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 in vitro and in vivo. 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 in vitro and in vivo 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.
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Cover Image
Cover Image
Nuclear localization of aryl hydrocarbon receptor (AhR) in HepG2 cells treated with Carbidopa. The green fluorescence signal for AhR is overlayed with the blue fluorescence (DAPI) signal for the nucleus, showing complete translocation of AhR from cytoplasm into nucleus. In this issue of the Biochemical Journal, Ogura et al, report on the potential role of Carbidopa in cancer therapy (pages 3391–3402).
Carbidopa is an activator of aryl hydrocarbon receptor with potential for cancer therapy
Jiro Ogura, Seiji Miyauchi, Kazumi Shimono, Shengping Yang, Sathisha Gonchigar, Vadivel Ganapathy, Yangzom D. Bhutia; Carbidopa is an activator of aryl hydrocarbon receptor with potential for cancer therapy. Biochem J 15 October 2017; 474 (20): 3391–3402. doi: https://doi.org/10.1042/BCJ20170583
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