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Combination of ciglitazone, a peroxisome proliferator-activated receptor gamma ligand, and cisplatin enhances the inhibition of growth of human ovarian cancers

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Journal of Cancer Research and Clinical Oncology Aims and scope Submit manuscript

Abstract

Purpose

We have recently reported that peroxisome proliferator-activated receptor gamma (PPARγ) ligands produce antitumor effects against human ovarian cancer in conjunction with reduction in angiogenesis and induction of apoptosis via regulating prostaglandin (PG) E2 level. In this study, we investigated the effects of combination of ciglitazone, a PPARγ ligand, and cisplatin, a cytotoxic anti-cancer drug, on growth of ovarian cancer.

Methods

Tumor growth and survival were examined in female nu/nu mice xenografted with subcutaneous OVCAR-3 tumors or with intraperitoneal DISS tumors and treated with cisplatin alone (5 mg/kg intraperitoneally once on day 1), ciglitazone alone (15 mg/kg intraperitoneally once a week), or the combination.

Results

Ciglitazone alone, cisplatin alone, or their combination significantly suppressed the growth of OVCAR-3 tumors xenotransplated subcutaneously and prolonged the survival of mice with malignant ascites derived from DISS cells as compared with the control. Furthermore, the combination produced a significantly greater antitumor effect than cisplatin or ciglitazone alone and also significantly prolonged the survival time as compared with cisplatin or ciglitazone alone. The combination significantly decreased PGE2 concentration in serum as well as in ascites, reduced vascular endothelial growth factor as well as microvessel density, and induced apoptosis in solid OVCAR-3 tumor as compared with cisplatin or ciglitazone alone. The combination remarkably decreased the expression of cyclooxygenase-2 (COX-2), microsomal PG E synthase (mPGES), and PG receptor 3 (EP3) in tumors. In vitro experiment showed that ciglitazone enhances the cytotoxicity of cisplatin against ovarian cancer cells.

Conclusion

In conclusion, the combination inhibited the growth of ovarian cancer in conjunction with reduction in angiogenesis and induction of apoptosis resulting from suppression of PGE2 activation through decreasing the expression of COX-2, mPGES, and EP3. The inhibitory effect of this combination treatment on growth of ovarian cancer suggests a potential to lead a novel therapeutic strategy against ovarian cancer.

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Acknowledgments

This study was supported in part by a Grant-in Aid for Cancer Research (No. 20591935) from the Ministry of Education, Science and Culture of Japan and by the Karoji Memorial Fund of the Hirosaki University Graduate School of Medicine.

Conflict of interest

We declare that we have no financial and personal relationships with other people or organizations that can inappropriately influence our work.

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Authors and Affiliations

  1. Department of Obstetrics and Gynecology, Hirosaki University Graduate School of Medicine, 5-Zaifu-cho, Hirosaki, Aomori, 036-8562, Japan

    Yoshihito Yokoyama, Tatsuhiko Shigeto & Hideki Mizunuma

  2. Department of Obstetrics and Gynecology, The Second Affiliated Hospital of China Medical University, Shenyang, 110004, China

    Bing Xin

Authors
  1. Yoshihito Yokoyama
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  2. Bing Xin
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  3. Tatsuhiko Shigeto
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  4. Hideki Mizunuma
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Correspondence to Yoshihito Yokoyama.

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Yokoyama, Y., Xin, B., Shigeto, T. et al. Combination of ciglitazone, a peroxisome proliferator-activated receptor gamma ligand, and cisplatin enhances the inhibition of growth of human ovarian cancers. J Cancer Res Clin Oncol 137, 1219–1228 (2011). https://doi.org/10.1007/s00432-011-0993-1

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  • DOI: https://doi.org/10.1007/s00432-011-0993-1

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