title: Ascochlorin Enhances the Sensitivity of Doxorubicin Leading to the Reversal of Epithelial-to-Mesenchymal Transition in Hepatocellular Carcinoma.
abstract: Increasing evidence has indicated that epithelial-to-mesenchymal transition (EMT) at the advanced stage of liver cancer not only has the ability to self-renew and progress cancer, but also enables greater resistance to conventional chemo- and radiotherapies. Here, we report that ascochlorin (ASC), an isoprenoid antibiotic, could potentiate the cytotoxic effect of doxorubicin on HCCLM3, SNU387, SNU49, and SK-Hep-1 hepatocellular carcinoma cells, which had a predominantly mesenchymal signature with low expression of E-cadherin but high expression of N-cadherin. Co-administration of ASC reduced doxorubicin-induced invasion/migration and modulated EMT characteristics in mesenchymal cells. This process was probably mediated by the E-cadherin repressors Snail and Slug. In addition, ASC increased sensitivity to doxorubicin treatment by directly inhibiting STAT3 binding to the Snail promoter. We also observed that ASC significantly enhanced the effect of doxorubicin against tumor growth and inhibited metastasis in an HCCLM3_Luc orthotopic mouse model. Collectively, our data demonstrate that ASC can increase sensitivity to doxorubicin therapy and reverse the EMT phenotype via the downregulation of STAT3-Snail expression, which could form the basis of a novel therapeutic approach against hepatocellular carcinoma. Mol Cancer Ther; 15(12); 2966-76. ©2016 AACR.
authors.affiliation: Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
authors.forename: Xiaoyun
authors.initials: X
authors.lastname: Dai
authors.affiliation: College of Oriental Medicine, Kyung Hee University, Seoul, Republic of Korea.
authors.forename: Kwang Seok
authors.initials: KS
authors.lastname: Ahn
authors.affiliation: Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.|Cancer Science Institute of Singapore, Centre for Translational Medicine, Singapore.
authors.forename: Ling Zhi
authors.initials: LZ
authors.lastname: Wang
authors.affiliation: College of Oriental Medicine, Kyung Hee University, Seoul, Republic of Korea.
authors.forename: Chulwon
authors.initials: C
authors.lastname: Kim
authors.affiliation: Division of Cellular and Molecular Research, Humphrey Oei Institute of Cancer Research, National Cancer Centre, Singapore.
authors.forename: Amudha
authors.initials: A
authors.lastname: Deivasigamni
authors.affiliation: Stem Cell and Cancer Biology Laboratory, School of Biomedical Sciences, Curtin Health Innovation Research Institute, Curtin University, Perth, Australia.
authors.forename: Frank
authors.initials: F
authors.lastname: Arfuso
authors.affiliation: Department of Science in Korean Medicine, Graduate School and College of Korean Medicine, Kyung Hee University, Seoul, Republic of Korea.
authors.forename: Jae-Young
authors.initials: JY
authors.lastname: Um
authors.affiliation: Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.|Cancer Science Institute of Singapore, Centre for Translational Medicine, Singapore.|School of Biomedical Sciences, Curtin Health Innovation Research Institute, Curtin University, Perth, WA, Australia.|Department of Biological Sciences, University of North Texas, Denton, Texas.
authors.forename: Alan Prem
authors.initials: AP
authors.lastname: Kumar
authors.affiliation: Department of Cell Biology, Catholic University of Daegu, School of Medicine, Daegu, Korea.
authors.forename: Young-Chae
authors.initials: YC
authors.lastname: Chang
authors.affiliation: Laboratory of Tumor Biology, Angiogenesis and Nanomedicine Research, National Centre for Cell Science, Pune, India.
authors.forename: Dhiraj
authors.initials: D
authors.lastname: Kumar
authors.affiliation: Laboratory of Tumor Biology, Angiogenesis and Nanomedicine Research, National Centre for Cell Science, Pune, India.
authors.forename: Gopal C
authors.initials: GC
authors.lastname: Kundu
authors.affiliation: Magae Bioscience Institute, Tsukuba, Japan.
authors.forename: Junji
authors.initials: J
authors.lastname: Magae
authors.affiliation: Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.|Cancer Science Institute of Singapore, Centre for Translational Medicine, Singapore.|Department of Haematology-Oncology, National University Health System, Singapore.
authors.forename: Boon Cher
authors.initials: BC
authors.lastname: Goh
authors.affiliation: Division of Cellular and Molecular Research, Humphrey Oei Institute of Cancer Research, National Cancer Centre, Singapore. phcgs@nus.edu.sg cmrhkm@nccs.com.sg.|Institute of Molecular and Cell Biology, A*STAR, Biopolis Drive Proteos, Singapore.|Cancer and Stem Cell Biology Program, Duke-National University of Singapore Graduate Medical School, Singapore.|Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
authors.forename: Kam Man
authors.initials: KM
authors.lastname: Hui
authors.affiliation: Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore. phcgs@nus.edu.sg cmrhkm@nccs.com.sg.|School of Biomedical Sciences, Curtin Health Innovation Research Institute, Curtin University, Perth, WA, Australia.
authors.forename: Gautam
authors.initials: G
authors.lastname: Sethi
mesh_terms: D000475:Alkenes / Q000494:pharmacology*; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D015415:Biomarkers; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy / Q000235:genetics / Q000473:pathology*; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D004317:Doxorubicin / Q000494:pharmacology*; D019008:Drug Resistance, Neoplasm; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects* / Q000235:genetics; D005260:Female; D015870:Gene Expression; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000473:pathology*; D051379:Mice; D010636:Phenols / Q000494:pharmacology*; D050796:STAT3 Transcription Factor / Q000378:metabolism; D000071250:Snail Family Transcription Factors / Q000235:genetics / Q000378:metabolism
chemical_list: D000475:Alkenes; D000903:Antibiotics, Antineoplastic; D015415:Biomarkers; D010636:Phenols; D050796:STAT3 Transcription Factor; D000071250:Snail Family Transcription Factors; D004317:Doxorubicin; C415745:ascochlorin