Effects of ligand activation of peroxisome proliferator-activated receptor gamma in human prostate cancer - PubMed (original) (raw)

Clinical Trial

. 2000 Sep 26;97(20):10990-5.

doi: 10.1073/pnas.180329197.

M Smith, P Sarraf, T Kroll, A Aiyer, D S Kaufman, W Oh, G Demetri, W D Figg, X P Zhou, C Eng, B M Spiegelman, P W Kantoff

Affiliations

Clinical Trial

Effects of ligand activation of peroxisome proliferator-activated receptor gamma in human prostate cancer

E Mueller et al. Proc Natl Acad Sci U S A. 2000.

Abstract

Peroxisome proliferator-activated receptor gamma (PPARgamma) is a nuclear hormone receptor that plays a key role in the differentiation of adipocytes. Activation of this receptor in liposarcomas and breast and colon cancer cells also induces cell growth inhibition and differentiation. In the present study, we show that PPARgamma is expressed in human prostate adenocarcinomas and cell lines derived from these tumors. Activation of this receptor with specific ligands exerts an inhibitory effect on the growth of prostate cancer cell lines. Further, we show that prostate cancer and cell lines do not have intragenic mutations in the PPARgamma gene, although 40% of the informative tumors have hemizygous deletions of this gene. Based on our preclinical data, we conducted a phase II clinical study in patients with advanced prostate cancer using troglitazone, a PPARgamma ligand used for the treatment of type 2 diabetes. Forty-one men with histologically confirmed prostate cancer and no symptomatic metastatic disease were treated orally with troglitazone. An unexpectedly high incidence of prolonged stabilization of prostate-specific antigen was seen in patients treated with troglitazone. In addition, one patient had a dramatic decrease in serum prostate-specific antigen to nearly undetectable levels. These data suggest that PPARgamma may serve as a biological modifier in human prostate cancer and its therapeutic potential in this disease should be further investigated.

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Figures

Figure 1

Figure 1

PPARγ is expressed in human normal prostate, carcinomas, and cell lines. Expression of PPARγ mRNA in (A) samples from five patients (from A to E), obtained from normal prostate tissue (N), neighboring carcinomas (T), and (B) in LNCaP, DU145, and PC3 prostate cancer cell lines and colon cancer cells (Moser), used as control. (C) PPARγ protein levels in LNCaP, DU145, and PC3 cells.

Figure 2

Figure 2

PPARγ activation inhibits cell growth in prostate cancer cell lines. (A) Time course and dose-response inhibition of cell growth of DU145 treated with troglitazone. (B) Comparison of the growth inhibitory effects of troglitazone at 10 μM in LNCaP, DU145, and PC3 cells. (C) Growth inhibition in DU145 cells treated for 7 days with 5 μM rosiglitazone (BRL) and 5 μM 15-deoxy-Δ12,14PGJ2 (PGJ2). DU145 treated with 10 μM M2, an inactive metabolite of troglitazone, 10 μM of Wy, or 5 μM of GW 00233, PPARα and PPARδ ligands, respectively, did not show any growth inhibition compared with troglitazone-treated cells.

Figure 3

Figure 3

PSA levels are decreased by troglitazone in vitro. LNCaP cells show decreased levels of PSA after treatment with different doses of troglitazone compared with vehicle-treated cells.

Figure 4

Figure 4

PSA levels are modulated by troglitazone in prostate cancer patients. The PSA levels of prostate cancer patients, treated with 800 mg of troglitazone/day, were measured every 4 weeks. (A) The patient received radiation therapy in 11/94, nadir of 0.1. (B) Patient had post radiation therapy nadir of 1.9 on 6/2/94.

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