Showing papers by "Gary K. Scott published in 2004"

Proteasome and histone deacetylase inhibitors repress ErbB2 transcript levels and additively inhibit breast cancer growth.

Abstract: Proc Amer Assoc Cancer Res, Volume 45, 2004 2447 We have reported on the development of a high-throughput tumor cell screening platform employing MCF-7 sublines bearing chromatin-integrated promoter-reporters (luciferase) capable of identifying from chemical libraries drug-like small molecules with tumor cell permeability and specific oncogene promoter-inhibiting potential. Among the structurally diverse lead compounds emerging from a screen to identify inhibitors of the ErbB2 promoter were a hydroxamic acid inhibitor of histone deacetylase (HDAC), trichostatin, further verified using more potent analogs now under clinical development including SAHA and LAQ824; and a synthetic peptide inhibitor of the proteasome, MG-132, further verified using the more potent and clinically approved dipeptidyl boronate, PS-341/bortezomib. Mechanistically, in addition to repressing ErbB2 promoter activity, both the HDAC and proteasome inhibitors destabilize mature cytoplasmic ErbB2 transcripts, inducing rapid (5 hr) declines in ErbB2 mRNA and protein levels as measured by Northern and Western blots of treated ErbB2-overexpressing breast cancer cells (MDA-453, SKBr3, BT-474). By comparison, proteasome and HDAC inhibitors show opposing effects on the expression of such other breast cancer gene products as ER and ESX. Investigations are currently underway to determine if proteasome inhibitors destabilize ErbB2 transcripts by the same 3’UTR-dependent and HuR-associated mechanism as shown for HDAC inhibitors. During 7-day culture growth assays, breast cancer cells exposed to growth-inhibiting concentrations of PS-341 (>1 nM) and LAQ824 (>5 nM) show at least additive growth suppression in combination as compared to their single agent activity. These findings suggest that proteasome and HDAC inhibitors may have clinical utility against breast cancers, especially those overexpressing ErbB2, thus warranting further preclinical evaluation of combined proteasome and HDAC inhibitor therapy.