2. Academic Validation
  3. Synthetic lethality of combined AT-101 with idarubicin in acute myeloid leukemia via blockade of DNA repair and activation of intrinsic apoptotic pathway

Synthetic lethality of combined AT-101 with idarubicin in acute myeloid leukemia via blockade of DNA repair and activation of intrinsic apoptotic pathway

  • Cancer Lett. 2019 Oct 1;461:31-43. doi: 10.1016/j.canlet.2019.07.003.
Qianying Yang 1,  Kai Chen 2,  Leisi Zhang 3,  Liying Feng 4,  Guofeng Fu 5,  Shan Jiang 5,  Silei Bi 4,  Chunjie Lin 5,  Yong Zhou 4,  Haijun Zhao 4,  Xiao Lei Chen 5,  Guo Fu 6,  Bing Xu 7
Affiliations

Affiliations

  • 1 Department of Hematology, The First Affiliated Hospital of Xiamen University, Xiamen, Fujian, 361003, China; State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiamen, Fujian, 361102, China.
  • 2 The First People's Hospital of Foshan (The Affiliated Foshan Hospital of Sun Yat-sen University), Foshan, Guangdong, 528000, China; Department of Hematology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, 510515, China.
  • 3 Department of Hematology, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, 215000, China.
  • 4 Department of Hematology, The First Affiliated Hospital of Xiamen University, Xiamen, Fujian, 361003, China.
  • 5 State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiamen, Fujian, 361102, China.
  • 6 State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiamen, Fujian, 361102, China. Electronic address: [email protected].
  • 7 Department of Hematology, The First Affiliated Hospital of Xiamen University, Xiamen, Fujian, 361003, China. Electronic address: [email protected].
PMID: 31301319 DOI: 10.1016/j.canlet.2019.07.003
Abstract

Leukemia stem cells (LSCs) are deemed to the mainspring for treatment failure in acute myeloid leukemia (AML). Conventional chemotherapeutic drugs fail to eradicate leukemia stem cells, which becomes the root of drug resistance and disease recurrence. Hence, new therapeutic strategies targeting LSCs are supposed to be critical for patients with AML. Here we report that combination of Bcl-2 Inhibitor AT-101 and chemotherapeutic drug idarubicin (IDA) results in synergistic lethality in CD34+CD38- leukemia stem-like cells sorted from KG-1α and Kasumi-1 AML cell lines and primary CD34+ AML cells in vitro while sparing the normal counterparts. In addition, combinatorial treatment also significantly inhibits the growth of patient-derived xenograft (PDX) mouse models generated from FLT3-ITDmut AML patient in vivo. Mechanistically, the synergistic effects of AT-101 with IDA to induce cell death are closely associated with blockage of DNA damage repair and thus activates the intrinsic apoptotic pathway. In summary, these findings suggest that combinatorial therapy with AT-101 and IDA selectively eliminates leukemia stem-like cells both in vitro and in vivo, representing a potent and alternative salvage therapy for the treatment of relapsed and refractory patients with AML.

Keywords

AT-101; Acute myeloid leukemia; DNA damage repair response; Idarubicin; Intrinsic apoptotic pathway.

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