title: Luteolin inhibits Cr(VI)-induced malignant cell transformation of human lung epithelial cells by targeting ROS mediated multiple cell signaling pathways.
abstract: Hexavalent chromium [Cr(VI)] is a well-known human carcinogen associated with the incidence of lung cancer. Inhibition of metal induced carcinogenesis by a dietary antioxidant is a novel approach. Luteolin, a natural dietary flavonoid found in fruits and vegetables, possesses potent antioxidant and anti-inflammatory activity. We found that short term exposure of human bronchial epithelial cells (BEAS-2B) to Cr(VI) (5μM) showed a drastic increase in ROS generation, NADPH oxidase (NOX) activation, lipid peroxidation, and glutathione depletion, which were significantly inhibited by the treatment with luteolin in a dose dependent manner. Treatment with luteolin decreased AP-1, HIF-1α, COX-2, and iNOS promoter activity induced by Cr(VI) in BEAS-2B cells. In addition, luteolin protected BEAS-2B cells from malignant transformation induced by chronic Cr(VI) exposure. Moreover, luteolin also inhibited the production of pro-inflammatory cytokines (IL-1β, IL-6, IL-8, TNF-α) and VEGF in chronic Cr(VI) exposed BEAS-2B cells. Western blot analysis showed that luteolin inhibited multiple gene products linked to survival (Akt, Fak, Bcl-2, Bcl-xL), inflammation (MAPK, NF-κB, COX-2, STAT-3, iNOS, TNF-α) and angiogenesis (HIF-1α, VEGF, MMP-9) in chronic Cr(VI) exposed BEAS-2B cells. Nude mice injected with BEAS-2B cells chronically exposed to Cr(VI) in the presence of luteolin showed reduced tumor incidence compared to Cr(VI) alone treated group. Overexpression of catalase (CAT) or SOD2, eliminated Cr(VI)-induced malignant transformation. Overall, our results indicate that luteolin protects BEAS-2B cells from Cr(VI)-induced carcinogenesis by scavenging ROS and modulating multiple cell signaling mechanisms that are linked to ROS. Luteolin, therefore, serves as a potential chemopreventive agent against Cr(VI)-induced carcinogenesis.
authors.affiliation: Center for Research on Environmental Disease, University of Kentucky, 1095 VA Drive, Lexington, KY 40536, USA; Graduate Center for Toxicology, University of Kentucky, 1095 VA Drive, Lexington, KY 40536, USA.
authors.forename: Poyil
authors.initials: P
authors.lastname: Pratheeshkumar
authors.affiliation: Center for Research on Environmental Disease, University of Kentucky, 1095 VA Drive, Lexington, KY 40536, USA; Graduate Center for Toxicology, University of Kentucky, 1095 VA Drive, Lexington, KY 40536, USA.
authors.forename: Young-Ok
authors.initials: YO
authors.lastname: Son
authors.affiliation: Center for Research on Environmental Disease, University of Kentucky, 1095 VA Drive, Lexington, KY 40536, USA; Graduate Center for Toxicology, University of Kentucky, 1095 VA Drive, Lexington, KY 40536, USA.
authors.forename: Sasidharan Padmaja
authors.initials: SP
authors.lastname: Divya
authors.affiliation: Center for Research on Environmental Disease, University of Kentucky, 1095 VA Drive, Lexington, KY 40536, USA; Graduate Center for Toxicology, University of Kentucky, 1095 VA Drive, Lexington, KY 40536, USA.
authors.forename: Ram Vinod
authors.initials: RV
authors.lastname: Roy
authors.affiliation: Center for Research on Environmental Disease, University of Kentucky, 1095 VA Drive, Lexington, KY 40536, USA; Graduate Center for Toxicology, University of Kentucky, 1095 VA Drive, Lexington, KY 40536, USA.
authors.forename: John Andrew
authors.initials: JA
authors.lastname: Hitron
authors.affiliation: Center for Research on Environmental Disease, University of Kentucky, 1095 VA Drive, Lexington, KY 40536, USA; Graduate Center for Toxicology, University of Kentucky, 1095 VA Drive, Lexington, KY 40536, USA.
authors.forename: Lei
authors.initials: L
authors.lastname: Wang
authors.affiliation: Graduate Center for Toxicology, University of Kentucky, 1095 VA Drive, Lexington, KY 40536, USA.
authors.forename: Donghern
authors.initials: D
authors.lastname: Kim
authors.affiliation: Graduate Center for Toxicology, University of Kentucky, 1095 VA Drive, Lexington, KY 40536, USA.
authors.forename: Jin
authors.initials: J
authors.lastname: Dai
authors.affiliation: National Centre for Aquatic Animal Health, Cochin University of Science and Technology, Cochin, India.
authors.forename: Padmaja
authors.initials: P
authors.lastname: Asha
authors.affiliation: Graduate Center for Toxicology, University of Kentucky, 1095 VA Drive, Lexington, KY 40536, USA.
authors.forename: Zhuo
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macau, China.
authors.forename: Yitao
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Center for Research on Environmental Disease, University of Kentucky, 1095 VA Drive, Lexington, KY 40536, USA; Graduate Center for Toxicology, University of Kentucky, 1095 VA Drive, Lexington, KY 40536, USA. Electronic address: xshi5@email.uky.edu.
authors.forename: Xianglin
authors.initials: X
authors.lastname: Shi
mesh_terms: D042501:Angiogenic Proteins / Q000378:metabolism; D000818:Animals; D016588:Anticarcinogenic Agents / Q000494:pharmacology*; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D001980:Bronchi / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D002471:Cell Transformation, Neoplastic / Q000139:chemically induced / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D002857:Chromium / Q000633:toxicity*; D019610:Cytoprotection; D004305:Dose-Response Relationship, Drug; D004847:Epithelial Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D016166:Free Radical Scavengers / Q000494:pharmacology*; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism; D008175:Lung Neoplasms / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D047311:Luteolin / Q000494:pharmacology*; D008819:Mice, Nude; D018384:Oxidative Stress / Q000187:drug effects*; D011192:Potassium Dichromate / Q000633:toxicity*; D017382:Reactive Oxygen Species / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*; D014162:Transfection; D023041:Xenograft Model Antitumor Assays
chemical_list: D042501:Angiogenic Proteins; D016588:Anticarcinogenic Agents; D051017:Apoptosis Regulatory Proteins; D016166:Free Radical Scavengers; D018836:Inflammation Mediators; D017382:Reactive Oxygen Species; D002857:Chromium; C074702:chromium hexavalent ion; D047311:Luteolin; D011192:Potassium Dichromate
keywords: Angiogenesis; Carcinogenesis; Hexavalent chromium; Inflammation; Luteolin