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Abdel-Rahim Faeq Aisheh
Chronic myelogenous leukemia (CML) is a myeloproliferative disorder characterized by the accumulation of all forms of mature and immature granulocytes. The underlying abnormality of CML is translocation of genetic material between chromosomes 9 and 22 resulting in a hybrid gene termed bcr-abl. Bcr-abl fusion gene is the cornerstone in the oncogeneses of CML, bcr-abl encodes for a tyrosine kinase characterized by enhanced and deregulated activity, which converts the growth factor dependent Baf-3 cells into growth factor independent, enhanced antiapoptotic activity and attachment defects to stromal layers. Collectively, these factors contribute to massive release of immature cells to the circulation, a characteristic feature of CML. Giving that bcr-abl is the hallmark of CML oncogeneses; therefore, inhibitors of bcr-abl could be good candidates for CML therapy. 152 medicinal plants were selected from which, 285 extracts were prepared. In vitro evaluation of the growth inhibition activity of these extracts was carried out in a mechanism-based screening targeting cells expressing bcr-abl hybrid gene. Primarily,
two cells were used Baf-3, a growth factor dependent B-lymphocyte, and Baf210, Baf-3 transfected with bcr-abl. XTT and MTT cell proliferation assays were used to monitor extract's activity in the screening stages. Out of 285, 104 (37% of the total) extracts have shown more than 40% inhibition against Baf-210 of which, seventeen extracts (9% of the total and 25% of the actives) were selective and were also potent against the human CML cells K562 and KBM2, more interestingly these extracts were inactive against other human cells such as the prostate cancer cell line PC-3. Ethanolic extracts of Majorana syriaca, Salvia fruticosa, A. oficinarum and of Teen Alfeel, have selectively and potently induced apoptosis of Baf-210, as measured by DNA laddering and caspase-3 assays,
these extracts have also induced apoptosis of K562 cells. Taken together, our results indicate that extracts selective against bcr-abl expressing cells might be acting on bcr-abl, the tyrosine kinase activity of bcr-abl or downstream effectors operated by bcr-abl. Therefore, there is a great need for further studying of these extracts including; separation and identification of the active molecules and elucidation of the mode of action for which more sophisticated techniques such as RT-PCR, SDSPAGE and western blotting should be used.
Abdel-Rahim Faeq Aisheh
Supervisors
Dr. Suleiman Al-Khalil
Dr. Jamal Mahajna
November 2001
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