1. Inhibition of mevalonate biosynthesis in rat C6 glioma by simvastatin confers sensitization to Carmustine by increasing G2/M and apoptosis

R. Baetta, R. Paoletti, R. Fumagalli, M. R. Soma

Research output: Contribution to journalArticle

Abstract

In a previous study, we provided in vitro and in vivo evidence that inhibition of intracellular mevalonate (MVA) biosynthesis by simvastatin (S) a hypocholesterolemic drug, resulted in a profound retardation of glioma C6 growth. Moreover, specifically and sinergistically enhanced the sensitivity of C6 glioma to carmustine (BCNU), a classical chemotherapeutic agent. This permitted the use of several-fold lower doses carmustine to achieve the same inihibition of C6 glioma growth in vivo, resulting in a lower systemic toxicity. The effect of drug combination could be completely reversed by MVA addition to the cultured cells, indicating that MVA or one of its products was directly involved in the synergy observed. The basis for the observed synergism is still unclear; however, the in vitro results allowed some hypotheses. The combination of S and BCNU, at concentrations uneffective as single agents, produced a specific arrest or retardation of C6 glioma cells in the G2/M phase of the cell cycle followed by massive apoptosis as assessed by cell cycle distribution and DNA fragmentation analyses. This indicates programmed cell death as a possible mechanism for the synergistic activity. Furthermore, the pro-apoptotic effect observed for the drug combination was mediated by a MVA-derived molecule since MVA addition completely prevented apoptosis in C6 cells simultaneously exposed to BCNU and S. Several in vitro and preclinical evidences support the hypothesis of utilizing HMGCoA reductase alone for tumor treatment. More recently a phase I study on lovastatin in glioma patients has been reported. The clinical outcome together with in vitro observation favor an uninterrupted administration of high doses of an HMGCoA reductase inhibitor to maintain biological activity by sustained MVA pathway inhibition. Therefore, undesirable toxicity would likely results, hence precluding their use in cancer therapy. Based on our results the alternative strategy to improve the therapeutic index of HMGCoA reductase inhibitors is the use of drug combinations which permit side effect-free remission against tumors. Thus this class of drugs merit further investigation as potential coadjuvant agents in the chemotherapy of these otherwise devastating tumors.

Original languageEnglish
Pages (from-to)241
Number of pages1
JournalItalian Journal of Neurological Sciences
Volume18
Issue number4
Publication statusPublished - 1997

ASJC Scopus subject areas

  • Neuroscience(all)
  • Clinical Neurology

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