Targeting of heat shock protein 32 (Hsp32)/heme oxygenase-1 (HO-1) in leukemic cells in chronic myeloid leukemia: a novel approach to overcome resistance against imatinib
Targeting of heat shock protein 32 (Hsp32)/heme oxygenase-1 (HO-1) in leukemic cells in chronic myeloid leukemia: a novel approach to overcome resistance against imatinib
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DOI：
10.1182/blood-2006-11-055723
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发表时间：
2008-02-15
期刊：
影响因子：
20.3
通讯作者：
Valent, Peter
中科院分区：
文献类型：
--
作者：
Mayerhofer, Matthias;Gleixner, Karoline V.;Valent, Peter
对伊马替尼和其他bcr/abl酪氨酸激酶抑制剂的耐药性仍然是慢性粒细胞白血病晚期治疗中日益严重的临床问题。我们最近发现热休克蛋白32(Hsp32)/血红素加氧酶-1(HO-1)是CML细胞中依赖于bcr/abl的生存分子。我们在这里表明，通过siRNA方法沉默民用细胞中的Hsp32/HO-1会诱导细胞凋亡。此外，聚乙二醇化锌原卟啉(PEG化锌原卟啉)或苯乙烯马来酸胶束包裹的锌卟啉(SMA-ZnPP)靶向Hsp32/HO-1均能抑制BCR/ABL转化细胞的生长。在携带各种bcr/abl伊马替尼耐药突变株的BA/F3细胞中，包括对所有临床上可用的bcr/abl酪氨酸激酶抑制剂都表现出耐药性的突变体T315I，均可观察到聚乙二醇化锌锌蛋白和SMA-锌锌蛋白的作用。在慢性粒细胞白血病细胞系K562和KU812中，以及从新诊断的民用或伊马替尼耐药的民用细胞中获得的原代白血病细胞中，也观察到了聚乙二醇锌多肽和SMA-锌多糖核酸的生长抑制作用。最后，发现Hsp32/HO-1靶向化合物与伊马替尼或尼洛替尼在对伊马替尼耐药的K562细胞和携带BCR/ABL T315I突变体的BA/F3细胞中具有协同作用。综上所述，这些数据表明HO-1是治疗伊马替尼耐药慢性粒细胞白血病的一个有前景的新靶点。
Resistance toward imatinib and other BCR/ABL tyrosine kinase inhibitors remains an increasing clinical problem in the treatment of advanced stages of chronic myeloid leukemia (CIVIL). We recently have identified the heat shock protein 32 (Hsp32)/heme oxygenase-1 (HO-1) as a BCR/ABL-dependent survival molecule in CML cells. We here show that silencing Hsp32/HO-1 in CIVIL cells by an siRNA approach results in induction of apoptosis. Moreover, targeting Hsp32/HO-1 by either pegylated zinc protoporphyrine (PEG-ZnPP) or styrene maleic acid-micelle-encapsulated ZnPP (SMA-ZnPP) resulted in growth inhibition of BCR/ABL-transformed cells. The effects of PEG-ZnPP and SMA-ZnPP were demonstrable in Ba/F3 cells carrying various imatinib-resistant mutants of BCR/ABL, including the T315I mutant, which exhibits resistance against all clinically available BCR/ABL tyrosine kinase inhibitors. Growth-inhibitory effects of PEG-ZnPP and SMA-ZnPP also were observed in the CML-derived human cell lines K562 and KU812 as well as in primary leukemic cells obtained from patients with freshly diagnosed CIVIL or imatinib-resistant CIVIL Finally, Hsp32/HO-1-targeting compounds were found to synergize with either imatinib or nilotinib in producing growth inhibition in imatinib-resistant K562 cells and in Ba/F3 cells harboring the T315I mutant of BCR/ABL. In summary, these data show that HO-1 is a promising novel target in imatinib-resistant CML.