Nobiletin is a citrus polymethoxy flavonoid that suppresses cell proliferation, angiogenesis and metastatic properties in various cancer cells. In this study, we investigated the combined effects of nobiletin and various chemotherapeutic agents on the cytotoxicity of human colon and esophageal cancer cells. We cultured cancer cells at serial dilution of chemotherapeutic agents with or without nobiletin and assessed cell cytotoxicity at 5 days after drug treatment. The addition of a suboptimal dose of nobiletin did not alter the growth of cancer cells, however cytotoxic effect of antimetabolites (gemcitabine and 5-FU) and DNA-platinating agent (cisplatin) were markedly attenuated by nobiletin. By contrast, nobiletin markedly enhanced antitumor effect of antimicrotubule agents such as docetaxel, paclitaxel, vincristine and MMAE. Moreover, enhanced cytotoxicity by nobiletin was also verified in the combination with MMAE- or DM1-conjugated antibodies to EpCAM and EphA2. We found the inhibition of phosphorylation and nuclear translocation of Pin1 (peptidyl-prolyl isomerase) by nobiletin, suggesting a rational molecular target of nobiletin is Pin1. Overall, these data suggest that nobiletin might useful for the chemotherapeutic treatment of microtubule inhibitors.

Citation Format: Kazunori Kato, Takumi Yamazaki, Masaaki Honma. Nobiletin synergizes cytotoxicity of antimicrotubule agents by inhibiting Pin1 pathway [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1054. doi:10.1158/1538-7445.AM2017-1054