title: Thiazolidinediones/PPARγ agonists and fatty acid synthase inhibitors as an experimental combination therapy for prostate cancer.
abstract: The prostate cancer (PCa) cell lines LNCaP, PC-3, and DU-145 express peroxisome proliferator-activated receptor γ (PPARγ) but its role in PCa is unclear. Thiazolidinediones (TZDs), a family of PPARγ activators and type 2 anti-diabetic drugs, exhibit anti-tumor apoptotic effects in human PCa cell lines. Likewise, pharmacological inhibitors of fatty acid synthase (FASN), a metabolic enzyme highly expressed in PCa, induce apoptosis in prostate and other cancer cells. Here, we show positive correlation between PPARγ and FASN protein in PCa cell lines and synergism between TZDs and FASN blockers in PCa cell viability reduction and apoptosis induction. Combined TZDs/FASN has enhanced anti-tumor properties in both androgen-dependent LNCaP and androgen-independent PC-3 and DU-145 cells when compared with single drug exposure. Low concentrations (5-10 μM) of the TZD drug rosiglitazone failed to alter cell viability but, paradoxically, upregulated lipogenic genes [PPARγ, FASN, sterol regulatory element binding protein-1c (SREBP-1c) and acetyl-Co A carboxylase-1 (ACC1)], which diminish the apoptotic effects of rosiglitazone. The mean IC50 in all cell lines was 45 ± 2 μM for rosiglitazone compared with significantly lower 5 ± 1 μM for rosiglitazone plus the FASN blocker cerulenin, and 10.2 ± 2 μM for rosiglitazone plus the cerulenin synthetic analog C75. The IC50 for the combined rosiglitazone and FASN blockers contrasts with the relatively higher IC50 for rosiglitazone (45 ± 2 μM), the TZD drug troglitazone (13 ± 2 μM), cerulenin (32 ± 1 μM), or C75 (26 ± 3 μM) when these drugs were used alone. In summary, this study shows proof-of-principle for combining FASN blockers and TZDs for PCa treatment.
authors.affiliation: Department of Anatomy, College of Veterinary Medicine, Auburn University, Auburn, AL 36849, USA. mansoma@auburn.edu
authors.forename: Mahmoud
authors.initials: M
authors.lastname: Mansour
authors.forename: Dean
authors.initials: D
authors.lastname: Schwartz
authors.forename: Robert
authors.initials: R
authors.lastname: Judd
authors.forename: Benson
authors.initials: B
authors.lastname: Akingbemi
authors.forename: Tim
authors.initials: T
authors.lastname: Braden
authors.forename: Edward
authors.initials: E
authors.lastname: Morrison
authors.forename: John
authors.initials: J
authors.lastname: Dennis
authors.forename: Frank
authors.initials: F
authors.lastname: Bartol
authors.forename: Amanda
authors.initials: A
authors.lastname: Hazi
authors.forename: India
authors.initials: I
authors.lastname: Napier
authors.forename: Asim B
authors.initials: AB
authors.lastname: Abdel-Mageed
mesh_terms: D000728:Androgens / Q000494:pharmacology; D000971:Antineoplastic Combined Chemotherapy Protocols; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D002470:Cell Survival / Q000187:drug effects; D002839:Chromans / Q000494:pharmacology*; D004797:Enzyme-Linked Immunosorbent Assay; D054890:Fatty Acid Synthase, Type I / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology; D008297:Male; D009376:Neoplasms, Hormone-Dependent / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D047495:PPAR gamma / Q000819:agonists* / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D012333:RNA, Messenger / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000077154:Rosiglitazone; D051780:Sterol Regulatory Element Binding Protein 1 / Q000378:metabolism; D045162:Thiazolidinediones / Q000494:pharmacology*; D000077288:Troglitazone; D014407:Tumor Cells, Cultured; D014665:Vasodilator Agents / Q000494:pharmacology
chemical_list: D000728:Androgens; D002839:Chromans; D007004:Hypoglycemic Agents; D047495:PPAR gamma; D012333:RNA, Messenger; D051780:Sterol Regulatory Element Binding Protein 1; D045162:Thiazolidinediones; D014665:Vasodilator Agents; D000077154:Rosiglitazone; C518729:FASN protein, human; D054890:Fatty Acid Synthase, Type I; D000077288:Troglitazone