Alpha tocopheryl succinate, retinoic acid and polar carotenoids enhanced the growth-inhibitory effect of a cholesterol-lowering drug on immortalized and transformed nerve cells in culture

Objective: Statins (cholesterol lowering drugs) with a closed-ring structure (lovastatin, simvastatin and mevastatin) and an open-ring structure (pravastatin and fluvastatin) are currently used in the management of cardiac disease. Lovastatin and simvastatin inhibit the growth of tumor cells; however, the studies on the effect of a statin in combination with micronutrients such as alpha-tocopheryl succinate (alpha-TS), 13-cis retinoic acid (RA) and polar carotenoids (PC) have never been performed. The primary objective of this study was to investigate the effect of mevastatin alone and in combination with the above micronutrients on the growth of mouse neuroblastoma (NB) cells and rat immortalized dopamine (DA) neurons in culture. In addition, a comparative efficacy of mevastatin and pravastatin on the growth of NB cells was studied. Methods: Cells were treated with mevastatin in combination with individual antioxidants, alpha-TS, RA and polar carotenoids, 24 hours after plating. Fresh growth medium and agents were changed at two days after treatment, and the viability in control and experimental groups was determined at three days after treatment by MTT assay. Each experiment was repeated three times with triplicate samples per treatment. Growth in experimental groups was expressed as % of untreated cells. Results: Mevastatin inhibited the growth of neuroblastoma (NB) cells and immortalized, non-tumorigenic dopamine (DA) neurons in culture in a dose-dependent manner. Immortalized DA neurons were more sensitive to mevastatin than NB cells. Pravastatin at similar concentrations was ineffective in inhibiting the growth of NB cells. Mevastatin in combination with alpha-TS, RA or PC was more effective in reducing the growth of NB and DA neurons than the individual agents. Conclusions: Statins with a closed-ring structure can inhibit the growth of established cancer cells as well as immortalized cells (equivalent to pre-malignant lesion), whereas statins with an open-ring structure may be ineffective. A combination of a statin having a closed-ring structure with alpha-TS, RA and PC may be one of the potentially useful anti-cancer agents for prevention and treatment strategies.