2. Academic Validation
  3. Targeting PI3K/AKT/mTOR pathway to enhance the anti-leukemia efficacy of venetoclax

Targeting PI3K/AKT/mTOR pathway to enhance the anti-leukemia efficacy of venetoclax

  • Exp Cell Res. 2022 Aug 15;417(2):113192. doi: 10.1016/j.yexcr.2022.113192.
Hongcai Liu 1,  Zubair Hussain 2,  Qingqing Xie 1,  Xueying Yan 1,  Chenxing Zeng 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, 110 Xiangya Road, Changsha, 410078, PR China; National Clinical Research Center for Geriatric Disorders, 87 Xiangya Road, Changsha, 410008, Hunan, PR China.
  • 2 Department of Clinical Laboratory, The Third Xiangya Hospital of Central South University, Changsha, 410013, 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, 110 Xiangya Road, Changsha, 410078, PR China; National Clinical Research Center for Geriatric Disorders, 87 Xiangya Road, Changsha, 410008, Hunan, PR China; Phase I Clinical Trial Research Center, Xiangya Hospital, Central South University, 87 Xiangya Road, Changsha, 410008, Hunan, PR China.
  • 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, 110 Xiangya Road, Changsha, 410078, PR China; National Clinical Research Center for Geriatric Disorders, 87 Xiangya Road, Changsha, 410008, Hunan, PR China. Electronic address: caoshan1106@csu.edu.cn.
PMID: 35568072 DOI: 10.1016/j.yexcr.2022.113192
Abstract

Background: The treatment of acute myeloid leukemia (AML) is developing towards "targeted therapy", which faces challenges such as low sensitivity and drug resistance. Therefore, targeted drugs need to be used in combination with Other drugs to overcome clinical problems.

Objective: AML cells and animal models were used to determine the synergistic anti-leukemic effect of Dactolisib (BEZ235) and Venetoclax (ABT199) and explore its mechanism.

Methods: In vitro experiments, we used cell counting kit-8 (CCK8), flow cytometry, real-time quantitative PCR (qPCR), and Western blot to detect the anti-leukemic effects of ABT199 and BEZ235. In vivo experiments, female nude mice were injected subcutaneously with THP-1 cells to form tumors, evaluate the combined effect of ABT199 and BEZ235 by indicators such as tumor size, tumor weight, Ki67 and cleaved-Caspase3 staining. The mice's body weight and HE staining were used to evaluate the liver injury and adverse drug reactions.

Results: The combination of BEZ235 and ABT199 has a synergistic effect through promoting Apoptosis and inhibiting proliferation. The BEZ235 increased the drug sensitivity of ABT199 by reducing the Mcl-1 protein synthesis and promoted the degradation of Mcl-1 protein, which is considered as the mechanism of reversing ABT199 resistance. Furthermore, the BEZ235 and ABT199 can synergistically enhance the inhibition of PI3K/Akt/mTOR pathway.

Conclusion: The combination of BEZ235 and ABT199 exhibits a synergistic anti-tumor effect in AML by down-regulating Mcl-1 protein.

Keywords

Acute myeloid leukemia (AML); Dactolisib (BEZ235); Inherent resistance; PI3K/AKT/mTOR pathway; Synergistic anti-tumor effect; Venetoclax (ABT199).

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