Department of Pharmacy, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, 325027, China.
College of Pharmacy and Research Institute of Pharmaceutical Sciences, Chonnam National University, Gwangju, 61186, Korea.
Invest New Drugs. 2022 Dec;40(6):1216-1230. doi: 10.1007/s10637-022-01289-5. Epub 2022 Sep 7.
Estrogen receptor-α (ERα) promotes breast cancer, and ER-positive cancer accounts for ~ 80% of breast cancers. This subtype responds positively to hormone/endocrine therapies involving either inhibition of estrogen synthesis or blockade of estrogen action. Carbidopa, a drug used to potentiate the therapeutic efficacy of L-DOPA in Parkinson's disease, is an agonist for aryl hydrocarbon receptor (AhR). Pharmacotherapy in Parkinson's disease decreases the risk for cancers, including breast cancer. The effects of carbidopa on ER-positive breast cancer were evaluated in cell culture and in mouse xenografts. The assays included cell proliferation, apoptosis, cell migration/invasion, subcellular localization of AhR, proteasomal degradation, and tumor growth in xenografts. Carbidopa decreased proliferation and migration of ER-positive human breast cancer cells in vitro with no significant effect on ER-negative breast cancer cells. Treatment of ER-positive cells with carbidopa promoted nuclear localization of AhR and expression of AhR target genes; it also decreased cellular levels of ERα via proteasomal degradation in an AhR-dependent manner. In vivo, carbidopa suppressed the growth of ER-positive breast cancer cells in mouse xenografts; this was associated with increased apoptosis and decreased cell proliferation. Carbidopa has therapeutic potential for ER-positive breast cancer either as a single agent or in combination with other standard chemotherapies.
雌激素受体-α（ERα）促进乳腺癌的发生，而 ER 阳性癌症占所有乳腺癌的~80%。这种亚型对涉及抑制雌激素合成或阻断雌激素作用的激素/内分泌治疗反应良好。卡比多巴是一种用于增强帕金森病中左旋多巴治疗效果的药物，是芳烃受体（AhR）的激动剂。帕金森病的药物治疗降低了癌症的风险，包括乳腺癌。在细胞培养和小鼠异种移植模型中评估了卡比多巴对 ER 阳性乳腺癌的作用。这些测定包括细胞增殖、凋亡、细胞迁移/侵袭、AhR 的亚细胞定位、蛋白酶体降解以及异种移植物中的肿瘤生长。卡比多巴可降低体外 ER 阳性人乳腺癌细胞的增殖和迁移，对 ER 阴性乳腺癌细胞无明显影响。用卡比多巴处理 ER 阳性细胞可促进 AhR 的核定位和 AhR 靶基因的表达；它还通过蛋白酶体降解以 AhR 依赖性方式降低细胞内 ERα的水平。在体内，卡比多巴可抑制 ER 阳性乳腺癌细胞在小鼠异种移植物中的生长；这与凋亡增加和细胞增殖减少有关。卡比多巴具有治疗 ER 阳性乳腺癌的潜力，无论是作为单一药物还是与其他标准化疗药物联合使用。
