title: Small-molecule inhibitors of c-Myc transcriptional factor suppress proliferation and induce apoptosis of promyelocytic leukemia cell via cell cycle arrest.
abstract: c-Myc plays a decisive role in the proliferation of HL-60 promyelocytic leukemia cells. In the present study, we demonstrated that an inhibitor of c-Myc/Max/DNA complex formation has a high potentiality as a suppressor of c-Myc-involved cell signaling. We prepared recombinant c-Myc and Max proteins encompassing the human-origin DNA binding and dimerization domains, and tested a chemical library of 6480 small molecules for their inhibitory effect on the in vitro formation of the c-Myc/Max/DNA complex as well as their influence on DMSO-differentiated HL-60 cells. We found several hit compounds through in vitro and cell-based screening tests, and also confirmed these compounds significantly inhibited the formation of the recombinant c-Myc/Max/DNA complex in the low micromolar range. Indeed, these inhibitors effectively blocked c-Myc-associated gene expression in cancer cell line, suppressed the proliferation and induced the apoptosis of HL-60 promyelocytic leukemia cells via cell cycle arrest without altering the expression level of c-Myc in the DMSO-differentiated HL-60 cells. These successive results suggest that our c-Myc/Max/DNA complex inhibitors potently contribute to the suppression of the Myc-dependent proliferation of leukemia cells and to the induction of apoptosis. Accordingly, we would expect that these compounds could serve as lead compounds in the development of novel anticancer drugs.
authors.affiliation: Cancer Cell and Molecular Biology Branch, Division of Cancer Biology, Research Institute, National Cancer Center, Gyeonggi-do, Republic of Korea. jeongkc@gmail.com
authors.forename: Kyung-Chae
authors.initials: KC
authors.lastname: Jeong
authors.forename: Kyung-Ohk
authors.initials: KO
authors.lastname: Ahn
authors.forename: Chul-Hak
authors.initials: CH
authors.lastname: Yang
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D002453:Cell Cycle / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects*; D015536:Down-Regulation / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor; D018922:HL-60 Cells; D006801:Humans; D015473:Leukemia, Promyelocytic, Acute / Q000473:pathology*; D016271:Proto-Oncogene Proteins c-myc / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000502:physiology; D011994:Recombinant Proteins / Q000235:genetics; D054852:Small Molecule Libraries / Q000032:analysis / Q000494:pharmacology*; D014157:Transcription Factors / Q000037:antagonists & inhibitors; D014407:Tumor Cells, Cultured
chemical_list: D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; C499330:MAX protein, human; C489427:MYC protein, human; D016271:Proto-Oncogene Proteins c-myc; D011994:Recombinant Proteins; D054852:Small Molecule Libraries; D014157:Transcription Factors