Abstract 5511: The proliferation-inhibiting effects of Efatutazone, a novel third-generation peroxisome proliferator-activated receptor gamma agonist, on esophageal squamous cell carcinoma in vitro and in vivo.
Authors: Sawayama Hiroshi , Ishimoto Takatsugu , Watanabe Masayuki , Yoshida Naoya , Baba Yoshifumi , Iwatsuki Masaaki , Sugihara Hidetaka , Onuma Hiroshi , Shiose Yoshinobu , Baba Hideo 
Published: August 2014

Background: Peroxisome proliferator-activated receptor gamma (PPARγ) inhibits the proliferation of several cancers. Efatutazone, a novel third-generation thiazolidinedione PPARγ agonist, demonstrated acceptable tolerability with evidence of disease control in patients with advanced alignancies in the phase 1 study. However, the status and function of PPARγ in esophageal squamous cell carcinoma (ESCC) remains unclear and the effects of the PPARγ agonist are unknown.

Methods: Immunohistochemical staining was performed using paraffin sections of specimens obtained from 145 ESCC patients who underwent curative resection. The anti-tumor effects of Efatutazone were investigated in ESCC cell lines both in vitro and in vivo.

Results: The expression of PPARγ was detected in the nucleus of the normal esophageal squamous epithelium in all patients, while positive staining in ESCC was observed in 24.8% of the patients. The expression of PPARγ decreases according to the depth of invasion and exhibits an inverse relationship with the expression of ki-67. Efatutazone inhibited the proliferation of the ESCC cell lines in a time- and dose-dependent manner in vitro. The anti-proliferation effect of Efatutazone was more evident in cell lines with high PPARγ expression than in those with low PPARγ expression. Efatutazone inhibited the sphere formation of TE-4, which is one of the high PPARγ expression cell lines. Efatutazone upregulated the cell cycle kinase inhibitor p21 WAF1 / CIP1 and induced G1 arrest. We confirmed that the antitumor effect of this drug occurred in a PPARγ dependent manner using si-RNA for PPARγ. In a mouse xenograft model established with TE-4, we compared three arms: the control group (n=8), the Troglitazone group (10 mg/kg, n=8) and the Efatutazone group (10 mg/kg, n=8). Although tumor volume did not differ between the control group and the Troglitazone group, 50.4±13.6% (average ± SD) reduction in tumor volume was observed in the Efatutazone group compared with the control group. The mRNA expression of PLIN-2, a transcription product of PPARγ, was two-fold higher in the Efatutazone group than in the control group. Immunohistochemical staining demonstrated enhanced p21 WAF1 / CIP1 expression and decreased the ki-67 expression in the Efatutazone group in comparison to either the control or Troglitazone group. Conclusions: The expression of PPARγ decreased in ESCC compared with normal esophageal epithelium. The anti-proliferation effect of the third-generation PPARγ agonist, Efatutazone, for ESCC was observed both in vitro and in vivo. Efatutazone is a candidate for novel anti-cancer agent against ESCC.

Citation Format: Hiroshi Sawayama, Takatsugu Ishimoto, Masayuki Watanabe, Naoya Yoshida, Yoshifumi Baba, Masaaki Iwatsuki, Hidetaka Sugihara, Hiroshi Onuma, Yoshinobu Shiose, Hideo Baba. The proliferation-inhibiting effects of Efatutazone, a novel third-generation peroxisome proliferator-activated receptor gamma agonist, on esophageal squamous cell carcinoma in vitro and in vivo. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5511. doi:10.1158/1538-7445.AM2013-5511