Kubota T, Koshizuka K, Williamson E A, Asou H, Said J W, Holden S, Miyoshi I, Koeffler H P
Division of Hematology/Oncology, Cedars-Sinai Research Institute, UCLA School of Medicine, Los Angeles, California 90048, USA.
Cancer Res. 1998 Aug 1;58(15):3344-52.
Troglitazone, a thiazolidinedione derivative, is a widely used antidiabetic drug that binds and activates peroxisome proliferator-activated receptor gamma (PPARgamma) and enhances insulin sensitivity. It induces differentiation of adipocytes, which highly express PPARgamma. We report that human prostate cancer cells expressed PPARgamma 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 PPARgamma ligands (BRL49653: ED50, 8 x 10(-8) M; 15-deoxy-delta12,14-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.
曲格列酮是一种噻唑烷二酮衍生物，是一种广泛使用的抗糖尿病药物，它能结合并激活过氧化物酶体增殖物激活受体γ（PPARγ），增强胰岛素敏感性。它能诱导高度表达PPARγ的脂肪细胞分化。我们报告，人类前列腺癌细胞中PPARγ表达水平显著，而正常前列腺组织中表达极低。用曲格列酮对PC-3前列腺癌细胞系进行剂量反应克隆形成试验显示有抗增殖作用（半数有效剂量[ED50]，3×10⁻⁷M），其他PPARγ配体（BRL49653：ED50，8×10⁻⁸M；15-脱氧-Δ¹²,¹⁴-前列腺素J2：ED50，2×10⁻⁶M；环格列酮：未达到ED50；吲哚美辛：未达到ED50）也显示出类似作用。曲格列酮与视黄酸X受体或视黄酸受体特异性配体联合使用未显示出协同作用。对曲格列酮（10⁻⁵M）进行不同时长的脉冲暴露试验表明，对该药物进行4天的脉冲暴露可不可逆地抑制PC-3细胞50%的克隆生长。有趣的是，用曲格列酮（10⁻⁵M）培养的PC-3细胞在光学显微镜和电子显微镜下均显示出显著的形态变化，表明细胞恶性程度降低。然而，曲格列酮对细胞周期或几种分化标志物均无影响。LNCaP细胞组成性产生前列腺特异性抗原，全反式维甲酸可使其水平显著升高。曲格列酮（10⁻⁵M，4天）可使这些细胞产生的前列腺特异性抗原水平降低50%。对雄性BNX三重免疫缺陷小鼠体内生长的PC-3肿瘤口服曲格列酮（500mg/kg/天）进行治疗，可显著抑制肿瘤生长（P = 0.01）。曲格列酮在小鼠中唯一明显的副作用是血清转氨酶升高。用曲格列酮（10⁻⁵M，4天）对手术获取的4个人类前列腺癌肿瘤进行短期培养，可使癌细胞（约60%）发生明显且选择性的坏死，但对相邻的正常前列腺细胞无影响。综上所述，这些结果表明曲格列酮可能是治疗前列腺癌的一种有用的治疗药物，尤其是在疾病负担较轻的情况下。
