Repurposing Metformin in hematologic tumor: State of art

Hu, Min; Chen, Yan; Ma, Tao; Li, Jingyuan

doi:10.1016/j.currproblcancer.2023.100972

Cited by 7 publications

(2 citation statements)

References 128 publications

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“…The mechanism by which metformin affects the G2/M cell cycle phase is not fully understood, but several hypotheses have been proposed, like AMP-activated protein kinase (AMPK) activation, mTOR inhibition, the activation of p53, or the alteration of mitochondrial function. It was shown that metformin activates AMPK and that this can lead to cell cycle arrest at the G1/S and G2/M checkpoints by inhibiting the activity of cyclin-dependent kinases (CDKs) and by modulating the expression of cell cycle regulatory proteins [25]. Also, the inhibition of mTOR by metformin may lead to cell cycle arrest at the G2/M phase by interfering with the translation of proteins required for cell cycle progression [25].…”

Section: Discussionmentioning

confidence: 99%

“…It was shown that metformin activates AMPK and that this can lead to cell cycle arrest at the G1/S and G2/M checkpoints by inhibiting the activity of cyclin-dependent kinases (CDKs) and by modulating the expression of cell cycle regulatory proteins [25]. Also, the inhibition of mTOR by metformin may lead to cell cycle arrest at the G2/M phase by interfering with the translation of proteins required for cell cycle progression [25]. Treatments with cytarabine, idarubicin, venetoclax, and a combination of metformin with S63845 increased the expression of pro-apoptotic genes such as BAK1, BAX, DAPK1, and APAF1.…”

Section: Discussionmentioning

confidence: 99%

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Metformin as an Enhancer for the Treatment of Chemoresistant CD34+ Acute Myeloid Leukemia Cells

Krastinaite,

Charkavliuk,

Navakauskiene

et al. 2024

Genes

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Acute myeloid leukemia is the second most frequent type of leukemia in adults. Due to a high risk of development of chemoresistance to first-line chemotherapy, the survival rate of patients in a 5-year period is below 30%. One of the reasons is that the AML population is heterogeneous, with cell populations partly composed of very primitive CD34+CD38- hematopoietic stem/progenitor cells, which are often resistant to chemotherapy. First-line treatment with cytarabine and idarubicin fails to inhibit the proliferation of CD34+CD38- cells. In this study, we investigated Metformin’s effect with or without first-line conventional chemotherapy, or with other drugs like venetoclax and S63845, on primitive and undifferentiated CD34+ AML cells in order to explore the potential of Metformin or S63845 to serve as adjuvant therapy for AML. We found that first-line conventional chemotherapy treatment inhibited the growth of cells and arrested the cells in the S phase of the cell cycle; however, metformin affected the accumulation of cells in the G2/M phase. We observed that CD34+ KG1a cells respond better to lower doses of cytarabine or idarubicin in combination with metformin. Also, we determined that treatment with cytarabine, venetoclax, and S63845 downregulated the strong tendency of CD34+ KG1a cells to form cell aggregates in culture due to the downregulation of leukemic stem cell markers like CD34 and CD44, as well as adhesion markers. Also, we found that idarubicin slightly upregulated myeloid differentiation markers, CD11b and CD14. Treatment with cytarabine, idarubicin, venetoclax, metformin, and S63845 upregulated some cell surface markers like HLA-DR expression, and metformin upregulated CD9, CD31, and CD105 cell surface marker expression. In conclusion, we believe that metformin has the potential to be used as an adjuvant in the treatment of resistant-to-first-line-chemotherapy AML cells. Also, we believe that the results of our study will stimulate further research and the potential use of changes in the expression of cell surface markers in the development of new therapeutic strategies.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%