Venetoclax-Resistant MV4-11 Leukemic Cells Activate PI3K/AKT Pathway for Metabolic Reprogramming and Redox Adaptation for Survival

Alkhatabi, Hind Ali; Zohny, Samir F.; Mohammed, Mohammed Razeeth Shait; Choudhry, Hani; Rehan, Mohd; Ahmad, Aamir; Ahmed, Farid; Khan, Mohammad Imran

doi:10.3390/antiox11030461

Cited by 15 publications

(10 citation statements)

References 31 publications

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“…After treatment with the AMPK activator A-769662, the cell line exhibited reduced sensitivity to venetoclax, and after treatment with the AMPK inhibitor dorsomorphin, it exhibited increased sensitivity to venetoclax. The abnormol intracellular OXPHOS caused by activation of the AMPK signalling pathway plays an important role in the decreased sensitivity of cells to venetoclax [ 83 ]. The increased MCL-1 in VEN-R AML cells also regulates pathways involved in bioenergetics and carbohydrate metabolism, including the TCA cycle, glycolysis and the pentose phosphate pathway, to change the OXPHOS level in the internal environment.…”

Section: Introductionmentioning

confidence: 99%

Progress in understanding the mechanisms of resistance to BCL-2 inhibitors

2022

Exp Hematol Oncol

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Venetoclax is a new type of BH3 mimetic compound that can target the binding site in the BCL-2 protein and induce apoptosis in cancer cells by stimulating the mitochondrial apoptotic pathway. Venetoclax is especially used to treat haematological malignancies. However, with the recent expansion in the applications of venetoclax, some cases of venetoclax resistance have appeared, posing a major problem in clinical treatment. In this article, we explored several common mechanisms of venetoclax resistance. Increased expression of the antiapoptotic proteins MCL-1 and BCL-XL plays a key role in conferring cellular resistance to venetoclax. These proteins can bind to the released BIM in the context of venetoclax binding to BCL-2 and thus continue to inhibit mitochondrial apoptosis. Structural mutations in BCL-2 family proteins caused by genetic instability lead to decreased affinity for venetoclax and inhibit the intrinsic apoptosis pathway. Mutation or deletion of the BAX gene renders the BAX protein unable to anchor to the outer mitochondrial membrane to form pores. In addition to changes in BCL-2 family genes, mutations in other oncogenes can also confer resistance to apoptosis induced by venetoclax. TP53 mutations and the expansion of FLT3-ITD promote the expression of antiapoptotic proteins MCL-1 and BCL-XL through multiple signalling pathways, and interfere with venetoclax-mediated apoptosis processes depending on their affinity for BH3-only proteins. Finally, the level of mitochondrial oxidative phosphorylation in venetoclax-resistant leukaemia stem cells is highly abnormal. Not only the metabolic pathways but also the levels of important metabolic components are changed, and all of these alterations antagonize the venetoclax-mediated inhibition of energy metabolism and promote the survival and proliferation of leukaemia stem cells. In addition, venetoclax can change mitochondrial morphology independent of the BCL-2 protein family, leading to mitochondrial dysfunction. However, mitochondria resistant to venetoclax antagonize this effect, forming tighter mitochondrial cristae, which provide more energy for cell survival.

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Section: Introductionmentioning

confidence: 99%

Progress in understanding the mechanisms of resistance to BCL-2 inhibitors

2022

Exp Hematol Oncol

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“…ABT-199, an FDA-approved Bcl2 inhibitor, is known to cause resistance in leukemic cells by elevating levels of a metabolite—phosphoinositides—in cells exhibiting a high glycolytic rate [ 81 ]. Interestingly, we observed that Disarib treatment reduced oncometabolite like myristoleic acid, carnitine, and Citrulline and increased the levels of AMP and acetylcarnitine.…”

Section: Discussionmentioning

confidence: 99%

Integrated Transcriptome and Metabolomic Analysis Reveal Anti-Angiogenic Properties of Disarib, a Novel Bcl2-Specific Inhibitor

