a 2010

Dasatinib Promotes BIM Dependent Apoptosis Via MEK/ERK without Need for Permanent BCR-ABL Inhibition

ŠIMARA, Pavel, Stanislav STEJSKAL, Martina PETERKOVÁ, Irena KRONTORÁD KOUTNÁ, Zdeněk RÁČIL et. al.

Basic information

Original name

Dasatinib Promotes BIM Dependent Apoptosis Via MEK/ERK without Need for Permanent BCR-ABL Inhibition

Authors

ŠIMARA, Pavel (203 Czech Republic, belonging to the institution), Stanislav STEJSKAL (203 Czech Republic, belonging to the institution), Martina PETERKOVÁ (203 Czech Republic, belonging to the institution), Irena KRONTORÁD KOUTNÁ (203 Czech Republic, guarantor, belonging to the institution), Zdeněk RÁČIL (203 Czech Republic, belonging to the institution) and Jiří MAYER (203 Czech Republic, belonging to the institution)

Edition

ASH 2010, 2010

Other information

Language

English

Type of outcome

Konferenční abstrakt

Field of Study

30200 3.2 Clinical medicine

Country of publisher

United States of America

Confidentiality degree

není předmětem státního či obchodního tajemství

References:

Impact factor

Impact factor: 10.558

RIV identification code

RIV/00216224:14330/10:00046220

Organization unit

Faculty of Informatics

ISSN

Keywords in English

dasatinib; CML
Změněno: 3/1/2011 15:19, Mgr. Pavel Šimara, Ph.D.

Abstract

V originále

Chronic myeloid leukaemia (CML) is a clonal disorder of haematopoietic stem cells, characterized by constitutively active BCR-ABL kinase. It was previously shown, that transient inhibition of BCR-ABL by tyrosin kinase inhibitor (TKI) dasatinib induces apoptosis in CML cells (Shah 2008). Dasatinib mediated apoptosis is accompanied by increasing expression level of proapoptotic protein BIM and inhibition of its degradation in proteasome. Our aim is to find alterations in BCR-ABL downstream pathways and changes in BIM expression after pulse (wash-out after 20min) or continuous treatment with TKI dasatinib alone or in combination with proteasome inhibitor bortezomib in K562 cells. Higher mRNA levels of BIM were confirmed in both transiently and continuously treated (100nM dasatinib) K562 cells compared to low dose continuous (1nM dasatinib) treatment. Western blot analysis of BCR-ABL induced signalling pathways activity revealed, among others, sustained inhibition of MEK/ERK pathway even in the case of re-activation of BCR-ABL after drug wash-out. MEK/ERK inhibition leads to activation of proapoptotic BIM expression and inhibition of its degradation. We used bortezomib, a reversible inhibitor of proteasome, in order to test the block of BIM degradation in dasatinib treated cells. However, we have not found any difference in cell viability caused by adding of 30nM bortezomib to dasatinib treated cells neither in continuous or transient exposure. These findings suggest that equal increase of BIM in the case of pulse and continuous dasatinib treatment is caused by MEK/ERK inhibition in cells with restored BCR-ABL activity.

Links

MSM0021622430, plan (intention)
Name: Funkční a molekulární charakteristiky nádorových a normálních kmenových buněk - identifikace cílů pro nová terapeutika a terapeutické strategie
Investor: Ministry of Education, Youth and Sports of the CR, Functional and molecular characteristics of cancer and normal stem cells - identification of targets for novel therapeutics and therapeutic strategies
2B06052, research and development project
Name: Vytipování markerů, screening a časná diagnostika nádorových onemocnění pomocí vysoce automatizovaného zpracování multidimenzionálních biomedicínských obrazů (Acronym: Biomarker)
Investor: Ministry of Education, Youth and Sports of the CR, Determination of markers, screening and early diagnostics of cancer diseases using highly automated processing of multidimensional biomedical images