Dramatic synergistic anticancer effect of clinically achievable doses of lovastatin and troglitazone.
Lovastatin (an HMG-CoA reductase inhibitor) and troglitazone (a PPAR-gamma 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.
Yao
Chih-Jung
CJ
Division of Cancer Research, National Health Research Institutes, Taipei, Taiwan.
Lai
Gi-Ming
GM
Chan
Chin-Feng
CF
Cheng
Ann-Lii
AL
Yang
Ya-Yu
YY
Chuang
Shuang-En
SE
D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D001932:Brain Neoplasms / Q000188:drug therapy / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects*; D002839:Chromans / Q000008:administration & dosage; D019925:Cyclin A / Q000378:metabolism; D051357:Cyclin-Dependent Kinase 2 / Q000378:metabolism; D050760:Cyclin-Dependent Kinase Inhibitor p27; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D050687:E2F1 Transcription Factor / Q000378:metabolism; D005909:Glioblastoma / Q000188:drug therapy / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D008148:Lovastatin / Q000008:administration & dosage; D008175:Lung Neoplasms / Q000188:drug therapy / Q000378:metabolism; D008297:Male; D010190:Pancreatic Neoplasms / Q000188:drug therapy / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000378:metabolism; D016160:Retinoblastoma Protein / Q000378:metabolism; D045162:Thiazolidinediones / Q000008:administration & dosage; D000077288:Troglitazone; D014407:Tumor Cells, Cultured / Q000187:drug effects
D002839:Chromans; D019925:Cyclin A; D050687:E2F1 Transcription Factor; C493753:E2F1 protein, human; D016160:Retinoblastoma Protein; D045162:Thiazolidinediones; D050760:Cyclin-Dependent Kinase Inhibitor p27; D008148:Lovastatin; C495894:CDK2 protein, human; D051357:Cyclin-Dependent Kinase 2; D000077288:Troglitazone