Department of Urologic Sciences, The Vancouver Prostate Centre, University of British Columbia, Vancouver, British Columbia, Canada.
Int J Cancer. 2012 Jun 15;130(12):2835-44. doi: 10.1002/ijc.26287. Epub 2011 Sep 14.
The androgen receptor (AR) plays a central role in prostate cancer progression to the castration-resistant (CR) lethal state. L-Dopa decarboxylase (DDC) is an AR coactivator that increases in expression with disease progression and is coexpressed with the receptor in prostate adenocarcinoma cells, where it may enhance AR activity. Here, we hypothesize that the DDC enzymatic inhibitor, carbidopa, can suppress DDC-coactivation of AR and retard prostate tumor growth. Treating LNCaP prostate cancer cells with carbidopa in transcriptional assays suppressed the enhanced AR transactivation seen with DDC overexpression and decreased prostate-specific antigen (PSA) mRNA levels. Carbidopa dose-dependently inhibited cell growth and decreased survival in LNCaP cell proliferation and apoptosis assays. The inhibitory effect of carbidopa on DDC-coactivation of AR and cell growth/survival was also observed in PC3 prostate cancer cells (stably expressing AR). In vivo studies demonstrated that serum PSA velocity and tumor growth rates elevated ∼2-fold in LNCaP xenografts, inducibly overexpressing DDC, were reverted to control levels with carbidopa administration. In castrated mice, treating LNCaP tumors, expressing endogenous DDC, with carbidopa delayed progression to the CR state from 6 to 10 weeks, while serum PSA and tumor growth decreased 4.3-fold and 5.4-fold, respectively. Our study is a first time demonstration that carbidopa can abrogate DDC-coactivation of AR in prostate cancer cells and tumors, decrease serum PSA, reduce tumor growth and delay CR progression. Since carbidopa is clinically approved, it may be readily used as a novel therapeutic strategy to suppress aberrant AR activity and delay prostate cancer progression.
雄激素受体 (AR) 在前列腺癌向去势抵抗 (CR) 致死状态的进展中起着核心作用。L-多巴脱羧酶 (DDC) 是 AR 的共激活剂，随着疾病的进展表达增加，并与前列腺腺癌细胞中的受体共表达，在那里它可能增强 AR 活性。在这里，我们假设 DDC 酶抑制剂卡比多巴可以抑制 DDC-AR 的共激活作用并延缓前列腺肿瘤的生长。在转录测定中用卡比多巴处理 LNCaP 前列腺癌细胞可抑制 DDC 过表达时观察到的增强的 AR 反式激活作用，并降低前列腺特异性抗原 (PSA) mRNA 水平。卡比多巴剂量依赖性地抑制 LNCaP 细胞增殖和凋亡测定中的细胞生长和存活。在 AR 稳定表达的 PC3 前列腺癌细胞中也观察到卡比多巴对 DDC-AR 共激活和细胞生长/存活的抑制作用。体内研究表明，在诱导性过表达 DDC 的 LNCaP 异种移植物中，血清 PSA 速度和肿瘤生长率升高了约 2 倍，用卡比多巴给药可将其恢复至对照水平。在去势小鼠中，用卡比多巴治疗表达内源性 DDC 的 LNCaP 肿瘤可将其从 6 周延迟至 10 周进入 CR 状态，同时血清 PSA 和肿瘤生长分别降低 4.3 倍和 5.4 倍。我们的研究首次证明卡比多巴可以在前列腺癌细胞和肿瘤中消除 DDC-AR 的共激活作用，降低血清 PSA，减少肿瘤生长并延迟 CR 进展。由于卡比多巴已在临床上获得批准，因此它可能很快被用作抑制异常 AR 活性和延缓前列腺癌进展的新治疗策略。
