title: The role of Nrf2 and apoptotic signaling pathways in oroxylin A-mediated responses in HCT-116 colorectal adenocarcinoma cells and xenograft tumors.
abstract: Oroxylin A is a flavonoid found in the roots of Scutellaria baicalensis Georgi, a herbal medicine commonly used as an antipyretic, analgesic, antitumor, and anti-in&fllig;ammatory agent. It has recently been investigated for its anticancer activities in hepatoma, gastric, and breast tumors. Here, we investigated the antitumor effects of oroxylin A in human colon carcinoma HCT-116 cells in vitro and in vivo. We characterized the proapoptotic effect of oroxylin A using diamidino-phenyl-indole (DAPI) and annexin V/PI staining. We then found that both caspase-3 and caspase-9 were activated, the expression of Bcl-2 protein decreased, and the expression of Bax protein increased after treatment with oroxylin A. In addition, oroxylin A increased nuclear transcription factor erythroid-related factor 2 (Nrf2) expression and induced Nrf2 translocation into the nucleus. Furthermore, we found that oroxylin A treatment elevated intracellular reactive oxygen species levels and increased the protein expression level of two of the Nrf2 target genes heme oxygenase-1 and NADP(H):quinone oxidoreductase-1 in HCT-116 cells. Finally, our study demonstrated that oral administration of oroxylin A significantly decreased tumor volume and weight in immunodeficient mice that were inoculated with HCT-116 cells. The in-vivo chemopreventive efficacy of oroxylin A against HCT-116 human colon cancer was accompanied by its proapoptotic and Nrf2-inducing activities, which correlates with the in-vitro study. This is the first demonstration of oroxylin A-dependent chemoprevention in colon cancer and may offer a potential mechanism for its anticancer action in vivo.
authors.affiliation: State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Carcinogenesis and Intervention, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, People's Republic of China.
authors.forename: Rong
authors.initials: R
authors.lastname: Hu
authors.forename: Nan
authors.initials: N
authors.lastname: Chen
authors.forename: Jing
authors.initials: J
authors.lastname: Yao
authors.forename: Qing
authors.initials: Q
authors.lastname: Zhao
authors.forename: Fengyi
authors.initials: F
authors.lastname: Zhang
authors.forename: Zhi-Yu
authors.initials: ZY
authors.lastname: Li
authors.forename: Qi-Dong
authors.initials: QD
authors.lastname: You
authors.forename: Qing-Long
authors.initials: QL
authors.lastname: Guo
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D000284:Administration, Oral; D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D053148:Caspase 3 / Q000378:metabolism; D053453:Caspase 9 / Q000378:metabolism; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D005419:Flavonoids / Q000494:pharmacology*; D015972:Gene Expression Regulation, Neoplastic; D045325:HCT116 Cells; D051547:Heme Oxygenase-1 / Q000235:genetics; D006801:Humans; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000235:genetics; D051267:NF-E2-Related Factor 2 / Q000502:physiology*; D021381:Protein Transport / Q000187:drug effects; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D005419:Flavonoids; D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; D019253:Proto-Oncogene Proteins c-bcl-2; C080669:5,7-dihydroxy-6-methoxy-2-phenylchromen-4-one; D051547:Heme Oxygenase-1; D016660:NAD(P)H Dehydrogenase (Quinone); C447479:NQO1 protein, human; D053148:Caspase 3; D053453:Caspase 9