PPARγ potentiates anticancer effects of gemcitabine on human pancreatic             cancer cells.
In order to improve the prognosis of patients with unresectable pancreatic             cancer, there is an urgent need for enhancement of the anticancer effect of gemcitabine             (Gem), a first-line drug for the disease. Here, we demonstrated that ligands for             peroxisome proliferator-activated receptor γ (PPARγ) such as pioglitazone (Pio)             and rosiglitazone potentiated the cytotoxic action of Gem on human pancreatic             cancer cells in a dosage-dependent manner. Notably, the synergistic effect was             PPARγ-dependent, since the effect was augmented by PPARγ overexpression and was             attenuated by both a PPARγ inhibitor (GW9662) and PPARγ-specific siRNA. To further             increase the collaborative effect, the histone deacetylase (HDAC) inhibitor valproic             acid (VPA), a known potentiator for PPARγ function, was added to the combinatorial             treatment, robustly inducing apoptosis mediated by highly expressed death receptors,             including Fas/CD95 and DR5. In xenograft tumor experiments in nude mice, Gem plus             Pio significantly suppressed tumor growth as compared with the control treatment,             while Gem-only treatment did not. Triple treatment with Gem, Pio, and VPA failed             to demonstrate a significant antitumor effect when compared with Gem plus Pio             in the current setting. Considered together, Gem plus PPARγ ligands, including             Pio, may have therapeutic advantage in the treatment of advanced pancreatic cancer.             Since Pio is widely used in the treatment of diabetes mellitus, it may become             a feasible partner of Gem-based chemotherapy, fine-tuning the strength of the             therapy in a dosage-dependent fashion.
Department of Medicine, Kurume University School of Medicine, Kurume, Japan. hirokoga@med.kurume-u.ac.jp
Hironori
H
Koga
Karuppaiyah
K
Selvendiran
Ramadoss
R
Sivakumar
Takafumi
T
Yoshida
Takuji
T
Torimura
Takato
T
Ueno
Michio
M
Sata
D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D045744:Cell Line, Tumor; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives; D006655:Histone Deacetylases / Q000378:metabolism; D006801:Humans; D008024:Ligands; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism; D047495:PPAR gamma / Q000235:genetics / Q000378:metabolism*; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism*; D000077205:Pioglitazone; D053218:Receptors, Death Domain / Q000378:metabolism; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000378:metabolism; D000077154:Rosiglitazone; D045162:Thiazolidinediones / Q000008:administration & dosage; D014635:Valproic Acid / Q000008:administration & dosage; D023041:Xenograft Model Antitumor Assays / Q000379:methods; D019014:fas Receptor / Q000378:metabolism; D000093542:Gemcitabine
D008024:Ligands; D016328:NF-kappa B; D047495:PPAR gamma; D053218:Receptors, Death Domain; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D045162:Thiazolidinediones; D019014:fas Receptor; D000077154:Rosiglitazone; D003841:Deoxycytidine; D014635:Valproic Acid; D006655:Histone Deacetylases; D000077205:Pioglitazone; D000093542:Gemcitabine