RT Journal Article
SR Electronic
T1 Triptolide induces cell death independent of cellular responses to imatinib in blast crisis chronic myelogenous leukemia cells including quiescent CD34<sup>+</sup> primitive progenitor cells
JF Molecular Cancer Therapeutics
JO Mol Cancer Ther
FD American Association for Cancer Research
SP 2509
OP 2516
DO 10.1158/1535-7163.MCT-09-0386
VO 8
IS 9
A1 Mak, Duncan H.
A1 Schober, Wendy D.
A1 Chen, Wenjing
A1 Konopleva, Marina
A1 Cortes, Jorge
A1 Kantarjian, Hagop M.
A1 Andreeff, Michael
A1 Carter, Bing Z.
YR 2009
UL http://mct.aacrjournals.org/content/8/9/2509.abstract
AB The advent of Bcr-Abl tyrosine kinase inhibitors (TKI) has revolutionized the treatment of chronic myelogenous leukemia (CML). However, resistance evolves due to BCR-ABL 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, promoted 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-Ablp210wt cells to triptolide. Importantly, triptolide induced apoptosis in primary samples from blast crisis CML patients, who 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, cells 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. [Mol Cancer Ther 2009;8(9):2509–16]© 2009 American Association for Cancer Research.