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Pyrrolo-1,5-benzoxazepines induce apoptosis in chronic myelogenous leukemia (CML) cells by bypassing the apoptotic suppressor bcr-abl.
J Pharmacol Exp Ther. 2001 Jan; 296(1):31-40.JP

Abstract

Expression of the transforming oncogene bcr-abl in chronic myelogenous leukemia (CML) cells is reported to confer resistance against apoptosis induced by many chemotherapeutic agents such as etoposide, ara-C, and staurosporine. In the present study some members of a series of novel pyrrolo-1,5-benzoxazepines potently induce apoptosis, as shown by cell shrinkage, chromatin condensation, DNA fragmentation, and poly(ADP-ribose) polymerase (PARP) cleavage, in three CML cell lines, K562, KYO.1, and LAMA 84. Induction of apoptosis by a representative member of this series, PBOX-6, was not accompanied by either the down-regulation of Bcr-Abl or by the attenuation of its protein tyrosine kinase activity up to 24 h after treatment, when approximately 50% of the cells had undergone apoptosis. These results suggest that down-regulation of Bcr-Abl is not part of the upstream apoptotic death program activated by PBOX-6. By characterizing the mechanism in which this novel agent executes apoptosis, this study has revealed that PBOX-6 caused activation of caspase 3-like proteases in only two of the three CML cell lines. In addition, inhibition of caspase 3-like protease activity using the inhibitor z-DEVD-fmk blocked caspase 3-like protease activity but did not prevent the induction of apoptosis, suggesting that caspase 3-like proteases are not essential in the mechanism by which PBOX-6 induces apoptosis in CML cells. In conclusion, this study demonstrates that PBOX-6 can bypass Bcr-Abl-mediated suppression of apoptosis, suggesting an important potential use of these compounds in the treatment of CML.

Authors+Show Affiliations

Department of Biochemistry, Trinity College, Dublin, Ireland.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

11123359

Citation

Mc Gee, M M., et al. "Pyrrolo-1,5-benzoxazepines Induce Apoptosis in Chronic Myelogenous Leukemia (CML) Cells By Bypassing the Apoptotic Suppressor Bcr-abl." The Journal of Pharmacology and Experimental Therapeutics, vol. 296, no. 1, 2001, pp. 31-40.
Mc Gee MM, Campiani G, Ramunno A, et al. Pyrrolo-1,5-benzoxazepines induce apoptosis in chronic myelogenous leukemia (CML) cells by bypassing the apoptotic suppressor bcr-abl. J Pharmacol Exp Ther. 2001;296(1):31-40.
Mc Gee, M. M., Campiani, G., Ramunno, A., Fattorusso, C., Nacci, V., Lawler, M., Williams, D. C., & Zisterer, D. M. (2001). Pyrrolo-1,5-benzoxazepines induce apoptosis in chronic myelogenous leukemia (CML) cells by bypassing the apoptotic suppressor bcr-abl. The Journal of Pharmacology and Experimental Therapeutics, 296(1), 31-40.
Mc Gee MM, et al. Pyrrolo-1,5-benzoxazepines Induce Apoptosis in Chronic Myelogenous Leukemia (CML) Cells By Bypassing the Apoptotic Suppressor Bcr-abl. J Pharmacol Exp Ther. 2001;296(1):31-40. PubMed PMID: 11123359.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Pyrrolo-1,5-benzoxazepines induce apoptosis in chronic myelogenous leukemia (CML) cells by bypassing the apoptotic suppressor bcr-abl. AU - Mc Gee,M M, AU - Campiani,G, AU - Ramunno,A, AU - Fattorusso,C, AU - Nacci,V, AU - Lawler,M, AU - Williams,D C, AU - Zisterer,D M, PY - 2000/12/21/pubmed PY - 2001/3/3/medline PY - 2000/12/21/entrez SP - 31 EP - 40 JF - The Journal of pharmacology and experimental therapeutics JO - J Pharmacol Exp Ther VL - 296 IS - 1 N2 - Expression of the transforming oncogene bcr-abl in chronic myelogenous leukemia (CML) cells is reported to confer resistance against apoptosis induced by many chemotherapeutic agents such as etoposide, ara-C, and staurosporine. In the present study some members of a series of novel pyrrolo-1,5-benzoxazepines potently induce apoptosis, as shown by cell shrinkage, chromatin condensation, DNA fragmentation, and poly(ADP-ribose) polymerase (PARP) cleavage, in three CML cell lines, K562, KYO.1, and LAMA 84. Induction of apoptosis by a representative member of this series, PBOX-6, was not accompanied by either the down-regulation of Bcr-Abl or by the attenuation of its protein tyrosine kinase activity up to 24 h after treatment, when approximately 50% of the cells had undergone apoptosis. These results suggest that down-regulation of Bcr-Abl is not part of the upstream apoptotic death program activated by PBOX-6. By characterizing the mechanism in which this novel agent executes apoptosis, this study has revealed that PBOX-6 caused activation of caspase 3-like proteases in only two of the three CML cell lines. In addition, inhibition of caspase 3-like protease activity using the inhibitor z-DEVD-fmk blocked caspase 3-like protease activity but did not prevent the induction of apoptosis, suggesting that caspase 3-like proteases are not essential in the mechanism by which PBOX-6 induces apoptosis in CML cells. In conclusion, this study demonstrates that PBOX-6 can bypass Bcr-Abl-mediated suppression of apoptosis, suggesting an important potential use of these compounds in the treatment of CML. SN - 0022-3565 UR - https://www.unboundmedicine.com/medline/citation/11123359/Pyrrolo_15_benzoxazepines_induce_apoptosis_in_chronic_myelogenous_leukemia__CML__cells_by_bypassing_the_apoptotic_suppressor_bcr_abl_ L2 - https://jpet.aspetjournals.org/cgi/pmidlookup?view=long&pmid=11123359 DB - PRIME DP - Unbound Medicine ER -