Components of the cell death machine and drug sensitivity of the National Cancer Institute cell line panel

Svingen, P. A., Loegering, D., Rodriquez, J., Meng, X. W., Mesner, P. W., Holbeck, S., Monks, A., Krajewski, S., Scudiero, D. A., Sausville, E. A., Reed, J. C., Lazebnik, Y. A., Kaufmann, S. H. (October 2004) Components of the cell death machine and drug sensitivity of the National Cancer Institute cell line panel. Clinical Cancer Research, 10 (20). pp. 6807-6820. ISSN 1078-0432

URL: http://clincancerres.aacrjournals.org/content/10/2...
DOI: 10.1158/1078-0432.CCR-0778-02

Abstract

Purpose: According to some studies, susceptibility of cells to anticancer drug-induced apoptosis is markedly inhibited by targeted deletion of genes encoding apoptotic protease activating factor 1 (Apaf-1) or certain caspases. Information about levels of these polypeptides in common cancer cell types and any possible correlation with drug sensitivity in the absence of gene deletion is currently fragmentary. Experimental Design: Immunoblotting was used to estimate levels of Apaf-1 as well as procaspase-2, -3, -6, -7, -8, and -9 in the 60-cell-line panel used for drug screening by the National Cancer Institute. Sensitivity of the same lines to >80,000 compounds was determined with 48-hour sulforhodamine B binding assays. Additional 6-day assays were performed for selected agents. Results: Levels of Apaf-1 and procaspases varied widely. Apaf-1 and procaspase-9, which are implicated in caspase activation after treatment of cells with various anticancer drugs, were detectable in all of the cell lines, with levels of Apaf-1 ranging from similar to1 X 10(5) to 2 X 10(6) molecules per cell and procaspase-9 from similar to5 X 10(3) to similar to1.6 X 10(5) molecules per cell. Procaspase-8 levels ranged from 1.7 X 10(5) to 8 X 10(6) molecules per cell. Procaspase-3, a major effector caspase, varied from undetectable to similar to1.6 X 10(6) molecules per cell. Correlations between levels of these polypeptides and sensitivity to any of a variety of experimental or conventional antineoplastic agents in either 2-day or 6-day cytotoxicity assays were weak at best. Conclusions: With the exception of caspase-3, all of the components of the core cell-death machinery are expressed in all of the cell lines examined. Despite variations in expression, levels of any one component are not a major determinant of drug sensitivity in these cells in vitro.

Item Type: Paper
Uncontrolled Keywords: ETOPOSIDE-INDUCED APOPTOSIS etoposide induced apoptosis STRESS-INDUCED APOPTOSIS stress induced apoptosis TRAIL-INDUCED trail induced APOPTOSIS COLON-CARCINOMA CELLS colon carcinoma cells CYTOCHROME-C cytochrome-C CASPASE ACTIVATION caspase activation IN-VITRO in-vitro MYELOGENOUS LEUKEMIA myelogenous leukemia ANTICANCER AGENTS anticancer agents ACTIVE CASPASES active caspases
Subjects: diseases & disorders > cancer
diseases & disorders > cancer > drugs and therapies
CSHL Authors:
Communities: CSHL labs > Labeznik lab
Depositing User: CSHL Librarian
Date: October 2004
Date Deposited: 25 Jan 2012 15:08
Last Modified: 25 Jan 2012 15:08
URI: http://repository.cshl.edu/id/eprint/22494

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