title: Dithiiranylmethyloxy azaxanthone shows potent anti-tumor activity via suppression of HER2 expression and HER2-mediated signals in HER2-overexpressing breast cancer cells.
abstract: Dithiiranylmethyloxy azaxanthone (CHO10), which was discovered by screening compounds in a reporter gene assay, inhibited the ESX-Sur2 interaction in a dose-dependent manner with potency similar to canertinib. The intervention of CHO10 during the ESX-Sur2 interaction caused down-regulation of both HER2 gene amplification and HER2 protein expression, which led to the attenuation of HER2-mediated downstream signal cascades and autocrine cell growth in SK-BR-3 cells, which are HER2 overexpressing breast cancer cells. The cell growth inhibitory activity of CHO10 was more potent in HER2-overexpressing breast cancer cells (AU-565, BT474 and SK-BR-3) than in HER2-negative cells (HEK293) and breast cancer cells (MCF-7) that express a basal level of HER2. Treatment with CHO10 in combination with tamoxifen sensitized BT474 cells, tamoxifen-resistant ER-positive breast cancer cell line, toward chemotherapeutic. The anti-tumor activity of CHO10 was validated by the significant reduction in tumor size of NCI-H460 or DLD-1 subcutaneously implanted xenograft tumors through treatment with 1mg/kg five times every other 2days.
authors.affiliation: College of Pharmacy, Graduate School of Pharmaceutical Sciences, Global Top5 Research Program, Ewha Womans University, Seoul 120-750, Republic of Korea.
authors.forename: Jung Min
authors.initials: JM
authors.lastname: Nam
authors.forename: Kyung-Hwa
authors.initials: KH
authors.lastname: Jeon
authors.forename: Hanbyeol
authors.initials: H
authors.lastname: Kwon
authors.forename: Eunyoung
authors.initials: E
authors.lastname: Lee
authors.forename: Kyu-Yeon
authors.initials: KY
authors.lastname: Jun
authors.forename: Yeung Bae
authors.initials: YB
authors.lastname: Jin
authors.forename: Yun-Sil
authors.initials: YS
authors.lastname: Lee
authors.forename: Younghwa
authors.initials: Y
authors.lastname: Na
authors.forename: Youngjoo
authors.initials: Y
authors.lastname: Kwon
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D001943:Breast Neoplasms / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004268:DNA-Binding Proteins / Q000378:metabolism*; D005260:Female; D057809:HEK293 Cells; D006801:Humans; D056892:Mediator Complex / Q000378:metabolism*; D051379:Mice; D008819:Mice, Nude; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009369:Neoplasms / Q000188:drug therapy / Q000473:pathology; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D050783:Proto-Oncogene Proteins c-ets; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism*; D015398:Signal Transduction; D013629:Tamoxifen / Q000494:pharmacology; D014157:Transcription Factors / Q000378:metabolism*; D047368:Tumor Burden / Q000187:drug effects; D044004:Xanthones / Q000494:pharmacology* / Q000627:therapeutic use; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D004268:DNA-Binding Proteins; D056892:Mediator Complex; D020928:Mitogen-Activated Protein Kinases; D011518:Proto-Oncogene Proteins; D050783:Proto-Oncogene Proteins c-ets; D018719:Erb-b2 Receptor Tyrosine Kinases; D013629:Tamoxifen; D014157:Transcription Factors; D044004:Xanthones; C105529:ELF3 protein, human; C492159:MED23 protein, human; C587043:dithiiranylmethyloxy azaxanthone; C508053:ERBB2 protein, human
keywords: Azaxanthone derivatives; ESX–Sur2 interaction inhibitor; Epidermal growth factor receptor; Human epidermal growth factor receptor 2; Tamoxifen resistant breast cancer