| Phosphoinositide-3-kinase/AKT/mTORC1/2 signaling determines sensitivity of Burkitt's Lymphoma cells to BH3-mimetics. | |
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MedLine Citation:
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PMID: 22241218 Owner: NLM Status: Publisher |
Abstract/OtherAbstract:
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Burkitt's lymphoma (BL), driven by translocation and over-expression of the c-MYC gene, is an aggressive, highly proliferative lymphoma and novel therapeutic strategies are required to overcome drug resistance following conventional treatments. The importance of the pro-survival BCL-2 family member BCL-XL in BL cell survival suggests that antagonistic BH3-mimetic compounds may have therapeutic potential. Here we show that treatment of BL cell lines with ABT-737 induces caspase-3/7 activation and apoptosis with varying potency. Using selective inhibitors, we identify phosphoinositide-3-kinase (PI3K) as a pro-proliferative/survival pathway in BL cells and investigate the potential of combined pharmacological inhibition of both the BCL-2 family and PI3K signaling pathway. PI3K/AKT inhibition and ABT-737 treatment induced synergistic caspase activation, augmented BL cell apoptosis and rendered chemo-resistant cells sensitive. Targeting mTORC1/2 with PP242 was also effective, either as a monotherapy or, more generally, in combination with ABT-737. The combined use of a dual specificity PI3K/mTOR inhibitor (PI 103) with ABT-737 proved highly efficacious. PI 103 treatment of BL cells was associated with an increase in BIM/MCL-1 expression ratios and loss of c-MYC expression. Furthermore, blocking c-MYC function using the inhibitor 10058-F4 also induced apoptosis synergistically with ABT-737, suggesting that maintenance of expression of BCL-2 family members and/or c-MYC by the PI3K/AKT/mTOR pathway could contribute to BL cell survival and resistance to ABT-737. The combined use of BH3-mimetics and selective mTORC1/2 inhibitors may therefore be a useful novel therapeutic approach for the treatment of B-cell malignancy, including chemo-resistant lymphomas. |
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Authors:
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Lindsay C Spender; Gareth J Inman |
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Publication Detail:
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Type: JOURNAL ARTICLE Date: 2012-1-12 |
Journal Detail:
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Title: Molecular cancer research : MCR Volume: - ISSN: 1557-3125 ISO Abbreviation: - Publication Date: 2012 Jan |
Date Detail:
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Created Date: 2012-1-13 Completed Date: - Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 101150042 Medline TA: Mol Cancer Res Country: - |
Other Details:
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Languages: ENG Pagination: - Citation Subset: - |
Affiliation:
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Dundee University. |
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From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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