TY - JOUR
T1 - Triptolide induces cell death independent of cellular responses to imatinib in blast crisis chronic myelogenous leukemia cells including quiescent CD34+ primitive progenitor cells
AU - Mak, Duncan H.
AU - Schober, Wendy D.
AU - Chen, Wenjing
AU - Konopleva, Marina
AU - Cortes, Jorge
AU - Kantarjian, Hagop M.
AU - Andreeff, Michael
AU - Carter, Bing Z.
PY - 2009/9/1
Y1 - 2009/9/1
N2 - The advent of Bcr-Abl tyrosine kinase inhibitors (TKI) has revolutionized the treatment of chronic myelogenous leukemia (CML). However,resistance evolves due to BCRABL mutations and other mechanisms. Furthermore, patients with blast crisis CML are less responsive and quiescent CML stem cells are insensitive to these inhibitors. We found that triptolide,a diterpenoid, at nanomolar concentrations, pro moted equally significant death of KBM5 cells,a cell line derived from a Bcr-Abl-bearing blast crisis CML patient and KBM5STI571 cells,an imatinib-resistant KBM5 subline bearing the T315I mutation. Similarly, Ba/F3 cells harboring mutated BCR-ABL were as sensitive as Ba/F3Bcr-Abl p210wt cells to triptolide. Importantly, triptolide induced apoptosis in primary samples from blast crisis CML patients,w ho showed resistance to Bcr-Abl TKIs in vivo,with less toxicity to normal cells. Triptolide decreased X-linked inhibitor of apoptosis protein, Mcl-1, and Bcr-Abl protein levels in K562, KBM5, and KBM5STI571 cells and in cells from blast crisis CML patients. It sensitized KBM5, but not KBM5STI571,ce lls to imatinib. More importantly, triptolide also induced death of quiescent CD34+ CML progenitor cells,a major problem in the therapy of CML with TKIs. Collectively, these results suggest that triptolide potently induces blast crisis CML cell death independent of the cellular responses to Bcr-Abl TKIs, suggesting that triptolide could eradicate residual quiescent CML progenitor cells in TKI-treated patients and benefit TKI-resistant blast crisis CML patients.
AB - The advent of Bcr-Abl tyrosine kinase inhibitors (TKI) has revolutionized the treatment of chronic myelogenous leukemia (CML). However,resistance evolves due to BCRABL mutations and other mechanisms. Furthermore, patients with blast crisis CML are less responsive and quiescent CML stem cells are insensitive to these inhibitors. We found that triptolide,a diterpenoid, at nanomolar concentrations, pro moted equally significant death of KBM5 cells,a cell line derived from a Bcr-Abl-bearing blast crisis CML patient and KBM5STI571 cells,an imatinib-resistant KBM5 subline bearing the T315I mutation. Similarly, Ba/F3 cells harboring mutated BCR-ABL were as sensitive as Ba/F3Bcr-Abl p210wt cells to triptolide. Importantly, triptolide induced apoptosis in primary samples from blast crisis CML patients,w ho showed resistance to Bcr-Abl TKIs in vivo,with less toxicity to normal cells. Triptolide decreased X-linked inhibitor of apoptosis protein, Mcl-1, and Bcr-Abl protein levels in K562, KBM5, and KBM5STI571 cells and in cells from blast crisis CML patients. It sensitized KBM5, but not KBM5STI571,ce lls to imatinib. More importantly, triptolide also induced death of quiescent CD34+ CML progenitor cells,a major problem in the therapy of CML with TKIs. Collectively, these results suggest that triptolide potently induces blast crisis CML cell death independent of the cellular responses to Bcr-Abl TKIs, suggesting that triptolide could eradicate residual quiescent CML progenitor cells in TKI-treated patients and benefit TKI-resistant blast crisis CML patients.
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U2 - 10.1158/1535-7163.MCT-09-0386
DO - 10.1158/1535-7163.MCT-09-0386
M3 - Article
C2 - 19723894
AN - SCOPUS:70349515363
SN - 1535-7163
VL - 8
SP - 2509
EP - 2516
JO - Molecular cancer therapeutics
JF - Molecular cancer therapeutics
IS - 9
ER -