| FK506 binding proteins as targets in anticancer therapy. | |
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MedLine Citation:
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PMID: 21182472 Owner: NLM Status: In-Data-Review |
Abstract/OtherAbstract:
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FK506 binding proteins (FKBPs) are the intracellular ligands of FK506 and rapamycin, two natural compounds with powerful and clinically efficient immunosuppressive activity. In recent decades, a relevant role for immunosuppressants as anticancer agents has emerged. Especially, rapamycin and its derivatives are used, with successful results, across a variety of tumors. Of note, rapamycin and FK506 bind to FKBP12, and the resulting complexes interfere with distinct intracellular signaling pathways driven, respectively, by the mammalian target of rapamycin and calcineurin phosphatase. These pathways are related to T-cell activation and growth. Hyperactivation of the mammalian target of rapamycin (mTOR), particularly in cancers that have lost the tumor suppressor gene PTEN, plays an important pathogenetic role in tumor transformation and growth. The signaling pathway involving calcineurin and nuclear factors of activated T-lymphocytes is also involved in the pathogenesis of different cancer types and in tumor metastasis, providing a rationale for use of FK506 in anticancer therapy. Recent studies have focused on FKBPs in apoptosis regulation: Targeting of FKBP12 promotes apoptosis in chronic lymphocytic leukemia, FKBP38 knockdown sensitizes hepatoma cells to apoptosis, and FKBP51 silencing overcomes resistance to apoptosis in acute lymphoblastic leukemia, prostate cancer, melanoma, and glioma. Interestingly, derivatives of FK506 that have the same FKBP12-binding properties as FK506 but lack functional immunosuppressant activity, exert the same apoptotic effect as FK506 in chronic lymphocytic leukemia.These findings suggest that a direct FKBP inhibition represents a further mechanism of immunosuppressants.' anticancer activity. In this review, we focus on the role of FKBP members in apoptosis control and summarize the data on the antitumor effect of selective targeting of FKBP. |
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Authors:
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Simona Romano; Annalaura Di Pace; Antonio Sorrentino; Rita Bisogni; Luigi Sivero; Maria Fiammetta Romano |
Publication Detail:
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Type: Journal Article |
Journal Detail:
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Title: Anti-cancer agents in medicinal chemistry Volume: 10 ISSN: 1875-5992 ISO Abbreviation: Anticancer Agents Med Chem Publication Date: 2010 Nov |
Date Detail:
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Created Date: 2011-01-26 Completed Date: - Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 101265649 Medline TA: Anticancer Agents Med Chem Country: Netherlands |
Other Details:
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Languages: eng Pagination: 651-6 Citation Subset: IM |
Affiliation:
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Department of Biochemistry and Medical Biotechnology, University Federico II, Naples, Italy. romano@dbbm.unina.it. |
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From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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