PP177. APOPTOTIC PATHWAYS INDUCED BY IMATINIB IN SENSITIVE AND IMATINIB-RESISTANT K562 CELLS
YUSUF BARAN1,3, Ufuk Gündüz1, Ali Uğur Ural2, Besim Öğretmen3. 1. Middle East Technical University, Department of Biology, TURKEY. 2. Gülhane Military Medical Academy, Department of Hematology, TURKEY. 3. Medical University of South Carolina, Department of Biochemistry and Molecular Biology, USA. e-mail: ybaran@metu.edu.tr
*Corresponding Author:
page: 127

Abstract

There are three different mechanisms by which a cell commits suicide by apoptosis; generating signals arising within the cell, death activators binding to receptors at the cell surface (TNF-?, Fas ligand) and dangerous reactive oxygen species. For the first mechanism, in response to cellular stress induced by chemotherapeutic agents, the cell's mitochondria are triggered to release cytochrome-c into the cytosol. Cytochrome-c is known to play a critical role in the formation of apoptosome resulting in the activation of caspases which carry out the cell death program. The ability to escape from apoptosis is a property of most cancer cells and often correlates with resistance to anticancer drugs. Imatinib is a very effective drug used for the treatment of chronic myeloid leukemia (CML). In this study, apoptotic pathways induced in imatinib exposed sensitive (K562) and imatinib-resistant (K562/IMA-1) CML cells were investigated. It was observed that treatment of K562 cells with imatinib resulted in a significant loss of mitochondrial membrane potential (MMP) and activation of caspase-3. Whereas treatment of K562/IMA-1 cells with imatinib did not have any significant effect neither on the MMP nor the activity of caspase-3. Steady state levels of MMP was increased and caspase-3 activity was decreased in parallel with increasing the levels of resistance in untreated controls. Taken together all these data showed that imatinib induce apoptosis through the activation of caspase-3 cascade. However in K562/IMA-1 cells, these apoptotic pathways were blocked by the overexpression of antiapoptotic proteins, Bcl-2 and Bcl-XL, and by the decreased expression of pro-apoptotic protein, Bax.




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