A small-molecule E2F inhibitor blocks growth in a melanoma culture model

Yihong Ma, Courtney A. Kurtyka, Sandhya Boyapalle, Shen Shu Sung, Harshani Lawrence, Wayne Guida, W. Douglas Cress

Research output: Contribution to journalArticle

51 Scopus citations

Abstract

HLM006474 was identified using a computer-based virtual screen and the known crystal structure of the DNA-bound E2F4/DP2 heterodimer. Treatment of multiple cell lines with HLM006474 resulted in the loss of intracellular E2F4 DNA-binding activity as measured by electrophoretic mobility shift assay within hours. Overnight exposure to HLM006474 resulted in down-regulation of total E2F4 protein as well as known E2F targets. The effects of HLM006474 treatment on different cell lines varied but included a reduction in cell proliferation and an increase in apoptosis. HLM006474 induced apoptosis in a manner distinct from cisplatin and doxorubicin. E2F4-null mouse embryonic fibroblasts were less sensitive than wild-type counterparts to the apoptosis-inducing activity of the compound, revealing its biological specificity. A375 cells were extremely sensitive to the apoptosis-inducing activity of the compound in two-dimensional culture, and HLM006474 was a potent inhibitor of melanocytes proliferation and subsequent invasion in a three-dimensional tissue culture model system. Together, these results suggest that interference with E2F activity using small molecules may have clinical application in cancer therapy.

Original languageEnglish (US)
Pages (from-to)6292-6299
Number of pages8
JournalCancer Research
Volume68
Issue number15
DOIs
StatePublished - Aug 1 2008

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

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    Ma, Y., Kurtyka, C. A., Boyapalle, S., Sung, S. S., Lawrence, H., Guida, W., & Cress, W. D. (2008). A small-molecule E2F inhibitor blocks growth in a melanoma culture model. Cancer Research, 68(15), 6292-6299. https://doi.org/10.1158/0008-5472.CAN-08-0121