title: Small-molecule c-Myc inhibitor, 10058-F4, inhibits proliferation, downregulates human telomerase reverse transcriptase and enhances chemosensitivity in human hepatocellular carcinoma cells.
abstract: c-Myc oncogene is critical for the development of hepatocellular carcinoma. Given the successful use of small-molecule inhibitors on cancers, targeting c-Myc with small-molecule inhibitors represents a promising approach. The potential of using small-molecule c-Myc inhibitor, 10058-F4, was evaluated on hepatocellular carcinoma cell lines, HepG2 and Hep3B cells. HepG2 cells were more sensitive to 10058-F4 than Hep3B cells, as demonstrated by reduced cell viability, marked morphological changes and decreased c-Myc levels. 10058-F4 arrested the cell cycle (at G0/G1 phase) and induced apoptosis upon extended treatment. These observations might be attributable to the increased cyclin-dependent kinase inhibitor, p21, and decreased cyclin D3 levels. Besides, 10058-F4 also significantly decreased the alpha-fetoprotein levels, an indicator for hepatocellular carcinoma differentiation. We further found that 10058-F4 inhibited the transactivation of human telomerase reverse transcriptase, downregulated human telomerase reverse transcriptase expression and abrogated telomerase activity. In addition, pretreatment with 10058-F4 increased the chemosensitivity of HepG2 cells to low-dose doxorubicin, 5-fluorouracil and cisplatin. Therefore, small-molecule c-Myc inhibitors might represent a novel agent, alone or in combination with conventional chemotherapeutic agents, for anti-hepatocellular carcinoma therapy.
authors.affiliation: Division of Hematology-Oncology, Department of Internal Medicine, Taipei City Hospital, Ren-Ai Branch, Taipei Medical University, Taipei, Taiwan.
authors.forename: Che-Pin
authors.initials: CP
authors.lastname: Lin
authors.forename: Jean-Dean
authors.initials: JD
authors.lastname: Liu
authors.forename: Jyh-Ming
authors.initials: JM
authors.lastname: Chow
authors.forename: Chien-Ru
authors.initials: CR
authors.lastname: Liu
authors.forename: Hsingjin Eugene
authors.initials: HE
authors.lastname: Liu
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology*; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004273:DNA, Neoplasm / Q000187:drug effects; D015536:Down-Regulation / Q000187:drug effects; D024202:Electrophoretic Mobility Shift Assay; D005434:Flow Cytometry; D006801:Humans; D015151:Immunoblotting; D016271:Proto-Oncogene Proteins c-myc / Q000037:antagonists & inhibitors*; D018894:Reverse Transcriptase Inhibitors / Q000494:pharmacology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D019098:Telomerase / Q000096:biosynthesis*; D000509:alpha-Fetoproteins / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D004273:DNA, Neoplasm; D016271:Proto-Oncogene Proteins c-myc; D018894:Reverse Transcriptase Inhibitors; D000509:alpha-Fetoproteins; D019098:Telomerase