Abstract
B-cell chronic lymphocytic leukemia (B-CLL) cells develop resistance to nucleoside analogs over time. This chemoresistance may be caused by selection for B-CLL cells with defects in the particular apoptosis pathway triggered by these drugs. Therefore, anticancer agents that induce apoptosis through alternative pathways might be useful in treating chemoresistant B-CLL. Farnesyltransferase inhibitors (FTIs) are a class of synthetic drugs with definite molecular targets, which have demonstrated cytotoxicity against leukemic cell lines. We have studied the ex vivo effect of the FTI BMS-214662 on cells from 18 patients with B-CLL. Low concentrations (<1 microM) of BMS-214662 prevented farnesylation of the chaperone marker HDJ-2 and had no effect on Akt activation. BMS-214662 induced apoptosis in B-CLL cells from all patients studied, including those showing resistance to cladribine and fludarabine ex vivo and in vivo. Treatment with BMS-214662 induced loss of mitochondrial membrane potential (DeltaPsi(m)), phosphatidylserine exposure, proapoptotic conformational changes of Bax and Bak, reduction in Mcl-1 levels and activation of caspases 9 and 3. The general caspase inhibitor Z-VAD-fmk did not prevent BMS-214662-induced cell death. ...Continue Reading
References
Jan 1, 1988·Leukemia Research·P J BrowettJ D Norton
Dec 1, 1988·Proceedings of the National Academy of Sciences of the United States of America·A NeriR Dalla-Favera
Dec 6, 1996·The Journal of Biological Chemistry·D M VanagsS Orrenius
May 2, 1997·International Journal of Cancer. Journal International Du Cancer·T NedergaardJ Zeuthen
Mar 23, 1999·The Journal of Cell Biology·G J GriffithsJ A Hickman
Jul 20, 1999·The Journal of Biological Chemistry·D G KirschJ M Hardwick
Dec 14, 1999·Molecular and Cellular Biology·K JiangJ Q Cheng
Mar 14, 2000·Cell Death and Differentiation·Q ChenA Almasan
Jul 6, 2000·Current Opinion in Hematology·T J Kipps
Aug 6, 2000·British Journal of Haematology·A R Pettitt, J C Cawley
Jun 28, 2001·Oncogene·S M Sebti, A D Hamilton
Jul 10, 2001·Acta Oncologica·E KimbyUNKNOWN SBU-group. Swedish Council of Technology Assessment in Health Care
Jul 12, 2001·Proceedings of the National Academy of Sciences of the United States of America·Y SuzukiR Takahashi
Nov 28, 2001·Hematology·K R RaiE Montserrat
Apr 4, 2002·Blood·Montserrat BarragánJoan Gil
Aug 24, 2002·The Journal of Biological Chemistry·Theocharis PanaretakisDan Grandér
Oct 3, 2002·Leukemia·P Pérez-GalánJ Naval
Oct 24, 2002·Blood·Ingo RingshausenThomas Decker
Nov 2, 2002·Blood·Jorge CortesHagop Kantarjian
Jun 5, 2003·Expert Opinion on Investigational Drugs·Francesco CaponigroJane Bryce
Jun 5, 2003·Genes & Development·Deepak NijhawanXiaodong Wang
Aug 28, 2003·Archives of Biochemistry and Biophysics·Daniel Iglesias-SerretJosé M López
Jan 23, 2004·Nature Reviews. Cancer·Saïd M Sebti, Channing J Der
Apr 8, 2004·Molecular Cell·Xiao-Ming SunGerald M Cohen
Citations
Jul 22, 2005·Cancer Immunology, Immunotherapy : CII·Øystein BruserudBjørn Tore Gjertsen
Jun 3, 2009·Nature Reviews. Clinical Oncology·Lisa PleyerRichard Greil
Dec 13, 2005·Cell Death and Differentiation·G MaletE Pérez-Payá
Feb 23, 2008·Blood·Marta MuzioPaolo Ghia
Nov 26, 2013·Biochemical Pharmacology·Adriana AportaAlberto Anel
Dec 25, 2007·Blood·Mhairi CoplandTessa L Holyoake
Jul 13, 2006·Cancer·Tomislav LetilovicAlessandra Ferrajoli
Aug 23, 2005·Cancer Chemotherapy and Biological Response Modifiers·Peter H Wiernik
Nov 10, 2005·Journal of Lipid Research·Andrea D BassoW Robert Bishop
Dec 13, 2005·Journal of Lipid Research·Richard T EastmanWesley C Van Voorhis
Nov 14, 2013·PloS One·Iwona HusJacek Roliński
May 12, 2007·The Journal of Biological Chemistry·Shi-Yong SunFadlo R Khuri
Oct 12, 2010·Journal of Medicinal Chemistry·Ioannis S VizirianakisAsterios S Tsiftsoglou