Lovastatin induces neuronal differentiation and apoptosis of embryonal carcinoma and neuroblastoma cells: enhanced differentiation and apoptosis in combination with dbcAMP.
Differentiation-based therapeutics are an underutilized but a potentially significant treatment option for cancer patients. We show that lovastatin, a competitive inhibitor of the rate-limiting enzyme of mevalonate synthesis HMG-CoA reductase, is able to induce tumour cell differentiation and apoptosis in vitro. We used embryonal carcinoma (EC) and neuroblastoma (NB) cell lines and found that lovastatin promoted apoptosis and induced expression of the neuronal differentiation markers, tyrosine hydroxylase (TH), and growth-associated protein 43. The apoptotic and differentiation responses were time and dose-dependant and rescued by the co-administration of mevalonate. The expression of TH is regulated primarily by a cyclic AMP (cAMP) response element (CRE) in its promoter. Lovastatin enhanced the expression of a CRE-driven luciferase construct in P19 cells. Furthermore, combining lovastatin with 1 mM dibutyryladenosine 3',5'-cyclic monophosphate treatments induced higher expression from the CRE construct, enhanced differentiation and cytotoxicity. This study suggests the potential of combining these therapeutic approaches in EC and NB patients.
Arnold
Danielle E
DE
Centre for Cancer Therapeutics, The Ottawa Hospital Research Institute, Ottawa Regional Cancer Centre, 503 Smyth Road, Third Floor, Ottawa, ON, K1H 1C4, Canada.
Gagne
Celine
C
Niknejad
Nima
N
McBurney
Michael W
MW
Dimitroulakos
Jim
J
D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D003994:Bucladesine / Q000494:pharmacology* / Q000627:therapeutic use; D018236:Carcinoma, Embryonal / Q000188:drug therapy*; D002454:Cell Differentiation / Q000187:drug effects*; D000242:Cyclic AMP / Q000235:genetics; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D006801:Humans; D008148:Lovastatin / Q000494:pharmacology* / Q000627:therapeutic use; D009447:Neuroblastoma / Q000188:drug therapy*; D020218:Response Elements / Q000187:drug effects; D014407:Tumor Cells, Cultured; D014446:Tyrosine 3-Monooxygenase / Q000235:genetics
D000970:Antineoplastic Agents; D003994:Bucladesine; D008148:Lovastatin; D000242:Cyclic AMP; D014446:Tyrosine 3-Monooxygenase