Synergistic induction of apoptosis by simultaneous disruption of the Bcl-2 and MEK/MAPK pathways in acute myelogenous leukemia

Michele Milella; Zeev Estrov; Steven M. Kornblau; Bing Z. Carter; Marina Konopleva; Ana Tari; Wendy D. Schober; David Harris; Clinton E. Leysath; Gabriel Lopez-Berestein; Ziwei Huang; Michael Andreeff

doi:10.1182/blood.V99.9.3461

Synergistic induction of apoptosis by simultaneous disruption of the Bcl-2 and MEK/MAPK pathways in acute myelogenous leukemia

Michele Milella, Zeev Estrov, Steven M. Kornblau, Bing Z. Carter, Marina Konopleva, Ana Tari, Wendy D. Schober, David Harris, Clinton E. Leysath, Gabriel Lopez-Berestein, Ziwei Huang, Michael Andreeff

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119 Scopus citations

Abstract

Recent sudies suggest that the Bcl-2 and mitogen-activated protein kinase (MAPK) pathways together confer an aggressive, apoptosis-resistant phenotype on acute myelogenous leukemia (AML) cells. In this study, we analyzed the effects of simultaneous inhibition of these 2 pathways. In AML cell lines with constitutively activated MAPK, MAPK kinase (MEK) blockade by PD184352 strikingly potentiated the apoptosis induced by the small-molecule Bcl-2 inhibitor HA14-1 or by Bcl-2 antisense oligonucleotides. Isobologram analysis confirmed the synergistic nature of this interaction. Moreover, MEK blockade overcame Bcl-2 overexpression-mediated resistance to the proapoptotic effects of HA14-1. Most importantly, simultaneous exposure to PD184352 significantly (P = .01) potentiated HA14-1-mediated inhibition of clonogenic growth in all primary AML samples tested. These findings show that the Bcl-2 and MAPK pathways are relevant molecular targets in AML and that their concurrent inhibition could be developed into a new therapeutic strategy for this disease.

Original language	English
Pages (from-to)	3461-3464
Number of pages	4
Journal	Blood
Volume	99
Issue number	9
DOIs	https://doi.org/10.1182/blood.V99.9.3461
State	Published - 1 May 2002
Externally published	Yes

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Milella, M., Estrov, Z., Kornblau, S. M., Carter, B. Z., Konopleva, M., Tari, A., Schober, W. D., Harris, D., Leysath, C. E., Lopez-Berestein, G., Huang, Z., & Andreeff, M. (2002). Synergistic induction of apoptosis by simultaneous disruption of the Bcl-2 and MEK/MAPK pathways in acute myelogenous leukemia. Blood, 99(9), 3461-3464. https://doi.org/10.1182/blood.V99.9.3461

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title = "Synergistic induction of apoptosis by simultaneous disruption of the Bcl-2 and MEK/MAPK pathways in acute myelogenous leukemia",

abstract = "Recent sudies suggest that the Bcl-2 and mitogen-activated protein kinase (MAPK) pathways together confer an aggressive, apoptosis-resistant phenotype on acute myelogenous leukemia (AML) cells. In this study, we analyzed the effects of simultaneous inhibition of these 2 pathways. In AML cell lines with constitutively activated MAPK, MAPK kinase (MEK) blockade by PD184352 strikingly potentiated the apoptosis induced by the small-molecule Bcl-2 inhibitor HA14-1 or by Bcl-2 antisense oligonucleotides. Isobologram analysis confirmed the synergistic nature of this interaction. Moreover, MEK blockade overcame Bcl-2 overexpression-mediated resistance to the proapoptotic effects of HA14-1. Most importantly, simultaneous exposure to PD184352 significantly (P = .01) potentiated HA14-1-mediated inhibition of clonogenic growth in all primary AML samples tested. These findings show that the Bcl-2 and MAPK pathways are relevant molecular targets in AML and that their concurrent inhibition could be developed into a new therapeutic strategy for this disease.",

author = "Michele Milella and Zeev Estrov and Kornblau, {Steven M.} and Carter, {Bing Z.} and Marina Konopleva and Ana Tari and Schober, {Wendy D.} and David Harris and Leysath, {Clinton E.} and Gabriel Lopez-Berestein and Ziwei Huang and Michael Andreeff",

year = "2002",

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doi = "10.1182/blood.V99.9.3461",

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T1 - Synergistic induction of apoptosis by simultaneous disruption of the Bcl-2 and MEK/MAPK pathways in acute myelogenous leukemia

AU - Milella, Michele

AU - Estrov, Zeev

AU - Kornblau, Steven M.

AU - Carter, Bing Z.

AU - Konopleva, Marina

AU - Tari, Ana

AU - Schober, Wendy D.

AU - Harris, David

AU - Leysath, Clinton E.

AU - Lopez-Berestein, Gabriel

AU - Huang, Ziwei

AU - Andreeff, Michael

PY - 2002/5/1

Y1 - 2002/5/1

N2 - Recent sudies suggest that the Bcl-2 and mitogen-activated protein kinase (MAPK) pathways together confer an aggressive, apoptosis-resistant phenotype on acute myelogenous leukemia (AML) cells. In this study, we analyzed the effects of simultaneous inhibition of these 2 pathways. In AML cell lines with constitutively activated MAPK, MAPK kinase (MEK) blockade by PD184352 strikingly potentiated the apoptosis induced by the small-molecule Bcl-2 inhibitor HA14-1 or by Bcl-2 antisense oligonucleotides. Isobologram analysis confirmed the synergistic nature of this interaction. Moreover, MEK blockade overcame Bcl-2 overexpression-mediated resistance to the proapoptotic effects of HA14-1. Most importantly, simultaneous exposure to PD184352 significantly (P = .01) potentiated HA14-1-mediated inhibition of clonogenic growth in all primary AML samples tested. These findings show that the Bcl-2 and MAPK pathways are relevant molecular targets in AML and that their concurrent inhibition could be developed into a new therapeutic strategy for this disease.

AB - Recent sudies suggest that the Bcl-2 and mitogen-activated protein kinase (MAPK) pathways together confer an aggressive, apoptosis-resistant phenotype on acute myelogenous leukemia (AML) cells. In this study, we analyzed the effects of simultaneous inhibition of these 2 pathways. In AML cell lines with constitutively activated MAPK, MAPK kinase (MEK) blockade by PD184352 strikingly potentiated the apoptosis induced by the small-molecule Bcl-2 inhibitor HA14-1 or by Bcl-2 antisense oligonucleotides. Isobologram analysis confirmed the synergistic nature of this interaction. Moreover, MEK blockade overcame Bcl-2 overexpression-mediated resistance to the proapoptotic effects of HA14-1. Most importantly, simultaneous exposure to PD184352 significantly (P = .01) potentiated HA14-1-mediated inhibition of clonogenic growth in all primary AML samples tested. These findings show that the Bcl-2 and MAPK pathways are relevant molecular targets in AML and that their concurrent inhibition could be developed into a new therapeutic strategy for this disease.

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DO - 10.1182/blood.V99.9.3461

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SP - 3461

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JO - Blood

JF - Blood

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ER -

Synergistic induction of apoptosis by simultaneous disruption of the Bcl-2 and MEK/MAPK pathways in acute myelogenous leukemia

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