Triptolide induces cell death independent of cellular responses to imatinib in blast crisis chronic myelogenous leukemia cells including quiescent CD34+ primitive progenitor cells.
Triptolide induces cell death independent of cellular responses to imatinib in blast crisis chronic myelogenous leukemia cells including quiescent CD34+ primitive progenitor cells.
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DOI：
10.1158/1535-7163.mct-09-0386
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发表时间：
2009-09
影响因子：
5.7
通讯作者：
Carter BZ
中科院分区：
文献类型：
--
作者：
Mak DH;Schober WD;Chen W;Konopleva M;Cortes J;Kantarjian HM;Andreeff M;Carter BZ
Bcr-Abl 酪氨酸激酶抑制剂 (TKI) 的出现彻底改变了 CML 的治疗。然而，由于 BCR-ABL 突变和其他机制，耐药性不断演变。此外，患有急变危象 (BC) CML 的患者反应较差，静止的 CML 干细胞对这些抑制剂不敏感。我们发现，雷公藤甲素（一种二萜类化合物）在 nM 浓度下，可同样显着地促进 KBM5 细胞（一种源自携带 Bcr-Abl 的 BC CML 患者的细胞系）和 KBM5STI571 细胞（一种携带 T315I 突变的伊马替尼耐药 KBM5 亚系）的死亡。类似地，携带突变 BCR-ABL 的 Ba/F3 细胞与 Ba/F3Bcr-Ablp210wt 细胞对雷公藤甲素同样敏感。重要的是，雷公藤甲素在 BC CML 患者的原始样本中诱导细胞凋亡，这些患者在体内表现出对 Bcr-Abl TKI 的耐药性，并且对正常细胞的毒性较小。雷公藤甲素可降低 K562、KBM5、KBM5STI571 细胞和 BC CML 患者细胞中的 XIAP、Mcl-1 和 Bcr-Abl 蛋白水平。它使 KBM5 细胞对伊马替尼敏感，但对 KBM5STI571 细胞不敏感。更重要的是，雷公藤甲素还诱导静止 CD34+ CML 祖细胞死亡，这是 TKI 治疗 CML 的一个主要问题。总的来说，这些结果表明，雷公藤甲素可有效诱导 BC CML 细胞死亡，与 Bcr-Abl TKI 的细胞反应无关，表明雷公藤甲素可以根除 TKI 治疗患者中残留的静止 CML 祖细胞，并使 TKI 耐药的 BC CML 患者受益。
The advent of Bcr-Abl tyrosine kinase inhibitors (TKIs) has revolutionized the treatment of CML. However, resistance evolves due to BCR-ABL mutations and other mechanisms. Furthermore, patients with blast crisis (BC) CML are less responsive and quiescent CML stem cells are insensitive to these inhibitors. We found that triptolide, a diterpenoid, at nM concentrations, promoted equally significant death of KBM5 cells, a cell line derived from a Bcr-Abl-bearing BC 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 BC CML patients, who showed resistance to Bcr-Abl TKIs in vivo, with less toxicity to normal cells. Triptolide decreased XIAP, Mcl-1, and Bcr-Abl protein levels in K562, KBM5, KBM5STI571 cells and in cells from BC 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 BC 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 BC CML patients.