3-m-bromoacetylamino benzoic acid ethyl ester: a new cancericidal agent that activates the apoptotic pathway through caspase-9.

Abstract

The mechanism underlying the cancericidal activity of 3-m-bromoacetylamino benzoic acid ethyl ester (3-BAABE) was investigated. 3-BAABE exerted a strong cancericidal effect on human leukemia and lymphoma cells (IC(50) < 0.2 microgram/mL) and on cell lines of prostate, colon, ductal, and kidney cancer (IC(50) 0.8 to 0.88 microgram/mL). Multiple drug resistance (MDR) had no effect on the susceptibility of human lymphoma cells to 3-BAABE, since Daudi/MDR(20) and wild-type Daudi cells had a similar susceptibility to the cytotoxic effect of 3-BAABE. The cancericidal effect of 3-BAABE, which was not associated with changes in the cell cycle, was mediated by apoptosis. Thus, cells exposed to 3-BAABE displayed the DNA fragmentation ladder characteristic for apoptosis, associated with a marked increase of the activity of apoptosis effector caspases-3 and -6, which was followed by proteolytic cleavage of DNA fragmentation factor (DFF) and poly(ADP-ribose) polymerase (PARP). Exposure of tumor cells to 3-BAABE increased the activity of apical caspase-9, but had no effect on caspase-8. Complete inhibition of 3-BAABE-induced apoptosis was exerted by LEHD-FMK, a caspase-9 inhibitor. DEVD-FMK, a caspase-3 inhibitor, and VEID-FMK, a caspase-6 inhibitor, partially inhibited 3-BAABE-induced apoptosis, whereas exposure to IETD-FMK, a caspase-8 inhibitor, had no effect. The fragmentation and elevated activity of caspase-9 in 3-BAABE-treated cells and the fact that only an inhibitor of caspase-9 abrogated 3-BAABE-induced apoptosis indicate that 3-BAABE is a distinctive compound that elicits apoptosis through a pathway that is limited specifically to activation of apical caspase-9.

• Authors: M Schlesinger, J D Jiang, J P Roboz, L Denner, Y H Ling, J F Holland, J G Bekesi
• Journal: Biochemical pharmacology (Biochem Pharmacol) Vol. 60 Issue 11 Pg. 1693-702 (Dec 01 2000) ISSN: 0006-2952 [Print] England
• PMID: 11077052 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• 3-bromoacetylamino benzoic acid ethyl ester
• Antineoplastic Agents
• Benzoates
• Esters
• meta-Aminobenzoates
• Benzoic Acid
• Poly(ADP-ribose) Polymerases
• CASP9 protein, human
• Casp9 protein, mouse
• Caspase 9
• Caspases

Topics

• Animals
• Antineoplastic Agents (pharmacology)
• Apoptosis (physiology)
• Benzoates
• Benzoic Acid (pharmacology)
• Caspase 9
• Caspases (metabolism)
• Cell Cycle (drug effects)
• DNA Fragmentation (drug effects)
• Esters (pharmacology)
• Humans
• Mice
• Microtubules (metabolism)
• Poly(ADP-ribose) Polymerases (metabolism)
• Tumor Cells, Cultured
• meta-Aminobenzoates