 羟基柠檬酸处理 72 小时后，观察到完全的细胞死亡。将α-硫辛酸和羟基柠檬酸组合施用于健康小鼠，剂量目前用于癌症以外的其他适应症；未观察到明显的毒性。该组合用于治疗小鼠同源性癌症模型：MBT-2 膀胱移行细胞癌、B16-F10 黑色素瘤和 LL/2 肺腺癌。该组合的疗效与传统化疗（顺铂或 5-氟尿嘧啶）相似，因为它导致肿瘤生长明显延迟和生存率提高。这项初步研究表明，该药物组合在体外和体内均能有效抑制癌细胞增殖。需要进行临床试验。
