title: The radio-sensitizing effect of xanthohumol is mediated by STAT3 and EGFR suppression in doxorubicin-resistant MCF-7 human breast cancer cells.
abstract: BACKGROUND
  Chemotherapeutic drug resistance remains a clinical obstacle in cancer management. Drug-resistant cancer cells usually exhibit cross-resistance to ionizing radiation, which has devastating consequences for patients. With a better understanding of the molecular mechanisms, it will be possible to develop strategies to overcome this cross-resistance and to increase therapeutic sensitivity.
  
  
  METHODS
  Natural and synthetic flavonoid compounds including xanthohumol, the principal flavonoid in hops, were investigated for its radio-sensitizing activity on human breast cancer MCF-7 and adriamycin-resistant MCF-7 (MCF-7/ADR) cells. Chemo-sensitizing or radio-sensitizing effect was analyzed by tetrazolium-based colorimetric assay and flow cytometry. Western blot analysis, confocal microscopy, gene silencing with siRNA transfection and luciferase reporter gene assay were performed to examine signaling molecule activation.
  
  
  RESULTS
  Among the tested flavonoid compounds, pretreatment of the cells with xanthohumol significantly sensitized MCF-7/ADR cells to the radiation treatment by inducing apoptosis. In MCF-7/ADR cells, treatment with xanthohumol alone or with gamma-rays significantly decreased levels of anti-apoptotic proteins. Multi-drug resistance 1 (MDR1), epidermal growth factor receptor (EGFR) and signal transducer and activator of transcription 3 (STAT3) expression levels in MCF-7/ADR cells were suppressed by xanthohumol treatment. In addition, xanthohumol treatment increased death receptor (DR)-4 and DR5 expression. The xanthohumol-induced changes of these resistance-related molecules in MCF-7/ADR cells were synergistically increased by gamma-ray treatment.
  
  
  CONCLUSIONS
  Xanthohumol restored sensitivity of MCF-7/ADR cells to doxorubicin and radiation therapies.
  
  
  CONCLUSIONS
  Our results suggest that xanthohumol may be a potent chemo- and radio-sensitizer, and its actions are mediated through STAT3 and EGFR inhibition.
authors.affiliation: College of Pharmacy, Yeungnam University, Gyeongsang 712-749, South Korea.
authors.forename: Youra
authors.initials: Y
authors.lastname: Kang
authors.forename: Min A
authors.initials: MA
authors.lastname: Park
authors.forename: Se-Woong
authors.initials: SW
authors.lastname: Heo
authors.forename: Su-Young
authors.initials: SY
authors.lastname: Park
authors.forename: Keon Wook
authors.initials: KW
authors.lastname: Kang
authors.forename: Pil-Hoon
authors.initials: PH
authors.lastname: Park
authors.forename: Jung-Ae
authors.initials: JA
authors.lastname: Kim
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D051017:Apoptosis Regulatory Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects / Q000528:radiation effects; D004317:Doxorubicin / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm / Q000187:drug effects / Q000235:genetics / Q000528:radiation effects; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D005260:Female; D005419:Flavonoids / Q000494:pharmacology*; D005720:Gamma Rays; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects* / Q000528:radiation effects; D006801:Humans; D051379:Mice; D011427:Propiophenones / Q000494:pharmacology*; D034741:RNA, Small Interfering / Q000235:genetics; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology*; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000819:agonists / Q000235:genetics / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000528:radiation effects
chemical_list: C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000903:Antibiotics, Antineoplastic; D051017:Apoptosis Regulatory Proteins; D005419:Flavonoids; D011427:Propiophenones; D034741:RNA, Small Interfering; D011838:Radiation-Sensitizing Agents; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; C105190:TNFRSF10A protein, human; D004317:Doxorubicin; C512478:EGFR protein, human; D066246:ErbB Receptors; C104536:xanthohumol