2. Academic Validation
  3. 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

  • Eur J Pharmacol. 2021 Dec 15;913:174633. doi: 10.1016/j.ejphar.2021.174633.
Lihong Ding 1,  Qinwei Chen 2,  Kai Chen 3,  Yuelong Jiang 2,  Genhong Li 2,  Qiuling Chen 4,  Dongyu Bai 1,  Dehong Gao 1,  Manman Deng 5,  Haiping Zhang 6,  Bing Xu 7
Affiliations

Affiliations

  • 1 Department of Pathology, The First Affiliated Hospital of Xiamen University, Xiamen, 361003, China.
  • 2 Department of Hematology, The First Affiliated Hospital of Xiamen University and Institute of Hematology, Medical College of Xiamen University, Xiamen, 361003, China; Key Laboratory of Xiamen for Diagnosis and Treatment of Hematological Malignancy, Xiamen, 361003, China.
  • 3 The First People's Hospital of Foshan (The Affiliated Foshan Hospital of Sun-Yat-Sen University), Foshan, 528000, China.
  • 4 The School of Clinical Medicine, Fujian Medical University, Fuzhou, 350000, China.
  • 5 Department of Hematology, The First Affiliated Hospital of Xiamen University and Institute of Hematology, Medical College of Xiamen University, Xiamen, 361003, China; Key Laboratory of Xiamen for Diagnosis and Treatment of Hematological Malignancy, Xiamen, 361003, China. Electronic address: marina_deng@outlook.com.
  • 6 Department of Pathology, The First Affiliated Hospital of Xiamen University, Xiamen, 361003, China. Electronic address: zhp3398@163.com.
  • 7 Department of Hematology, The First Affiliated Hospital of Xiamen University and Institute of Hematology, Medical College of Xiamen University, Xiamen, 361003, China; Key Laboratory of Xiamen for Diagnosis and Treatment of Hematological Malignancy, Xiamen, 361003, China. Electronic address: xubingzhangjian@126.com.
PMID: 34843676 DOI: 10.1016/j.ejphar.2021.174633
Abstract

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 cells in vitro and in 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.

Keywords

BCR-ABL; Chronic myeloid leukemia (CML); Imatinib; Myc; PI3K/AKT; Simvastatin; Wnt/β-Catenin.

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