Simvastatin potentiates the cell-killing activity of imatinib in imatinib-resistant chronic myeloid leukemia cells mainly through PI3K/AKT pathway attenuation and Myc downregulation.
Simvastatin potentiates the cell-killing activity of imatinib in imatinib-resistant chronic myeloid leukemia cells mainly through PI3K/AKT pathway attenuation and Myc downregulation.
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DOI：
10.1016/j.ejphar.2021.174633
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发表时间：
2021-11
影响因子：
5
通讯作者：
Lihong Ding;Qinwei Chen;Kai Chen;Yuelong Jiang;Genhong Li;Qiu-ling Chen;D. Bai;D. Gao;Manman Deng;Haiping Zhang;Bing Xu
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文献类型：
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作者：
Lihong Ding;Qinwei Chen;Kai Chen;Yuelong Jiang;Genhong Li;Qiu-ling Chen;D. Bai;D. Gao;Manman Deng;Haiping Zhang;Bing Xu
结构性激活的bcr-abl激酶被认为是慢性粒细胞白血病(CML)发生发展的驱动因素。第一个bcr-abl抑制剂伊马替尼的问世显著改善了CML患者的临床结局。然而，对伊马替尼的耐药性发生在25%-30%的CML患者中。由于缺乏有效的治疗策略，迫切需要新的治疗方法来治疗伊马替尼耐药的CML。辛伐他汀是一种著名的HMG-CoA还原酶抑制剂，在心血管疾病中具有巨大的临床益处，因其对多种肿瘤类型具有强大的抗肿瘤作用而受到越来越多的关注。在这项研究中，我们证明了辛伐他汀单一治疗对伊马替尼敏感的和对伊马替尼耐药的CML细胞(包括T351I突变细胞)都有效地降低了细胞活力，后者比前者更不容易受到辛伐他汀的影响。值得注意的是，我们发现辛伐他汀作为伊马替尼的强大细胞毒性增敏剂，在体内外杀死了伊马替尼耐药和T315I突变的CML细胞。从机制上讲，辛伐他汀和伊马替尼的协同作用与PI3K/Akt信号通路的失活有关，PI3K/Akt信号通路是BCR-ABL激酶的经典下游促生存级联反应。此外，这种药物组合通过减弱典型的Wnt/β-catenin信号，明显降低Myc的表达，并增加H3K27的三甲基化。综上所述，我们为辛伐他汀和伊马替尼联合治疗耐伊马替尼和T315I突变的CML细胞提供了诱人的临床前结果。这种联合用药方案为对伊马替尼耐药的慢性粒细胞白血病患者提供了进一步的临床研究。
Constitutively activated BCR-ABL kinase is considered the driver event responsible in the initiation and development of chronic myeloid leukemia (CML). The advent of the first BCR-ABL inhibitor imatinib has significantly improved the clinical outcome of CML cases. However, resistance to imatinib occurs in 25–30% of CML patients. Due to the lack of effective therapeutic strategies, novel treatment approaches are urgently required for imatinib-resistant CML. Simvastatin, a well-known HMG-CoA reductase inhibitor that confers tremendous clinical benefits in cardiovascular diseases, has attracted mounting attentions for its potent antitumor effects on multiple tumor types. In this study, we demonstrated that simvastatin monotherapy was effective in diminishing cell viability in both imatinib-sensitive and imatinib-resistant CML cells, including T351I mutated cells, with the latter being less vulnerable to the simvastatin than the former. Notably, we found that simvastatin acted as a robust cytotoxic sensitizer of imatinib to kill imatinib-resistant and T315I mutated CML cellsin vitro andin vivo. Mechanistically, the cooperative interaction of simvastatin and imatinib was associated with the inactivation of the PI3K/Akt signaling pathway, which was a classical downstream pro-survival cascade of the BCR-ABL kinase. In addition, this drug combination obviously decreased Myc expression through attenuation of canonical Wnt/β-catenin signaling and increased H3K27 trimethylation. Taken together, we provide attractive preclinical results for the combinatorial regimen of simvastatin and imatinib against imatinib-resistant and T315I mutated CML cells. This combined regimens warrants further clinical investigations in patients with imatinib-resistant CML.