2. Academic Validation
  3. SIRT2 inhibitor SirReal2 enhances anti-tumor effects of PI3K/mTOR inhibitor VS-5584 on acute myeloid leukemia cells

SIRT2 inhibitor SirReal2 enhances anti-tumor effects of PI3K/mTOR inhibitor VS-5584 on acute myeloid leukemia cells

  • Cancer Med. 2023 Sep;12(18):18901-18917. doi: 10.1002/cam4.6480.
Yiming Luo 1 2 3,  Haijun Zhao 1 2 3,  Jingtao Zhu 4 5,  Liyi Zhang 6 7,  Jie Zha 1 2 3,  Li Zhang 1 2 3,  Yi Ding 8,  Xinyi Jian 9,  Junjie Xia 10 11 12,  Bing Xu 1 2 3,  Zhongquan Qi 10 11 13
Affiliations

Affiliations

  • 1 Department of Hematology, The First Affiliated Hospital of Xiamen University and Institute of Hematology, School of Medicine, Xiamen University, Xiamen, Fujian, China.
  • 2 Key Laboratory of Xiamen for Diagnosis and Treatment of Hematological Malignancy, Xiamen, Fujian, China.
  • 3 The School of Clinical Medicine, Fujian Medical University, Fuzhou, Fujian, China.
  • 4 Department of Gastrointestinal Oncology Surgery, Cancer Center, The First Affiliated Hospital of Xiamen University, Xiamen, Fujian, China.
  • 5 The Third Clinical Medical College, Fujian Medical University, Fuzhou, Fujian, China.
  • 6 Department of Breast Surgery, Key Laboratory of Breast Cancer in Shanghai, Fudan University Shanghai Cancer Center, Shanghai, China.
  • 7 Department of Oncology, Fudan University Shanghai Medical College, Shanghai, China.
  • 8 Department of Pathology, The First Affiliated Hospital, School of Medicine, Xiamen University, Xiamen, China.
  • 9 Graduate College of Fujian Medical University, Fuzhou, Fujian, China.
  • 10 Organ Transplantation Institute of Xiamen University, Xiamen, Fujian, China.
  • 11 Fujian Provincial Key Laboratory of Organ and Tissue Regeneration, Xiamen, Fujian, China.
  • 12 Xiamen Key Laboratory of Regeneration Medicine, School of Medicine, Xiamen University, Xiamen, China.
  • 13 Medical College of Guangxi University, Nanning, Guangxi, China.
PMID: 37658623 DOI: 10.1002/cam4.6480
Abstract

Background: Acute myeloid leukemia (AML) is a highly aggressive form of Cancer that is frequently diagnosed in adults and small molecule inhibitors have gained significant attention as a potential treatment option for AML.

Methods: The up-regulated genes in AML were identified through bioinformatics analysis. Potential candidate agents were selected through pharmacogenomics analysis. Proteomic experiments were conducted to determine the molecular mechanism after inhibitor treatment. To evaluate drug synergy, both cellular functional experiments and an AML mouse model were used.

Results: Through bioinformatics analysis, we conducted a screening for genes that are highly expressed in AML, which led to the identification of nine small-molecule inhibitors. Among these inhibitors, the PI3K/mTOR Inhibitor VS-5584 demonstrated significant effectiveness in inhibiting AML cell proliferation at low concentrations. Further testing revealed that VS-5584 induced Apoptosis and cycle arrest of AML cells in a dose- and time-dependent manner. Proteomics analysis showed significant changes in protein expression profiles of AML cells after VS-5584 treatment, with 287 proteins being down-regulated and 71 proteins being up-regulated. The proteins that exhibited differential expression were primarily involved in regulating the cell cycle and Apoptosis, as determined by GO analysis. Additionally, KEGG analysis indicated that the administration of VS-5584 predominantly affected the P53 and SIRT2 signaling pathways. The use of SIRT2 Inhibitor SirReal2 alongside VS-5584 caused a significant reduction in the half-maximal inhibitory concentration (IC50 ) of VS-5584 on AML cells. In vivo, experiments suggested that VS-5584 combined with SirReal2 suppressed tumor growth in the subcutaneous model and extended the survival rate of mice injected with tumor cells via tail vein.

Conclusions: Taken together, the PI3K/mTOR Inhibitor VS-5584 was effective in suppressing AML cell proliferation. PI3K/mTOR Inhibitor combined with SIRT2 Inhibitor exhibited a synergistic inhibitory effect on AML cells. Our findings offer promising therapeutic strategies and drug candidates for the treatment of AML.

Keywords

PI3K/mTOR; SIRT2; acute myeloid leukemia; anti-tumor effect.

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