Synergistic cytotoxic effects in myeloid leukemia cells upon cotreatment with farnesyltransferase and geranylgeranyl transferase-I inhibitors
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چکیده
منابع مشابه
Resistance of K - RasBVl 2 proteins to farnesyltransferase inhibitors in Ratl cells ( protein prenylation / geranylgeranyl transferase I / transformed cells / benzodiazepine - 5 B / L - 739 , 749 )
Benzodiazepine (BZA)-5B, a CAAX farnesyltransferase inhibitor, was previously shown to block the farnesylation of H-Ras and to reverse the transformed morphology of Ratl cells expressing oncogenic H-Rasvl2. Nontransformed Ratl cells were not affected by BZA-5B, suggesting that they produce a form of Ras whose prenylation is not blocked by this compound. The likely candidate is K-RasB, which dif...
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The mutant JAK2V617F tyrosine kinase (TK) is present in the majority of patients with BCR-ABL–negative myeloproliferative neoplasms (MPNs). JAK2V617F activates downstream signaling through the signal transducers and activators of transcription (STAT), RAS/mitogen-activated protein kinase (MAPK), and phosphatidylinositol 3 (PI3)/AKT pathways, conferring proliferative and survival advantages in t...
متن کاملIn Vitro Apoptotic Effects of Farnesyltransferase blockade in Acute Myeloid Leukemia Cells
Farnesyltransferase inhibitors (FTIs) are a class of oral anti-cancer drugs currently tested in phase I-II clinical trials for treatment of hematological malignancies. The in vitro effects of various FTIs (alpha-hydroxyfarnesylphosphonic acid, manumycin-A and SCH66336) were tested on CD34+ KG1a cell line and in primary acute myeloid leukemia (AML) cells from 64 patients. By cell viability and c...
متن کاملChemical genetics identifies Rab geranylgeranyl transferase as an apoptotic target of farnesyl transferase inhibitors.
A chemical genetics approach identified a cellular target of several proapoptotic farnesyl transferase inhibitors (FTIs). Treatment with these FTIs caused p53-independent apoptosis in Caenorhabditis elegans, which was mimicked by knockdown of endosomal trafficking proteins, including Rab5, Rab7, the HOPS complex, and notably the enzyme Rab geranylgeranyl transferase (RabGGT). These FTIs were fo...
متن کاملInvolvement of nitric oxide in farnesyltransferase inhibitor-mediated apoptosis in chronic myeloid leukemia cells.
The mechanism of action of farnesyltransferase inhibitors (FTIs) has not been fully clarified. We investigated the cytotoxic effects of various FTIs in chronic myeloid leukemia (CML), using LAMA cells and marrow cells from 40 CML patients in chronic phase. FTI-mediated cytotoxic effect was observed in LAMA cells and in 65% of primary CML cells, whereas marrow cells from controls were only weakl...
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ژورنال
عنوان ژورنال: Leukemia
سال: 2003
ISSN: 0887-6924,1476-5551
DOI: 10.1038/sj.leu.2403022