Open Access

PPARγ potentiates anticancer effects of gemcitabine on human pancreatic cancer cells

  • Authors:
    • Hironori Koga
    • Karuppaiyah Selvendiran
    • Ramadoss Sivakumar
    • Takafumi Yoshida
    • Takuji Torimura
    • Takato Ueno
    • Michio Sata
  • View Affiliations

  • Published online on: October 20, 2011     https://doi.org/10.3892/ijo.2011.1237
  • Pages: 679-685
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Abstract

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.

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March 2012
Volume 40 Issue 3

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Spandidos Publications style
Koga H, Selvendiran K, Sivakumar R, Yoshida T, Torimura T, Ueno T and Sata M: PPARγ potentiates anticancer effects of gemcitabine on human pancreatic cancer cells. Int J Oncol 40: 679-685, 2012
APA
Koga, H., Selvendiran, K., Sivakumar, R., Yoshida, T., Torimura, T., Ueno, T., & Sata, M. (2012). PPARγ potentiates anticancer effects of gemcitabine on human pancreatic cancer cells. International Journal of Oncology, 40, 679-685. https://doi.org/10.3892/ijo.2011.1237
MLA
Koga, H., Selvendiran, K., Sivakumar, R., Yoshida, T., Torimura, T., Ueno, T., Sata, M."PPARγ potentiates anticancer effects of gemcitabine on human pancreatic cancer cells". International Journal of Oncology 40.3 (2012): 679-685.
Chicago
Koga, H., Selvendiran, K., Sivakumar, R., Yoshida, T., Torimura, T., Ueno, T., Sata, M."PPARγ potentiates anticancer effects of gemcitabine on human pancreatic cancer cells". International Journal of Oncology 40, no. 3 (2012): 679-685. https://doi.org/10.3892/ijo.2011.1237