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Cotargeting BCL-2 and PI3K Induces BAX-Dependent Mitochondrial Apoptosis in AML Cells.

ABSTRACT: Inhibitors targeting BCL-2 apoptotic proteins have significant potential for the treatment of acute myeloid leukemia (AML); however, complete responses are observed in only 20% of patients, suggesting that targeting BCL-2 alone is insufficient to yield durable responses. Here, we assessed the efficacy of coadministration of the PI3K/mTOR inhibitor GDC-0980 or the p110?-sparing PI3K inhibitor taselisib with the selective BCL-2 antagonist venetoclax in AML cells. Tetracycline-inducible downregulation of BCL-2 significantly sensitized MV4-11 and MOLM-13 AML cells to PI3K inhibition. Venetoclax/GDC-0980 coadministration induced rapid and pronounced BAX mitochondrial translocation, cytochrome c release, and apoptosis in various AML cell lines in association with AKT/mTOR inactivation and MCL-1 downregulation; ectopic expression of MCL-1 significantly protected cells from this regimen. Combined treatment was also effective against primary AML blasts from 17 patients, including those bearing various genetic abnormalities. Venetoclax/GDC-0980 markedly induced apoptosis in primitive CD34+/38-/123+ AML cell populations but not in normal hematopoietic progenitor CD34+ cells. The regimen was also active against AML cells displaying intrinsic or acquired venetoclax resistance or tumor microenvironment-associated resistance. Either combinatorial treatment markedly reduced AML growth and prolonged survival in a systemic AML xenograft mouse model and diminished AML growth in two patient-derived xenograft models. Venetoclax/GDC-0980 activity was partially diminished in BAK-/- cells and failed to induce apoptosis in BAX-/- and BAX-/-BAK-/- cells, whereas BIM-/- cells were fully sensitive. Similar results were observed with venetoclax alone in in vitro and in vivo systemic xenograft models. Collectively, these studies demonstrate that venetoclax/GDC-0980 exhibits potent anti-AML activity primarily through BAX and, to a lesser extent, BAK. These findings argue that dual BCL-2 and PI3K inhibition warrants further evaluation in AML.Significance: Combined treatment with clinically relevant PI3K and BCL-2 inhibitors may prove effective in the treatment of acute myeloid leukemia. Cancer Res; 78(11); 3075-86. ©2018 AACR.

SUBMITTER: Rahmani M

PROVIDER: S-EPMC5984704 | biostudies-literature | 2018 Jun

REPOSITORIES: biostudies-literature

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Cotargeting BCL-2 and PI3K Induces BAX-Dependent Mitochondrial Apoptosis in AML Cells.

Rahmani Mohamed M Nkwocha Jewel J Hawkins Elisa E Pei Xinyan X Parker Rebecca E RE Kmieciak Maciej M Leverson Joel D JD Sampath Deepak D Ferreira-Gonzalez Andrea A Grant Steven S

Cancer research 20180320 11

Inhibitors targeting BCL-2 apoptotic proteins have significant potential for the treatment of acute myeloid leukemia (AML); however, complete responses are observed in only 20% of patients, suggesting that targeting BCL-2 alone is insufficient to yield durable responses. Here, we assessed the efficacy of coadministration of the PI3K/mTOR inhibitor GDC-0980 or the p110β-sparing PI3K inhibitor taselisib with the selective BCL-2 antagonist venetoclax in AML cells. Tetracycline-inducible downregulat ...[more]

PMID: 29559471

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Project description:BackgroundLobaplatin (LBP) is a third-generation platinum-based drug that has been approved only in China for the treatment of several cancer types. Nonetheless, its efficacy in treating bladder cancer (BC) is unclear thus far. Through in vitro and in vivo experiments, this study aimed to explore whether LBP has an antitumor effect on T24 and 5637 BC cells and whether the effect is related to B-cell lymphoma-2 (Bcl-2), Bcl-2-associated X protein (Bax) and regulation of the phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt) pathway.MethodsFor in vitro experiments, the cell counting kit-8 (CCK-8) method was used to determine how different concentrations of LBP affect the viability of two types of BC cells. A wound healing assay was used to test the inhibitory effect of LBP on the migration of the two cell lines. Annexin V-fluorescein isothiocyanate isomer I (V-FITC)/propidium iodide (PI) staining was used to detect changes in cell apoptosis before and after LBP treatment, and Western blotting was used to detect the expression of apoptosis-related proteins and PI3K/Akt pathway proteins. For in vivo experiments, a cell-derived xenograft (CDX) model was employed, and the weight of nude mice and the tumor size were measured. Immunohistochemistry was used to detect the effect of LBP on the expression of apoptosis-related proteins in tumor xenografts.ResultsIn vitro, LBP reduced proliferation (P<0.05), inhibited migration (P<0.05), and induced apoptosis in T24 (31.25%±1.20%, P<0.01) and 5637 (14.3%±2.24%, P<0.05) BC cells, in a dose-dependent manner (P<0.05); increased the expression of proapoptotic proteins, including Bax, caspase-3 and cleaved caspase-3 (P<0.05); and suppressed the expression of antiapoptotic proteins, including Bcl-2, PI3K, Akt and phosphorylated Akt (p-Akt). The in vivo experiment confirmed that LBP can reduce the size of subcutaneous tumors in nude mice (P<0.05), increase the expression levels of Bax and cleaved caspase-3 and lower the expression of Bcl-2 (P<0.05) in bladder tumor tissue.ConclusionsThe results obtained from both experiments suggest that LBP can inhibit the proliferation of T24 and 5637 BC cells, which might be credited to its effects in regulating Bcl-2 and Bax expression and inhibiting the PI3K/Akt pathway.

Dataset Information

Cotargeting BCL-2 and PI3K Induces BAX-Dependent Mitochondrial Apoptosis in AML Cells.

Publications

Cotargeting BCL-2 and PI3K Induces BAX-Dependent Mitochondrial Apoptosis in AML Cells.

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