Accession Number:

ADA434112

Title:

Exploiting Novel Calcium-Mediated Apoptotic Processes for the Treatment of Human Breast

Descriptive Note:

Annual summary rept. 6 Feb 2004-5 Feb 2005

Corporate Author:

CASE WESTERN RESERVE UNIV CLEVELAND OH

Report Date:

2005-03-01

Pagination or Media Count:

8.0

Abstract:

Alterations in the regulation and initiation of cell death, in particular caspase-mediated apoptotic cell death, have been associated with a vast array of pathological disease states such as cancer, and the development of resistance to cancer chemotherapies. Beta-Lapachone Beta-Lap, a naturally occurring 1,2 naphthoquinone, has been shown by our laboratory to induce non-caspase-mediated apoptosis in breast and prostate cancer cells that express the two electron oxidoreductase, NADPHquinone oxidoreductaseNQO1. Here, we demonstrate that polyADP-ribose polymerase PARP hyperactivation, occurs shortly after Beta-lap exposure in an NQO1 dependent manner. Hyperactivation of PARP is consistent with the presence of DNA strand breaks detected by comet and gammaH2AX formation. Chemical Inhibition of PARP activity in MCF-7 human breast cancer cells by 3-aminobenzamide or DPQ suppressed beta-lab-induced apoptosis consistent with a role for PARP hyperactivation in beta-lap induced cell death. Chelation of Interacellular Ca2 using BATPA-AM after beta-lap treatment abrogated gammaH2AX formation, PARP activation, and dramatically blocked beta-lap induced death as measured by long-term growth assays. Collectively, these data demonstrate the importance of Ca2 mediated PARP hyperactivation in beta-lab-induced cell death. We will discuss how this Ca2 dependent cell death can be exploited to effectively target and treat tumors that have lost their ability to undergo caspase-mediated apoptosis.

Subject Categories:

  • Biochemistry
  • Medicine and Medical Research

Distribution Statement:

APPROVED FOR PUBLIC RELEASE