title: Inhibition of beta-oxidative respiration is a therapeutic window associated with the cancer chemo-preventive activity of PPARgamma agonists.
abstract: We demonstrate expression and coordinate induction of PPARgamma and lipogenic enzymes (HMG-CoA synthase, HMG-CoA reductase and fatty acid synthase) in a murine lung alveolar carcinoma cell line (Line 1) treated with the PPARgamma agonist troglitazone (TRO) [0-100 microM]. We postulate that TRO induces a shift in cellular energy metabolism towards fatty acid oxidation (beta-oxidative respiration). Accordingly, co-treatment with TRO [30 microM] and increasing concentrations of trimetazidine (TMZ) [0.1-3 mM], an inhibitor of beta-oxidation, results in a dose dependent decrease cellular ATP levels and a dose dependent induction of apoptosis. These findings, suggest that inhibition of beta-oxidative respiration is a therapeutic window associated with the cancer chemo-preventive activity of PPARgamma agonists.
authors.affiliation: The James P Wilmot Cancer Center and the Department of Orthopaedics, University of Rochester Medical Center, 601 Elmwood Avenue Box 665 Rochester, NY 14642, USA. valentine_andela@urmc.rochester.edu
authors.forename: Valentine B
authors.initials: VB
authors.lastname: Andela
authors.forename: Saleh
authors.initials: S
authors.lastname: Altuwaijri
authors.forename: James
authors.initials: J
authors.lastname: Wood
authors.forename: Randy N
authors.initials: RN
authors.lastname: Rosier
mesh_terms: D002282:Adenocarcinoma, Bronchiolo-Alveolar / Q000378:metabolism / Q000517:prevention & control; D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D017209:Apoptosis; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D019069:Cell Respiration / Q000187:drug effects; D002839:Chromans / Q000494:pharmacology*; D003066:Coenzyme A Ligases / Q000235:genetics / Q000378:metabolism; D064429:Fatty Acid Synthases / Q000235:genetics / Q000378:metabolism; D005227:Fatty Acids / Q000378:metabolism*; D015870:Gene Expression / Q000187:drug effects; D005947:Glucose / Q000378:metabolism; D006903:Hydroxymethylglutaryl CoA Reductases / Q000235:genetics / Q000378:metabolism; D006904:Hydroxymethylglutaryl-CoA Synthase; D008175:Lung Neoplasms / Q000378:metabolism / Q000517:prevention & control; D051379:Mice; D009374:Neoplasms, Experimental / Q000378:metabolism*; D010084:Oxidation-Reduction / Q000187:drug effects; D010101:Oxygen Consumption / Q000187:drug effects; D047495:PPAR gamma / Q000819:agonists* / Q000502:physiology; D045162:Thiazolidinediones / Q000494:pharmacology*; D014292:Trimetazidine / Q000494:pharmacology*; D000077288:Troglitazone
chemical_list: D000970:Antineoplastic Agents; D002839:Chromans; D005227:Fatty Acids; D047495:PPAR gamma; D045162:Thiazolidinediones; D000255:Adenosine Triphosphate; D006903:Hydroxymethylglutaryl CoA Reductases; D064429:Fatty Acid Synthases; D006904:Hydroxymethylglutaryl-CoA Synthase; D003066:Coenzyme A Ligases; D000077288:Troglitazone; D005947:Glucose; D014292:Trimetazidine