Manjunath

Saiswaroop

Pradhan

et al. 2022

Genes

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Transcriptomic profiling of several drugs in cancer cell lines has been utilised to obtain drug-specific signatures and guided combination therapy to combat drug resistance and toxicity. Global metabolomics reflects changes due to altered activity of enzymes, environmental factors, etc. Integrating transcriptomics and metabolomics can provide genotype-phenotype correlation, providing meaningful insights into alterations in gene expression and its outcome to understand differential metabolism and guide therapy. This study uses a multi-omics approach to understand the global gene expression and metabolite changes induced by Disarib, a novel Bcl2-specific inhibitor in the Ehrlich adenocarcinoma (EAC) breast cancer mouse model. RNAseq analysis was performed on EAC mouse tumours treated with Disarib and compared to the controls. The expression of 6 oncogenes and 101 tumour suppressor genes interacting with Bcl2 and Bak were modulated upon Disarib treatment. Cancer hallmark pathways like DNA repair, Cell cycle, angiogenesis, and mitochondrial metabolism were downregulated, and programmed cell death platelet-related pathways were upregulated. Global metabolomic profiling using LC-MS revealed that Oncometabolites like carnitine, oleic acid, glycine, and arginine were elevated in tumour mice compared to normal and were downregulated upon Disarib treatment. Integrated transcriptomic and metabolomic profiles identified arginine metabolism, histidine, and purine metabolism to be altered upon Disarib treatment. Pro-angiogenic metabolites, arginine, palmitic acid, oleic acid, and myristoleic acid were downregulated in Disarib-treated mice. We further validated the effect of Disarib on angiogenesis by qRT-PCR analysis of genes in the VEGF pathway. Disarib treatment led to the downregulation of pro-angiogenic markers. Furthermore, the chorioallantoic membrane assay displayed a reduction in the formation of the number of secondary blood vessels upon Disarib treatment. Disarib reduces tumours by reducing oncometabolite and activating apoptosis and downregulating angiogenesis.

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“…GSK864-treated cells were incubated in a culture medium with 500 nM CELLROX for 60 min at 37 °C and 5% CO 2 . Flow cytometry immediately analyzed the samples using 488 nm excitation for the CellROX ® Green [ 22 , 23 ].…”

Section: Methodsmentioning

confidence: 99%

Profiling the Effect of Targeting Wild Isocitrate Dehydrogenase 1 (IDH1) on the Cellular Metabolome of Leukemic Cells

Mohammed

Alzahrani

Hosawi

et al. 2022

IJMS

Self Cite

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Leukemia is one of the most common primary malignancies of the hematologic system in both children and adults and remains a largely incurable or relapsing disease. The elucidation of disease subtypes based on mutational profiling has not improved clinical outcomes. IDH1/2 are critical enzymes of the TCA cycle that produces α-ketoglutarate (αKG). However, their mutated version is well reported in various cancer types, including leukemia, which produces D-2 hydroxyglutarate (D-2HG), an oncometabolite. Recently, some studies have shown that wild-type IDH1 is highly expressed in non-small cell lung carcinoma (NSCLC), primary glioblastomas (GBM), and several hematological malignancies and is correlated with disease progression. This work shows that the treatment of wild-type IDH1 leukemia cells with a specific IDH1 inhibitor shifted leukemic cells toward glycolysis from the oxidative phosphorylation (OXPHOS) phenotype. We also noticed a reduction in αKG in treated cells, possibly suggesting the inhibition of IDH1 enzymatic activity. Furthermore, we found that IDH1 inhibition reduced the metabolites related to one-carbon metabolism, which is essential for maintaining global methylation in leukemic cells. Finally, we observed that metabolic alteration in IDH1 inhibitor-treated leukemic cells promoted reactive oxygen species (ROS) formation and the loss of mitochondrial membrane potential, leading to apoptosis in leukemic cells. We showed that targeting wild-type IDH1 leukemic cells promotes metabolic alterations that can be exploited for combination therapies for a better outcome.

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Venetoclax-Resistant MV4-11 Leukemic Cells Activate PI3K/AKT Pathway for Metabolic Reprogramming and Redox Adaptation for Survival

Cited by 15 publications

References 31 publications

Progress in understanding the mechanisms of resistance to BCL-2 inhibitors

Progress in understanding the mechanisms of resistance to BCL-2 inhibitors

Integrated Transcriptome and Metabolomic Analysis Reveal Anti-Angiogenic Properties of Disarib, a Novel Bcl2-Specific Inhibitor

Profiling the Effect of Targeting Wild Isocitrate Dehydrogenase 1 (IDH1) on the Cellular Metabolome of Leukemic Cells

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