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一种新的前列腺癌治疗方法:雄激素剥夺与COX-2抑制剂联合使用。

A new prostate cancer therapeutic approach: combination of androgen ablation with COX-2 inhibitor.

作者信息

Cai Yi, Lee Yi-Fen, Li Gonghui, Liu Su, Bao Bo-Ying, Huang Jiaoti, Hsu Cheng-Lung, Chang Chawnshang

机构信息

George H. Whipple Laboratory for Cancer Research, Department of Pathology, University of Rochester Medical Center, Rochester, NY 14642, USA.

出版信息

Int J Cancer. 2008 Jul 1;123(1):195-201. doi: 10.1002/ijc.23481.

Abstract

Prostate cancer is initially responsive to hormonal therapy, but cancers inevitably progress in an androgen-independent fashion with virtually all tumors evolving into more aggressive androgen refractory disease. Immunohistological comparisons of cyclooxygenase 2 (COX-2) expressions in 3 pairs of prostate cancer patients before and after the combined androgen blockade (CAB) therapy show elevated COX-2 expressions. This observation from clinical specimens is further supported by in vitro laboratory data using human prostate cancer cells in which the antiandrogen hydroxyflutamide (HF) induced COX-2 expression, and androgen suppressed COX-2 expression. By applying knockdown and overexpression strategies to modulate AR expression in prostate cancer cells, we confirmed that androgen/AR signal suppressed, and HF induced COX-2 expression at both protein and mRNA levels. COX-2 promoter reporter assay indicated that the suppression of COX-2 by androgen/AR is at the transcriptional level via modulation of NF-kappaB signals. Treatment of LNCaP and LAPC4 cells with 1 microM HF in the presence of 1 nM DHT, which mimics the CAB therapy condition, promotes cell growth, and this growth induction can be suppressed via adding the COX-2 specific inhibitor, NS398. This suggests that HF promoted prostate cancer cell growth is COX-2 dependent and this HF-COX-2 activation pathway can account for one reason of CAB therapy failure. Together, these findings provide a possible explanation how CAB with antiandrogen HF therapy might fail and provide a potential new therapeutic approach to battle prostate cancer via combination of CAB therapy with COX-2 inhibitor(s).

摘要

前列腺癌最初对激素治疗有反应,但癌症不可避免地会以雄激素非依赖的方式进展,几乎所有肿瘤都会演变成更具侵袭性的雄激素难治性疾病。对3对前列腺癌患者在联合雄激素阻断(CAB)治疗前后的环氧合酶2(COX-2)表达进行免疫组织学比较,结果显示COX-2表达升高。使用人前列腺癌细胞的体外实验室数据进一步支持了从临床标本中观察到的结果,其中抗雄激素药物羟基氟他胺(HF)诱导COX-2表达,而雄激素抑制COX-2表达。通过应用基因敲低和过表达策略来调节前列腺癌细胞中的雄激素受体(AR)表达,我们证实雄激素/AR信号在蛋白质和mRNA水平上均抑制COX-2表达,而HF诱导COX-2表达。COX-2启动子报告基因检测表明,雄激素/AR对COX-2的抑制作用是通过调节核因子κB信号在转录水平上实现的。在模拟CAB治疗条件的1 nM双氢睾酮(DHT)存在下,用1 μM HF处理LNCaP和LAPC4细胞可促进细胞生长,而添加COX-2特异性抑制剂NS398可抑制这种生长诱导。这表明HF促进前列腺癌细胞生长是COX-2依赖性的,并且这种HF-COX-2激活途径可以解释CAB治疗失败的一个原因。总之,这些发现为使用抗雄激素HF的CAB治疗可能失败的原因提供了一种可能的解释,并为通过将CAB治疗与COX-2抑制剂联合使用来对抗前列腺癌提供了一种潜在的新治疗方法。

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