Dramatic synergistic anticancer effect of clinically achievable doses of lovastatin and troglitazone

Abstract

Lovastatin (an HMG-CoA reductase inhibitor) and troglitazone (a PPAR-c agonist) have been intensively studied prospectively for their application in cancer treatment. However, clinical trials of lovastatin or troglitazone in cancer treatment resulted in only limited responses. To improve their efficacy, lovastatin and troglitazone have, respectively, been tried to combine with other anticancer agents with varied outcomes. In our study, we found a dramatic synergism between lovastatin and troglitazone in anticancer at clinically achievable concentrations. This synergism was found in far majority of cell lines tested including DBTRG 05 MG (glioblastoma) and CL1-0 (lung). This amazing synergism was accompanied by synergistic modulation of E2F-1 and p27 Kip1, which were reported to mediate the anticancer activities of lovastatin and troglitazone, respectively, and other cell cycle regulating proteins such as CDK2, cyclin A and RB phosphorylation status. With this dramatic combination effect of lovastatin and troglitazone, a promising regimen of cancer therapy may be materialized in the future. ' 2005 Wiley-Liss, Inc.Key words: lovastatin; HMG-CoA reductase; PPAR-gamma; synergism; troglitazone; statin The statin family drugs inhibit HMG-CoA reductase, the ratelimiting enzyme of the mevalonate (MVA) pathway, and are used clinically as safe and effective medicines in hypercholesterolemia. In addition to their primary use, the anticancer activity of statins were intensively studied and several phase I-II clinical trials have been conducted. 1 However, the overall response rates in these trials were limited.1 Troglitazone, a thiazolinedione type peroxisome proliferator-activated receptor g (PPARg) agonist, was also found to exhibit anticancer activity 2 besides its primary use in improving insulin sensitivity in type 2 diabetes mellitus patients. Clinical trials of troglitazone have been conducted in patients with metastatic colon cancer and refractory breast cancer; however, these trials also failed to produce effective outcomes. 3,4 To improve the efficacy of lovastatin and troglitazone, they have respectively been tried to combine with other anticancer agents with varied outcomes. Recently, Hsu et al.5 tried to improve the troglitazoneinduced anticancer activity by the addition of 9-cis-retinoic acid or cytotoxic anticancer agents; however, no synergistic effect was found in hepatocellular carcinoma cells. Identification of agents that can synergize with statins or troglitazone may substantially improve their application in cancer clinic. With this in mind, we have found that the combination of clinically achievable concentrations of lovastatin and troglitazone can produce a dramatic synergistic effect against a broad spectrum of cancer cell lines. This synergism was quantified by the combination index (CI) method of Chou and Talalay 6 and was at least partially ascribed to the production of synergistic changes in cell cycle-regulating proteins such as cyclin-dependent kinase 2 (CDK2), cyclin A, p27 Kip1 , E2F-1 and ...

Ciglitazone, an agonist of peroxisome proliferator-activated receptor γ, exerts potentiated cytostatic/cytotoxic effects against tumor cells when combined with lovastatin

“…It has recently been demonstrated that lovastatin significantly potentiates antitumor effects of troglitazone against lung, prostate, pancreas, and uterine cancer cells as well as against glioblastoma cells in vitro (27). Here we have extended these studies by showing that lovastatin can also effectively potentiate cytostatic/cytotoxic effects of ciglitazone, another thiazolidinedione against mammary, colon, and pancreas carcinomas and, to a lesser degree, against osteosarcoma cells (data not shown).…”

Anti-cancer characteristics of mevinolin against three different solid tumor cell lines was not solely p53-dependent

“…The safety profile of MVN both in experimental and clinical stages were encouraging for further clinical trials for the treatment of various types of tumors. The dose of MVN suggested for anti-cancer treatments was believed to be clinically safe 6,7 . Therefore, very high doses of MVN administered every four hours to patients have been found tolerable 23 .…”

“…Mevinolin (MVN) or lovastatin was a potent HMGCo-A reductase enzyme inhibitor that interfered with de novo steroidogenesis 5 . MVN was used clinically for the treatment of hypercholesterolemia with very good patient tolerance profiles 6,7 . In the last decade, several epidemiological evidences have drawn attention to possible beneficial roles of research artIcle Anti-cancer characteristics of mevinolin against three different solid tumor cell lines was not solely p53-dependent HMGCo-A reductase inhibitors (statins), such as MVN, in neoblastic disorders.…”

Interaction of Factors Related to the Metabolic Syndrome and Vitamin D on Risk of Prostate Cancer

“…Lately, combinations of treatments against metabolic syndrome and diabetes, the statins and the glitazones, have been found to have powerful anticancer effects (59,60). Vitamin D may be one possible component (45).…”