[Cancer Research 58, 3344-3352, August 1, 1998]
© 1998 American Association for Cancer Research
Ligand for Peroxisome Proliferator-activated Receptor 
(Troglitazone) Has Potent Antitumor Effect against Human Prostate Cancer Both in Vitro and in Vivo1
Tetsuya Kubota2,
Kozo Koshizuka,
Elizabeth A. Williamson,
Hiroya Asou,
Jonathan W. Said,
Stuart Holden,
Isao Miyoshi and
H. Phillip Koeffler
Division of Hematology/Oncology [T. K., K. K., E. A. W., H. A., H. P. K.], Division of Pathology [J. W. S.], Department of Surgery [S. H.], Cedars-Sinai Research Institute, UCLA School of Medicine, Los Angeles, California 90048, and Department of Medicine, Kochi Medical School, Kochi 783-8505, Japan [I. M.]
Troglitazone, a thiazolidinedione derivative, is a widely used antidiabetic drug that binds and activates peroxisome proliferator-activated receptor 
(PPAR) and enhances insulin sensitivity. It induces differentiation of adipocytes, which highly express PPAR. We report that human prostate cancer cells expressed PPAR at prominent levels and normal prostate tissues had very low expression. Dose-response clonogenic assays of the PC-3 prostate cancer cell line with troglitazone showed an antiproliferative effect (ED50, 3 x 10-7 M) and other PPAR ligands (BRL49653: ED50, 8 x 10-8 M; 15-deoxy-
12,14-prostaglandin J2: ED50, 2 x 10-6 M; ciglitizone: ED50, not reached; indomethacin: ED50, not reached) showed similar effects. Combinations of troglitazone and a ligand specific for either retinoid X receptor or retinoic acid receptor did not show a synergistic effect. Pulse-exposure to troglitazone (10-5 M) for different durations showed that 4 days of pulse-exposure to the agent irreversibly inhibited 50% clonal growth of PC-3 cells. Interestingly, PC-3 cells cultured with troglitazone (10-5 M) showed dramatic morphological changes both by light and electron microscopy, suggesting that the cells became less malignant. Nevertheless, troglitazone did not affect either the cell cycle or several markers of differentiation. LNCaP cells constitutively produced prostate-specific antigen, and levels were markedly enhanced by all-trans-retinoic acid. Troglitazone (10-5 M, 4 days) decreased by 50% the levels of prostate-specific antigen produced by these cells. In vivo treatment of PC-3 tumors growing in male BNX triple immunodeficient mice with oral troglitazone (500 mg/kg/day) produced significant inhibition of tumor growth (P = 0.01). The only objective side effect of troglitazone in mice was the elevation of serum transaminases. Short-term culture of four surgically obtained human prostate cancer tumors with troglitazone (10-5 M, 4 days) produced marked and selective necrosis of the cancer cells (about 60%) but not the adjacent normal prostate cells. Taken together, these results suggest that troglitazone may be a useful therapeutic agent for the treatment of prostate cancer, especially in the setting of low disease burden.
1 This work was supported by NIH and United States Army grants and also in part by the CaP CURE Foundation and Parker Hughes Fund.
2 To whom requests for reprints should be addressed, at Division of Hematology/Oncology, Cedars-Sinai Medical Center, UCLA School of Medicine, 8700 Beverly Boulevard, Los Angeles, CA 90048. Phone: (310) 855-4609; Fax: (310) 659-9741.
Received 10/22/97.
Accepted 6/ 2/98.
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L. Pavan, A. Tarrade, A. Hermouet, C. Delouis, M. Titeux, M. Vidaud, P. Therond, D. Evain-Brion, and T. Fournier
Human invasive trophoblasts transformed with simian virus 40 provide a new tool to study the role of PPAR{gamma} in cell invasion process
Carcinogenesis,
August 1, 2003;
24(8):
1325 - 1336.
[Abstract]
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E. J. Kim, I.-J. Kang, H. J. Cho, W. K. Kim, Y.-L. Ha, and J. H. Y. Park
Conjugated Linoleic Acid Downregulates Insulin-Like Growth Factor-I Receptor Levels in HT-29 Human Colon Cancer Cells
J. Nutr.,
August 1, 2003;
133(8):
2675 - 2681.
[Abstract]
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S. Landi, V. Moreno, L. Gioia-Patricola, E. Guino, M. Navarro, J. de Oca, G. Capella, and F. Canzian
Association of Common Polymorphisms in Inflammatory Genes Interleukin (IL)6, IL8, Tumor Necrosis Factor {alpha}, NFKB1, and Peroxisome Proliferator-activated Receptor {gamma} with Colorectal Cancer ,
Cancer Res.,
July 1, 2003;
63(13):
3560 - 3566.
[Abstract]
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R. A. Gupta, P. Sarraf, E. Mueller, J. A. Brockman, J. J. Prusakiewicz, C. Eng, T. M. Willson, and R. N. DuBois
Peroxisome Proliferator-activated Receptor {gamma}-mediated Differentiation: A MUTATION IN COLON CANCER CELLS REVEALS DIVERGENT AND CELL TYPE-SPECIFIC MECHANISMS
J. Biol. Chem.,
June 13, 2003;
278(25):
22669 - 22677.
[Abstract]
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D. Bruemmer, F. Yin, J. Liu, J. P. Berger, T. Kiyono, J. Chen, E. Fleck, A. J. Van Herle, B. M. Forman, and R. E. Law
Peroxisome Proliferator-Activated Receptor {gamma} Inhibits Expression of Minichromosome Maintenance Proteins in Vascular Smooth Muscle Cells
Mol. Endocrinol.,
June 1, 2003;
17(6):
1005 - 1018.
[Abstract]
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H. J. Cho, W. K. Kim, E. J. Kim, K. C. Jung, S. Park, H. S. Lee, A. L. Tyner, and J. H. Y. Park
Conjugated linoleic acid inhibits cell proliferation and ErbB3 signaling in HT-29 human colon cell line
Am J Physiol Gastrointest Liver Physiol,
June 1, 2003;
284(6):
G996 - G1005.
[Abstract]
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K. D. Houston, J. A. Copland, R. R. Broaddus, M. M. Gottardis, S. M. Fischer, and C. L. Walker
Inhibition of Proliferation and Estrogen Receptor Signaling by Peroxisome Proliferator-activated Receptor {gamma} Ligands in Uterine Leiomyoma
Cancer Res.,
March 15, 2003;
63(6):
1221 - 1227.
[Abstract]
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P. D Terry, T. E Rohan, and A. Wolk
Intakes of fish and marine fatty acids and the risks of cancers of the breast and prostate and of other hormone-related cancers: a review of the epidemiologic evidence
Am. J. Clinical Nutrition,
March 1, 2003;
77(3):
532 - 543.
[Abstract]
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