Palbociclib promotes the antitumor activity of Venetoclax plus Azacitidine against acute myeloid leukemia

Anyou Wang; Mingmeng Fang; Hui Jiang; Dongyao Wang; Xuhan Zhang; Baolin Tang; Xiaoyu Zhu; Wanglai Hu; Xin Liu

Biomedicine & Pharmacotherapy (Sep 2022)

Palbociclib promotes the antitumor activity of Venetoclax plus Azacitidine against acute myeloid leukemia

Anyou Wang,
Mingmeng Fang,
Hui Jiang,
Dongyao Wang,
Xuhan Zhang,
Baolin Tang,
Xiaoyu Zhu,
Wanglai Hu,
Xin Liu

Affiliations

Anyou Wang: Department of Hematology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230001, Anhui, China; Blood and Cell Therapy Institute, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230001, Anhui, China; Anhui Provincial Key Laboratory of Blood Research and Applications, Hefei 230001, Anhui, China; Corresponding authors at: Department of Hematology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230001, Anhui, China.
Mingmeng Fang: Department of Hematology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230001, Anhui, China; Blood and Cell Therapy Institute, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230001, Anhui, China; Anhui Provincial Key Laboratory of Blood Research and Applications, Hefei 230001, Anhui, China
Hui Jiang: Department of Hematology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230001, Anhui, China; Blood and Cell Therapy Institute, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230001, Anhui, China; Anhui Provincial Key Laboratory of Blood Research and Applications, Hefei 230001, Anhui, China
Dongyao Wang: Department of Hematology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230001, Anhui, China; Blood and Cell Therapy Institute, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230001, Anhui, China; Anhui Provincial Key Laboratory of Blood Research and Applications, Hefei 230001, Anhui, China; Anhui Province Key Laboratory of Immunology in Chronic Diseases, Bengbu Medical College, Bengbu, Anhui 233030, China
Xuhan Zhang: Department of Hematology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230001, Anhui, China; Blood and Cell Therapy Institute, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230001, Anhui, China; Anhui Provincial Key Laboratory of Blood Research and Applications, Hefei 230001, Anhui, China
Baolin Tang: Department of Hematology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230001, Anhui, China; Blood and Cell Therapy Institute, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230001, Anhui, China; Anhui Provincial Key Laboratory of Blood Research and Applications, Hefei 230001, Anhui, China
Xiaoyu Zhu: Department of Hematology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230001, Anhui, China; Blood and Cell Therapy Institute, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230001, Anhui, China; Anhui Provincial Key Laboratory of Blood Research and Applications, Hefei 230001, Anhui, China
Wanglai Hu: Translational Research Institute, People’s Hospital of Zhengzhou University, Academy of Medical Science, Henan International Joint Laboratory of Non-coding RNA and Metabolism in Cancer, Zhengzhou University, Zhengzhou, China; Corresponding author.
Xin Liu: Department of Hematology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230001, Anhui, China; Blood and Cell Therapy Institute, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230001, Anhui, China; Anhui Provincial Key Laboratory of Blood Research and Applications, Hefei 230001, Anhui, China; Corresponding authors at: Department of Hematology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230001, Anhui, China.

Journal volume & issue: Vol. 153
p. 113527

Abstract

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Around 70 % of patients diagnosed with acute myeloid leukemia (AML) survive less than 5 years due to drug resistance and disease relapse. Consequently, improved clinical treatments are urgently needed. Some but not all AML patients benefit from the combination of the BCL-2 inhibitor Venetoclax with the hypomethylation agent Azacitidine. Here we investigated the utility of employing the cyclin dependent kinase (CDK6) inhibitor Palbociclib to improve the efficacy of Venetoclax/Azacitidine combination therapy. Our analysis of publicly available RNA sequencing datasets showed CDK6 was highly expressed in the major acute forms of leukemia including AML. Consistently, using qPCR and flow cytometry we found that CDK6 was overexpressed in bone marrow mononuclear cells from AML patients compared to healthy controls. Subsequent in vitro testing of Palbociclib, Venetoclax and Azacitidine, alone and in combination against CDK6-overexpressing AML cells lines THP-1 and KG-1 and primary AML cells showed that the Palbociclib/Venetoclax/Azacitidine combination improved treatment efficacy compared to Venetoclax/Azacitidine treatment alone. Additional investigations in a subcutaneous KG-1 mouse model showed similarly the three-drug combination produced the most significant reductions in tumor load together with the least amount of spleen infiltration. We established Palbociclib functioned in combination with Venetoclax/Azacitidine by increasing the rates of apoptosis in AML cells. Further investigations revealed that Palbociclib does not affect BCL-2 activity but downregulated the anti-apoptotic proteins MCL-1 and BCL-XL, making AML cells more sensitive to Venetoclax/Azacitidine treatment. Our results propose that the Palbociclib/Venetoclax/Azacitidine regimen warrants further preclinical research for clinical application in AML patients.

Published in Biomedicine & Pharmacotherapy

ISSN: 0753-3322 (Print); 1950-6007 (Online)
Publisher: Elsevier
Country of publisher: France
LCC subjects: Medicine: Therapeutics. Pharmacology
Website: https://www.journals.elsevier.com/biomedicine-and-pharmacotherapy

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