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E1A overcomes the apoptosis block in BCR-ABL+ leukemia cells and renders cells susceptible to induction of apoptosis by chemotherapeutic agents.
Cancer Res. 2000 Jul 15; 60(14):3957-64.CR

Abstract

A crucial function of the BCR-ABL chimeric gene in chronic myeloid leukemia is the prolongation of cell survival by inhibition of apoptosis. BCR-ABL expression confers cross-resistance to multiple genotoxic anticancer drugs by inhibition of the apoptotic response to DNA damage in association with cell cycle arrest at the G2-M restriction point. Previous reports indicated that BCR-ABL exerts its antiapoptotic effect against various apoptotic stimuli upstream to the cleavage and activity of caspase-3. Here we show that the adenovirus E1A protein induces substantial apoptosis in BCR-ABL expressing K562 and LAMA-84 leukemia cells. This apoptotic activity of E1A is accompanied by processing of caspase-3 and cleavage of poly(ADP-ribose) polymerase and can be significantly blocked by z-VAD-fmk Z-Val-Ala-Asp(OCH3)-CH2F and the caspase-3-specific inhibitor Z-DEVD-FMK Z-Asp(OCH3)-Glu-Val-Asp(OCH3)-CH2F. Moreover, E1A renders K562 cells, which are particularly resistant to cell death irrespective of the inducing agent, susceptible to induction of apoptosis by the chemotherapeutic agents etoposide and daunorubicin. Counteracting the DNA damage-induced inactivation of cdc2 kinase, E1A reverses the drug-induced G2-M arrest These results indicate that solitary delivery of E1A significantly antagonizes BCR-ABL-induced antiapoptotic functions and circumvents the inherent resistance to DNA damage-induced apoptosis, supporting the use of E1A in combination with chemotherapeutic agents as a promising therapeutic strategy for successful treatment of Philadelphia chromosome-positive leukemia in vivo.

Authors+Show Affiliations

Institute of Molecular Biology, University of Essen Medical School, Germany.No 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

10919674

Citation

Stiewe, T, et al. "E1A Overcomes the Apoptosis Block in BCR-ABL+ Leukemia Cells and Renders Cells Susceptible to Induction of Apoptosis By Chemotherapeutic Agents." Cancer Research, vol. 60, no. 14, 2000, pp. 3957-64.
Stiewe T, Parssanedjad K, Esche H, et al. E1A overcomes the apoptosis block in BCR-ABL+ leukemia cells and renders cells susceptible to induction of apoptosis by chemotherapeutic agents. Cancer Res. 2000;60(14):3957-64.
Stiewe, T., Parssanedjad, K., Esche, H., Opalka, B., & Pützer, B. M. (2000). E1A overcomes the apoptosis block in BCR-ABL+ leukemia cells and renders cells susceptible to induction of apoptosis by chemotherapeutic agents. Cancer Research, 60(14), 3957-64.
Stiewe T, et al. E1A Overcomes the Apoptosis Block in BCR-ABL+ Leukemia Cells and Renders Cells Susceptible to Induction of Apoptosis By Chemotherapeutic Agents. Cancer Res. 2000 Jul 15;60(14):3957-64. PubMed PMID: 10919674.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - E1A overcomes the apoptosis block in BCR-ABL+ leukemia cells and renders cells susceptible to induction of apoptosis by chemotherapeutic agents. AU - Stiewe,T, AU - Parssanedjad,K, AU - Esche,H, AU - Opalka,B, AU - Pützer,B M, PY - 2000/8/5/pubmed PY - 2000/8/29/medline PY - 2000/8/5/entrez SP - 3957 EP - 64 JF - Cancer research JO - Cancer Res VL - 60 IS - 14 N2 - A crucial function of the BCR-ABL chimeric gene in chronic myeloid leukemia is the prolongation of cell survival by inhibition of apoptosis. BCR-ABL expression confers cross-resistance to multiple genotoxic anticancer drugs by inhibition of the apoptotic response to DNA damage in association with cell cycle arrest at the G2-M restriction point. Previous reports indicated that BCR-ABL exerts its antiapoptotic effect against various apoptotic stimuli upstream to the cleavage and activity of caspase-3. Here we show that the adenovirus E1A protein induces substantial apoptosis in BCR-ABL expressing K562 and LAMA-84 leukemia cells. This apoptotic activity of E1A is accompanied by processing of caspase-3 and cleavage of poly(ADP-ribose) polymerase and can be significantly blocked by z-VAD-fmk Z-Val-Ala-Asp(OCH3)-CH2F and the caspase-3-specific inhibitor Z-DEVD-FMK Z-Asp(OCH3)-Glu-Val-Asp(OCH3)-CH2F. Moreover, E1A renders K562 cells, which are particularly resistant to cell death irrespective of the inducing agent, susceptible to induction of apoptosis by the chemotherapeutic agents etoposide and daunorubicin. Counteracting the DNA damage-induced inactivation of cdc2 kinase, E1A reverses the drug-induced G2-M arrest These results indicate that solitary delivery of E1A significantly antagonizes BCR-ABL-induced antiapoptotic functions and circumvents the inherent resistance to DNA damage-induced apoptosis, supporting the use of E1A in combination with chemotherapeutic agents as a promising therapeutic strategy for successful treatment of Philadelphia chromosome-positive leukemia in vivo. SN - 0008-5472 UR - https://www.unboundmedicine.com/medline/citation/10919674/E1A_overcomes_the_apoptosis_block_in_BCR_ABL+_leukemia_cells_and_renders_cells_susceptible_to_induction_of_apoptosis_by_chemotherapeutic_agents_ L2 - http://cancerres.aacrjournals.org/cgi/pmidlookup?view=long&pmid=10919674 DB - PRIME DP - Unbound Medicine ER -