2. Academic Validation
  3. Inhibition of Nrf2-mediated glucose metabolism by brusatol synergistically sensitizes acute myeloid leukemia to Ara-C

Inhibition of Nrf2-mediated glucose metabolism by brusatol synergistically sensitizes acute myeloid leukemia to Ara-C

  • Biomed Pharmacother. 2021 Oct;142:111652. doi: 10.1016/j.biopha.2021.111652.
Cong Cheng 1,  Fang Yuan 1,  Xiao-Ping Chen 1,  Wei Zhang 1,  Xie-Lan Zhao 2,  Zhi-Ping Jiang 2,  Hong-Hao Zhou 1,  Gan Zhou 3,  Shan Cao 4
Affiliations

Affiliations

  • 1 Department of Clinical Pharmacology, Xiangya Hospital, Central South University, 87 Xiangya Road, Changsha 410008, PR China; Institute of Clinical Pharmacology, Central South University, Hunan Key Laboratory of Pharmacogenetics, 110 Xiangya Road, Changsha 410078, PR China; Engineering Research Center of Applied Technology of Pharmacogenomics, Ministry of Education, Changsha 410078, PR China; National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Center South University, Changsha 410008, Hunan, PR China.
  • 2 Department of Hematology, Xiangya Hospital, Central South University, 87 Xiangya Road, Changsha 410008, PR China.
  • 3 Department of Clinical Pharmacology, Xiangya Hospital, Central South University, 87 Xiangya Road, Changsha 410008, PR China; Institute of Clinical Pharmacology, Central South University, Hunan Key Laboratory of Pharmacogenetics, 110 Xiangya Road, Changsha 410078, PR China; Engineering Research Center of Applied Technology of Pharmacogenomics, Ministry of Education, Changsha 410078, PR China; National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Center South University, Changsha 410008, Hunan, PR China; National Institution of Drug Clinical Trial, Xiangya Hospital, Central South University, 110 Xiangya Road, Changsha, Hunan 410008, PR China. Electronic address: zhougan@csu.edu.cn.
  • 4 Department of Clinical Pharmacology, Xiangya Hospital, Central South University, 87 Xiangya Road, Changsha 410008, PR China; Institute of Clinical Pharmacology, Central South University, Hunan Key Laboratory of Pharmacogenetics, 110 Xiangya Road, Changsha 410078, PR China; Engineering Research Center of Applied Technology of Pharmacogenomics, Ministry of Education, Changsha 410078, PR China; National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Center South University, Changsha 410008, Hunan, PR China. Electronic address: caoshan1106@csu.edu.cn.
PMID: 34112534 DOI: 10.1016/j.biopha.2021.111652
Abstract

Chemotherapy resistance remains to be the primary barrier to acute myeloid leukemia (AML) treatment failure. Nuclear factor-erythroid 2-related factor 2 (Nrf2) has been well established as a truly pleiotropic transcription factor. Inhibition of Nrf2 function increases the sensitivity of various chemotherapeutics and overcomes chemoresistance effectively. Brusatol (Bru) has been reported to decrease Nrf2 protein expression specifically by ubiquitin degradation of Nrf2. However, it remains elusive whether combination of Brusatol and Cytarabine (Ara-C) elicits a synergistic antitumor effect in AML. Our results demonstrated that combination of Ara-C and Brusatol synergistically exerted remarkable pro-apoptosis effect in HL-60 and THP-1 cells. Mechanistically, synergistic anti-tumor effect of Ara-C/Brusatol in AML cells is mediated by attenuating Nrf2 expression. To our surprise, Nrf2 inhibition by Brusatol causes downregulation of the expression of glycolysis-related proteins and decreased glucose consumption and lactate production, whereas the level of ROS production was unaffected. The activation of Nrf2 by Sulforaphane (SFP) could reverse the chemotherapeutic effect and changes of glycolysis of concomitant of Ara-C with Brusatol in AML cell lines. Additionally, Ara-C/Brusatol co-treatment decreased Glucose-6-phosphate dehydrogenase (G6PD) protein expression and increased the sensitivity of Ara-C. Moreover, the mouse xenograft in vivo experiment confirmed that combining Ara-C with Brusatol exerted stronger antileukemia than Ara-C alone. The efficacy, together with the mechanistic observations, reveals the potential of simultaneously giving these two drugs and provides a rational basis for targeting glucose catabolism in future clinical therapeutic approach.

Keywords

Acute myeloid leukemia; Brusatol; Cytarabine; Drug synergism; Nrf2.

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