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¹ Molecular Aspects of Drug Design, Structural Biophysics Laboratory, Center for Cancer Research; ² Screening Technologies Branch, Laboratory of Functional Genomics, Science Applications International Corporation, National Cancer Institute at Frederick, Frederick, Maryland; and ³ Department of Radiation Oncology, University of Texas Health Science Center, San Antonio, Texas

Requests for reprints: Christopher J. Michejda, Molecular Aspects of Drug Design, Structural Biophysics Laboratory, Center for Cancer Research, National Cancer Institute at Frederick, Frederick, MD 21702. Phone: 301-846-1216; Fax: 301-846-6231. E-mail: michejda{at}ncifcrf.gov

WMC-79 is a synthetic agent with potent activity against colon and hematopoietic tumors. In vitro, the agent is most potent against colon cancer cells that carry the wild-type p53 tumor suppressor gene (HCT-116 and RKO cells: GI₅₀ <1 nmol/L, LC₅₀ 40 nmol/L). Growth arrest of HCT-116 and RKO cells occurs at the G₁ and G₂-M check points at sublethal concentrations (10 nmol/L) but the entire cell population was killed at 100 nmol/L. WMC-79 is localized to the nucleus where it binds to DNA. We hypothesized that WMC-79 binding to DNA is recognized as an unrepairable damage in the tumor cells, which results in p53 activation. This triggers transcriptional up-regulation of p53-dependent genes involved in replication, cell cycle progression, growth arrest, and apoptosis as evidenced by DNA microarrays. The change in the transcriptional profile of HCT-116 cells is followed by a change in the levels of cell cycle regulatory proteins and apoptosis. The recruitment of the p53-dependent apoptosis pathway was suggested by the up-regulation of p53, p21, Bax, DR-4, DR-5, and p53 phosphorylated on Ser15; down-regulation of Bcl-2; and activation of caspase-8, -9, -7, and -3 in cells treated with 100 nmol/L WMC-79. Apoptosis was also evident from the flow cytometric studies of drug-treated HCT-116 cells as well as from the appearance of nuclear fragmentation. However, whereas this pathway is important in wild-type p53 colon tumors, other pathways are also in operation because colon cancer cell lines in which the p53 gene is mutated are also affected by higher concentrations of WMC-79.