title: Luteolin inhibits the Nrf2 signaling pathway and tumor growth in vivo.
abstract: Nuclear factor erythroid 2-related factor 2 (Nrf2) is over-expressed in many types of tumor, promotes tumor growth, and confers resistance to anticancer therapy. Hence, Nrf2 is regarded as a novel therapeutic target in cancer. Previously, we reported that luteolin is a strong inhibitor of Nrf2 in vitro. Here, we showed that luteolin reduced the constitutive expression of NAD(P)H quinone oxidoreductase 1 in mouse liver in a time- and dose-dependent manner. Further, luteolin inhibited the expression of antioxidant enzymes and glutathione transferases, decreasing the reduced glutathione in the liver of wild-type mice under both constitutive and butylated hydroxyanisole-induced conditions. In contrast, such distinct responses were not detected in Nrf2(-/-) mice. In addition, oral administration of luteolin, either alone or combined with intraperitoneal injection of the cytotoxic drug cisplatin, greatly inhibited the growth of xenograft tumors from non-small-cell lung cancer (NSCLC) cell line A549 cells grown subcutaneously in athymic nude mice. Cell proliferation, the expression of Nrf2, and antioxidant enzymes were all reduced in tumor xenograft tissues. Furthermore, luteolin enhanced the anti-cancer effect of cisplatin. Together, our findings demonstrated that luteolin inhibits the Nrf2 pathway in vivo and can serve as an adjuvant in the chemotherapy of NSCLC.
authors.affiliation: Department of Biochemistry and Genetics, School of Medicine, Zhejiang University, Hangzhou 310058, PR China.
authors.forename: Song
authors.initials: S
authors.lastname: Chian
authors.affiliation: Department of Biochemistry and Genetics, School of Medicine, Zhejiang University, Hangzhou 310058, PR China.
authors.forename: Ruby
authors.initials: R
authors.lastname: Thapa
authors.affiliation: Department of Biochemistry and Genetics, School of Medicine, Zhejiang University, Hangzhou 310058, PR China.
authors.forename: Zhexu
authors.initials: Z
authors.lastname: Chi
authors.affiliation: Department of Pharmacology, School of Medicine, Zhejiang University, Hangzhou 310058, PR China.
authors.forename: Xiu Jun
authors.initials: XJ
authors.lastname: Wang
authors.affiliation: Department of Biochemistry and Genetics, School of Medicine, Zhejiang University, Hangzhou 310058, PR China. Electronic address: xiuwentang@zju.edu.cn.
authors.forename: Xiuwen
authors.initials: X
authors.lastname: Tang
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000494:pharmacology; D005260:Female; D051547:Heme Oxygenase-1 / Q000378:metabolism; D006801:Humans; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D047311:Luteolin / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008819:Mice, Nude; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000378:metabolism; D051267:NF-E2-Related Factor 2 / Q000037:antagonists & inhibitors* / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; C495636:Nfe2l2 protein, mouse; C496541:HMOX1 protein, human; D051547:Heme Oxygenase-1; D016660:NAD(P)H Dehydrogenase (Quinone); C447479:NQO1 protein, human; D047311:Luteolin; D002945:Cisplatin
keywords: Anti-cancer drugs; Drug resistance; Glutathione; Luteolin; Non-small-cell lung cancer; Nrf2