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首页> 外文期刊>Cell cycle >Dual PPARalpha/gamma ligand TZD18 either alone or in combination with imatinib inhibits proliferation and induces apoptosis of human CML cell lines.
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Dual PPARalpha/gamma ligand TZD18 either alone or in combination with imatinib inhibits proliferation and induces apoptosis of human CML cell lines.

机译:单独的PPARalpha /γ双配体TZD18或与伊马替尼组合可抑制增殖,并诱导人CML细胞系凋亡。

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摘要

Despite progress in the treatment of early-stage chronic myeloid leukemia (CML), the accelerated and blastic phases of CML still remain a therapeutic challenge. Persistence of BCR-ABL-positive (bcr-abl(+)) cells or secondary resistance during imatinib therapy frequently occurs. In this study, we investigated the activity of a novel dual ligand specific for peroxisome proliferator-activated receptor alpha and gamma (PPARalpha/gamma) against CML blast crisis cell lines. Exposure of these cell lines (K562, KU812 and KCL22) to TZD18 resulted in a growth inhibition in a dose- and time-dependent manner. This effect may not be mediated through PPARgamma and PPARalpha activation, since antagonists of PPARgamma and/or PPARalpha could not reverse this inhibition. Western blotting analysis showed that expression of the cyclin dependent kinase inhibitor (CDKI) p27(kip1) was enhanced, whereas levels of cyclin E, cyclin D2 and cyclin dependent kinase 2 (CDK-2) were decreased when these cells were treated with TZD18.Most interestingly, TZD18 synergistically enhanced the antiproliferative and pro-apoptotic effect of imatinib. Overall, our findings strongly suggest that either TZD18, either alone or in combination with imatinib may be beneficial for the treatment of CML in myeloid blast crisis.
机译:尽管在早期慢性粒细胞白血病(CML)的治疗方面取得了进展,但CML的加速期和破伤期仍是治疗上的挑战。伊马替尼治疗期间BCR-ABL阳性(bcr-abl(+))细胞持续存在或继发耐药。在这项研究中,我们研究了针对过氧化物酶体增殖物激活的受体α和γ(PPARalpha /γ)的新型双配体针对CML blast危机细胞系的活性。这些细胞系(K562,KU812和KCL22)暴露于TZD18会导致剂量和时间依赖性的生长抑制。由于PPARgamma和/或PPARalpha的拮抗剂不能逆转这种抑制作用,因此可能无法通过PPARgamma和PPARalpha激活来介导这种作用。 Western印迹分析表明,将这些细胞用TZD18处理后,细胞周期蛋白依赖性激酶抑制剂(CDKI)p27(kip1)的表达增强,而细胞周期蛋白E,细胞周期蛋白D2和细胞周期蛋白依赖性激酶2(CDK-2)的水平降低。最有趣的是,TZD18协同增强了伊马替尼的抗增殖和促凋亡作用。总体而言,我们的发现强烈表明,单独的TZD18或与伊马替尼组合的TZD18可能对治疗髓样母细胞危机中的CML有益。

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