XXII. BIOCHEMICKÝ ZJAZD - Jesseniova lekárska fakulta

Posters
63.
STUDY OF ANTIAPOPTOTIC PROTEINS RESPONSIBLE FOR DEVELOPMENT
OF DRUG RESISTANCE IN ACUTE LEUKEMIA
Jana Jurečeková, Jozef Hatok, Andrea Štefániková, Dušan Dobrota and Peter Račay
Comenius University in Bratislava, Jessenius Faculty of Medicine in Martin,
Department of Medical Biochemistry
Deregulation of apoptosis disrupts the complex and delicate balance between cell proliferation,
survival and cell death and plays a major role in the development of diseases
such as cancer, and particularly acute leukemia. Malignant cells that have alterations in
proteins involed in cell death signaling are very frequently resistant to chemotherapy
and are difficult to treat with chemotherapeutic agents that primarily act by inducing
apoptosis. Structural analysis of antiapoptotic proteins together with studies of their
biochemical mechanisms have outlines strategies for generation of drugs, resulting in
numerous novel chemical entities with mechanism-based activity.
In presented study, the influence of ABT-737, the synthetic inhibitor of antiapoptotic
proteins Bcl-2 and Bcl-xL, on induction of apoptosis and viability of leukemic cell lines
HL-60 and K-562 was tested. Higher sensitivity of HL-60 (EC 50
= 4,5 µM) probably correlates
with mildly lower expression of Mcl-1, which overexpression may be responsible
for resistance to ABT-737. Fragmentation of DNA was observed already after 3 hours of
cultivation with ABT-737, so we confirmed that ABT-737 acts via induction of apoptosis.
ABT-737 was also found to enhance the effects of chemotherapy in HL-60.
Understanding of the core components of the apoptotic machinery at the molecular and
structural levels may lead to creating a new era in cancer therapy where the intrinsic and
acquired resistance of malignant cells to apoptosis can be pharmacologically reversed,
reinstating natural pathways of cell suicide.
Acknowledgements: This work was supported by the Grant UK/38/2010.
XXII. Biochemistry Congress, Martin
185