In vitro and in vivo anticancer effects of mevalonate pathway modulation on human cancer cells

• Published in: British journal of cancer 2014-10, Vol.111 (8), p.1562-1571
• Main Authors: Jiang, P, Mukthavaram, R, Chao, Y, Nomura, N, Bharati, I S, Fogal, V, Pastorino, S, Teng, D, Cong, X, Pingle, S C, Kapoor, S, Shetty, K, Aggrawal, A, Vali, S, Abbasi, T, Chien, S, Kesari, S
• Format: Article
• Language: English
• Subjects: 631/67/1059/99; 631/67/1347; 631/67/1922; Animals; Antineoplastic Agents - pharmacology; Autophagy; Autophagy - drug effects; Biological and medical sciences; Biomedical and Life Sciences; Biomedicine; Brain cancer; Brain Neoplasms - drug therapy; Brain Neoplasms - metabolism; Brain Neoplasms - pathology; Breast cancer; Breast Neoplasms - drug therapy; Breast Neoplasms - metabolism; Breast Neoplasms - pathology; Cancer Research; Cancer therapies; Cell cycle; Cell Line, Tumor; Cell Proliferation - drug effects; Cholesterol; Computer Simulation; Disease Models, Animal; Drug Resistance; Drugs; Epidemiology; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors - pharmacology; Hydroxymethylglutaryl-CoA Reductase Inhibitors - therapeutic use; In Vitro Techniques; Medical research; Medical sciences; Mevalonic Acid - metabolism; Mice; Mice, Nude; Molecular Medicine; Multiple tumors. Solid tumors. Tumors in childhood (general aspects); Neurology; Oncology; Software; Statins; Stem cells; Translational Therapeutics; Tumors; Tumors of the nervous system. Phacomatoses
• ISSN: 0007-0920; 1532-1827
• DOI: 10.1038/bjc.2014.431

Background: The increasing usage of statins (the 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors) has revealed a number of unexpected beneficial effects, including a reduction in cancer risk. Methods: We investigated the direct anticancer effects of different statins approved for clinical use on human breast and brain cancer cells. We also explored the effects of statins on cancer cells using in silico simulations. Results: In vitro studies showed that cerivastatin, pitavastatin, and fluvastatin were the most potent anti-proliferative, autophagy inducing agents in human cancer cells including stem cell-like primary glioblastoma cell lines. Consistently, pitavastatin was more effective than fluvastatin in inhibiting U87 tumour growth in vivo . Intraperitoneal injection was much better than oral administration in delaying glioblastoma growth. Following statin treatment, tumour cells were rescued by adding mevalonate and geranylgeranyl pyrophosphate. Knockdown of geranylgeranyl pyrophosphate synthetase-1 also induced strong cell autophagy and cell death in vitro and reduced U87 tumour growth in vivo . These data demonstrate that statins main effect is via targeting the mevalonate synthesis pathway in tumour cells. Conclusions: Our study demonstrates the potent anticancer effects of statins. These safe and well-tolerated drugs need to be further investigated as cancer chemotherapeutics in comprehensive clinical studies.