Ogura Jiro, Miyauchi Seiji, Shimono Kazumi, Yang Shengping, Gonchigar Sathisha, Ganapathy Vadivel, Bhutia Yangzom D
Department of Cell Biology and Biochemistry, Texas Tech University Health Sciences Center, Lubbock, TX 79430, U.S.A.
Department of Pharmacokinetics, Faculty of Pharmaceutical Sciences, Toho University, 2-2-1 Miyama, Funabashi, Chiba 274-8510, Japan.
Biochem J. 2017 Sep 28;474(20):3391-3402. doi: 10.1042/BCJ20170583.
Carbidopa is used with l-DOPA (l-3,4-dihydroxyphenylalanine) to treat Parkinson's disease (PD). PD patients exhibit lower incidence of most cancers including pancreatic cancer, but with the notable exception of melanoma. The decreased cancer incidence is not due to l-DOPA; however, the relevance of Carbidopa to this phenomenon has not been investigated. Here, we tested the hypothesis that Carbidopa, independent of l-DOPA, might elicit an anticancer effect. Carbidopa inhibited pancreatic cancer cell proliferation both and Based on structural similarity with phenylhydrazine, an inhibitor of indoleamine-2,3-dioxygenase-1 (IDO1), we predicted that Carbidopa might also inhibit IDO1, thus providing a molecular basis for its anticancer effect. The inhibitory effect was confirmed using human recombinant IDO1. To demonstrate the inhibition in intact cells, AhR (aryl hydrocarbon receptor) activity was monitored as readout for IDO1-mediated generation of the endogenous AhR agonist kynurenine in pancreatic and liver cancer cells. Surprisingly, Carbidopa did not inhibit but instead potentiated AhR signaling, evident from increased CYP1A1 (cytochrome P450 family 1 subfamily A member 1), CYP1A2, and CYP1B1 expression. In pancreatic and liver cancer cells, Carbidopa promoted AhR nuclear localization. AhR antagonists blocked Carbidopa-dependent activation of AhR signaling. The inhibitory effect on pancreatic cancer cells and and the activation of AhR occurred at therapeutic concentrations of Carbidopa. Chromatin immunoprecipitation assay further confirmed that Carbidopa promoted AhR binding to its target gene CYP1A1 leading to its induction. We conclude that Carbidopa is an AhR agonist and suppresses pancreatic cancer. Hence, Carbidopa could potentially be re-purposed to treat pancreatic cancer and possibly other cancers as well.
卡比多巴与左旋多巴（L-3,4-二羟基苯丙氨酸）联合用于治疗帕金森病（PD）。PD患者患包括胰腺癌在内的大多数癌症的发病率较低，但黑色素瘤是个显著例外。癌症发病率的降低并非由于左旋多巴；然而，卡比多巴与这一现象的相关性尚未得到研究。在此，我们测试了一个假设，即卡比多巴独立于左旋多巴可能会引发抗癌作用。卡比多巴在体外和体内均抑制胰腺癌细胞增殖。基于与吲哚胺-2,3-双加氧酶-1（IDO1）抑制剂苯肼的结构相似性，我们预测卡比多巴也可能抑制IDO1，从而为其抗癌作用提供分子基础。使用人重组IDO1证实了这种抑制作用。为了证明在完整细胞中的抑制作用，监测芳烃受体（AhR）活性作为胰腺和肝癌细胞中IDO1介导的内源性AhR激动剂犬尿氨酸生成的读数。令人惊讶的是，卡比多巴并未抑制而是增强了AhR信号传导，这从细胞色素P450家族1亚家族A成员1（CYP1A1）、CYP1A2和CYP1B1表达增加中明显可见。在胰腺和肝癌细胞中，卡比多巴促进AhR核定位。AhR拮抗剂阻断了卡比多巴依赖性的AhR信号激活。对胰腺癌细胞的抑制作用以及AhR的激活发生在卡比多巴的治疗浓度下。染色质免疫沉淀试验进一步证实，卡比多巴促进AhR与其靶基因CYP1A1结合，导致其诱导。我们得出结论，卡比多巴是一种AhR激动剂，可抑制胰腺癌。因此，卡比多巴有可能被重新用于治疗胰腺癌以及可能的其他癌症。
