Therapeutic Interaction of Apatinib and Chidamide in T-Cell Acute Lymphoblastic Leukemia through Interference with Mitochondria Associated Biogenesis and Intrinsic Apoptosis

  • J Pers Med. 2021 Sep 29;11(10):977. doi: 10.3390/jpm11100977.
Mengya Zhong  1  2 ,  Fusheng Lin  1  2 ,  Yuelong Jiang  1  2 ,  Guangchao Pan  1  2 ,  Jinshui Tan  1  2 ,  Hui Zhou  1  2 ,  Qian Lai  1  2 ,  Qinwei Chen  1  2 ,  Manman Deng  1  2 ,  Jie Zha  1  2 ,  Bing Xu  1  2
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. Key Laboratory of Xiamen for Diagnosis and Treatment of Hematological Malignancy, No. 55, Shizhen Hai Road, Xiamen 361003, China.
PMID: 34683119 DOI: 10.3390/jpm11100977
Abstract

T-cell Acute Lymphoblastic Leukemia (T-ALL) shows poor clinical outcome and has limited therapeutic options, indicating that new treatment approaches for this disease are urgently required. Our previous study demonstrated that apatinib, an orally selective VEGFR-2 antagonist, is highly effective in T-ALL. Additionally, chidamide, a histone deacetylase inhibitor, has proven to be cytotoxic against T-ALL in preclinical and clinical settings. However, whether the therapeutic interaction of apatinib and chidamide in T-ALL remains unknown. In this study, apatinib and chidamide acted additively to decrease cell viability and induce Apoptosis in T-ALL in vitro. Notably, compared with apatinib or chidamide alone, the combinational regimen was more efficient in abrogating the leukemia burden in the spleen and bone marrow of T-ALL patient-derived xenograft (PDX) models. Mechanistically, the additive antileukemia effect of apatinib and chidamide was associated with suppression of mitochondrial respiration and downregulation of the abundance levels of several rate-limiting Enzymes that are involved in the citric acid cycle and Oxidative Phosphorylation (OXPHOS). In addition, apatinib enhanced the antileukemia effect of chidamide on T-ALL via activation of the mitochondria-mediated Apoptosis pathway and impediment of mitochondrial biogenesis. Taken together, the study provides a potential role for apatinib in combination with chidamide in the management of T-ALL and warrants further clinical evaluations of this combination in patients with T-ALL.

Keywords
T-cell acute lymphoblastic leukemia (T-ALL); apatinib; chidamide; citric acid cycle or tricarboxylic acid cycle (TCA); mitochondria; oxidative phosphorylation (OXPHOS); synergy.
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