2. Academic Validation
  3. Preclinical Evaluation of the Multiple Tyrosine Kinases Inhibitor Anlotinib in Leukemia Stem Cells

Preclinical Evaluation of the Multiple Tyrosine Kinases Inhibitor Anlotinib in Leukemia Stem Cells

  • Pharmaceuticals (Basel). 2022 Oct 25;15(11):1313. doi: 10.3390/ph15111313.
Yuelong Jiang 1 2,  Long Liu 1 2,  Yirong Jiang 3,  Zhifeng Li 1 2,  Liying Feng 1 2,  Xinguo Zhuang 1 2,  Zhijuan Lin 1 2,  Qiuling Chen 1 2,  Guoshu Chen 4,  Jixiang He 3,  Guowei Li 4,  Jie Zha 1 2,  Bing Xu 1 2
Affiliations

Affiliations

  • 1 Department of Hematology, The First Affiliated Hospital of Xiamen University and Institute of Hematology, School of Medicine, Xiamen University, Xiamen 361003, China.
  • 2 Xiamen Key Laboratory of Diagnosis and Therapy for Hematological Malignancies, Xiamen 361003, China.
  • 3 Department of Hematology, Affiliated Dongguan People's Hospital, Southern Medical University (Dongguan People's Hospital), Dongguan 523059, China.
  • 4 Department of Hematology, Huizhou Municipal Central Hospital, Huizhou 516001, China.
PMID: 36355485 DOI: 10.3390/ph15111313
Abstract

Leukemia stem cells (LSCs) constitute the critical barrier to the cure of acute myeloid leukemia (AML) due to their chemoresistance and immune evasion property. Herein, the role of anlotinib, a multiple tyrosine kinase inhibitor, in killing LSCs and regulating chemoresistance and immune evasion was explored. Anlotinib treatment induced Apoptosis of LSC-like cells as well as primary AML LSCs, while sparing the normal mononuclear cells in vitro. Moreover, anlotinib could impair the regeneration capacity of LSCs in the patient-derived leukemia xenograft mouse model. Mechanistically, anlotinib inhibited phosphorylation of c-Kit, JAK2/STAT3, and STAT5, and downregulated STAT3 and STAT5 expression. In addition, anlotinib downregulated the anti-apoptotic proteins Bcl-2 and Bcl-xL, and upregulated Bax, thereby enhancing the sensitivity of LSCs to idarubicin in vitro. Intriguingly, anlotinib could also partially rescue the interferon-g production of T cells cocultured with LSCs by downregulating PD-L1 expression. In conclusion, anlotinib showed anti-LSC activity and the potential to enhance the sensitivity to idarubicin and inhibit the immunosuppressive feature of LSCs via JAK2/STAT signaling pathway downregulation in the preclinical study. Our results provided a rational basis for combinatory strategies involving anlotinib and chemotherapy or immunotherapy.

Keywords

JAK; STAT3; acute myeloid leukemia; anlotinib; chemoresistance; leukemia stem cell.

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