Accession Number:

ADA409418

Title:

Radiosensitization of Human Mammary Carcinoma Cells by Specific Inhibition of Signal Transduction Cascades

Descriptive Note:

Annual summary rept. 1 Aug 2001-31 Jul 2002

Corporate Author:

VIRGINIA COMMONWEALTH UNIV RICHMOND

Personal Author(s):

Report Date:

2002-08-01

Pagination or Media Count:

61.0

Abstract:

We investigated the impact of combined exposure to the check-point abrogator UCN-01 in conjunction with MEK12 inhibitors upon survival of mammary carcinoma cells. Treatment of cells with UCN-01 resulted in prolonged activation of the MAPK pathway. Inhibition of MEK12 caused modest reductions in basal MAPK activity and suppressed UCN-01-stimulated MAPK activity below that of MEK12 inhibitor alone. Significantly, combined, but not individual, exposure of cells to UCN-01 and MEK12 inhibitors enhanced BAX association with mitochondria and triggered release of cytochrome c into the cytosol, accompanied by activation of effector pro-caspases, resulting in a synergistic potentiation of apoptosis within 18-24th. Radiation exposure of drug treated cells did not further enhance apoptosis. Treatment of cells with both caspase 9 and caspase 8 inhibitors was required to completely inhibit apoptosis in carcinoma cells.

Subject Categories:

  • Anatomy and Physiology
  • Medicine and Medical Research

Distribution Statement:

APPROVED FOR PUBLIC RELEASE