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

Michael Schlesinger, Jian Dong Jiang, Julia P. Roboz, Larry Denner, Yi He Ling, James F. Holland, J. George Bekesi

Research output: Contribution to journalArticle

10 Citations (Scopus)

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 (IC50 < 0.2 μg/mL) and on cell lines of prostate, colon, ductal, and kidney cancer (IC50 0.8 to 0.88 μg/mL). Multiple drug resistance (MDR) had no effect on the susceptibility of human lymphoma cells to 3-BAABE, since Daudi/MDR20 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. (C) 2000 Elsevier Science Inc.

Original languageEnglish (US)
Pages (from-to)1693-1702
Number of pages10
JournalBiochemical Pharmacology
Volume60
Issue number11
DOIs
StatePublished - Dec 1 2000
Externally publishedYes

Fingerprint

Caspase 9
Apoptosis
Caspase Inhibitors
Caspase 6
Cells
Caspase 8
DNA Fragmentation
Caspase 3
Inhibitory Concentration 50
3-bromoacetylamino benzoic acid ethyl ester
Lymphoma
Effector Caspases
Poly(ADP-ribose) Polymerases
Kidney Neoplasms
DNA
Ladders
Multiple Drug Resistance
Colonic Neoplasms
Tumors
Prostate

Keywords

  • Apoptosis
  • Cancericidal drug
  • Caspases

ASJC Scopus subject areas

  • Pharmacology

Cite this

3-m-bromoacetylamino benzoic acid ethyl ester : A new cancericidal agent that activates the apoptotic pathway through caspase-9. / Schlesinger, Michael; Jiang, Jian Dong; Roboz, Julia P.; Denner, Larry; Ling, Yi He; Holland, James F.; Bekesi, J. George.

In: Biochemical Pharmacology, Vol. 60, No. 11, 01.12.2000, p. 1693-1702.

Research output: Contribution to journalArticle

Schlesinger, Michael ; Jiang, Jian Dong ; Roboz, Julia P. ; Denner, Larry ; Ling, Yi He ; Holland, James F. ; Bekesi, J. George. / 3-m-bromoacetylamino benzoic acid ethyl ester : A new cancericidal agent that activates the apoptotic pathway through caspase-9. In: Biochemical Pharmacology. 2000 ; Vol. 60, No. 11. pp. 1693-1702.
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