Abstract：
:For several years the IMP/GMP-preferring cytosolic 5'-nucleotidase II (cN-II) has been considered as a therapeutic target in oncology. Indeed, various reports have indicated associations between cN-II expression level and resistance to anticancer agents in several cancer cell lines and in patients affected with neoplasia, mainly by hematologic malignancies. In this paper we present evidence showing that, among the commonly used cytotoxic nucleoside analogs, fludarabine can act as a cN-II inhibitor. In vitro studies using the wild type recombinant cN-II demonstrated that fludarabine inhibited enzymatic activity in a mixed manner (Ki 0.5 mM and Ki' 9 mM), whereas no inhibition was observed with clofarabine and cladribine. Additional experiments with mutant recombinant proteins and an in silico molecular docking indicated that this inhibition is due to an interaction with a regulatory site of cN-II known to interact with adenylic compounds. Moreover, synergy experiments between fludarabine and 6-mercaptopurine in human follicular lymphoma (RL) and human acute promyelocytic leukemia (HL-60) cells transfected with control or cN-II-targeting shRNA-encoding plasmids, showed synergy in control cells and antagonism in cells with decreased cN-II expression. This is in line with the hypothesis that fludarabine acts as a cN-II inhibitor and supports the idea of using cN-II inhibitors in association with other drugs to increase their therapeutic effect and decrease their resistance.
journal_name
Biochem Pharmacoljournal_title
Biochemical pharmacologyauthors
Cividini F,Pesi R,Chaloin L,Allegrini S,Camici M,Cros-Perrial E,Dumontet C,Jordheim LP,Tozzi MGdoi
10.1016/j.bcp.2015.01.010subject
Has Abstractpub_date
2015-03-15 00:00:00pages
63-8issue
2eissn
0006-2952issn
1873-2968pii
S0006-2952(15)00079-9journal_volume
94pub_type
杂志文章abstract：:Nephrotoxicity due to renal proximal tubule accumulation of aminoglycoside (AG) antibiotics, such as gentamicin, represents a major clinical problem. Receptor-mediated endocytosis via the multi-ligand receptor megalin is thought to be a key mechanism in the cellular uptake of AGs and nephrotoxicity. This process can b...
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pub_type： 杂志文章
doi：10.1016/0006-2952(90)90405-a
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pub_type： 杂志文章
doi：10.1016/0006-2952(92)90525-n
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pub_type： 杂志文章
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pub_type： 杂志文章
doi：10.1016/0006-2952(91)90092-j
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pub_type： 杂志文章
doi：10.1016/j.bcp.2008.10.022
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pub_type： 杂志文章
doi：10.1016/0006-2952(92)90283-o
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pub_type： 杂志文章
doi：10.1016/0006-2952(92)90335-g
更新日期：1992-12-01 00:00:00
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pub_type： 杂志文章
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更新日期：2007-01-01 00:00:00
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pub_type： 杂志文章
doi：10.1016/j.bcp.2007.02.006
更新日期：2007-06-01 00:00:00
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journal_title：Biochemical pharmacology
pub_type： 杂志文章
doi：10.1016/j.bcp.2005.07.035
更新日期：2005-11-15 00:00:00
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pub_type： 杂志文章
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更新日期：1994-08-17 00:00:00
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pub_type： 杂志文章
doi：10.1016/0006-2952(90)90621-q
更新日期：1990-06-15 00:00:00
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pub_type： 杂志文章
doi：10.1016/0006-2952(92)90184-k
更新日期：1992-05-28 00:00:00
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pub_type： 杂志文章
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pub_type： 杂志文章
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更新日期：1990-03-01 00:00:00
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pub_type： 杂志文章
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pub_type： 杂志文章
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更新日期：2003-12-01 00:00:00
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pub_type： 杂志文章
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pub_type： 杂志文章
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journal_title：Biochemical pharmacology
pub_type： 杂志文章
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更新日期：1988-10-15 00:00:00
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journal_title：Biochemical pharmacology
pub_type： 杂志文章
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更新日期：1987-01-01 00:00:00
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pub_type： 杂志文章
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更新日期：2014-06-01 00:00:00
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pub_type： 杂志文章
doi：10.1016/0006-2952(90)90068-v
更新日期：1990-02-01 00:00:00
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journal_title：Biochemical pharmacology
pub_type： 杂志文章
doi：10.1016/0006-2952(90)90188-q
更新日期：1990-07-01 00:00:00
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journal_title：Biochemical pharmacology
pub_type： 杂志文章
doi：10.1016/0006-2952(82)90244-1
更新日期：1982-01-01 00:00:00
