OPEN IN READ APP
JOURNAL ARTICLE

Thiazolidinediones/PPARγ agonists and fatty acid synthase inhibitors as an experimental combination therapy for prostate cancer

Mahmoud Mansour, Dean Schwartz, Robert Judd, Benson Akingbemi, Tim Braden, Edward Morrison, John Dennis, Frank Bartol, Amanda Hazi, India Napier, Asim B Abdel-Mageed
International Journal of Oncology 2011, 38 (2): 537-46
21170507
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.

Discussion

You are not logged in. Sign Up or Log In to join the discussion.

Related Papers

Available on the App Store

Available on the Play Store
Remove bar
Read by QxMD icon Read
21170507
×

Search Tips

Use Boolean operators: AND/OR

diabetic AND foot
diabetes OR diabetic

Exclude a word using the 'minus' sign

Virchow -triad

Use Parentheses

water AND (cup OR glass)

Add an asterisk (*) at end of a word to include word stems

Neuro* will search for Neurology, Neuroscientist, Neurological, and so on

Use quotes to search for an exact phrase

"primary prevention of cancer"
(heart or cardiac or cardio*) AND arrest -"American Heart Association"