Abstract：
:Heat shock protein 90 (Hsp90) is a molecular chaperone engaging in multiple cellular signaling by stabilizing oncoproteins (e.g. Akt and c-Raf) in tumor cells. Whereas Hsp90 inhibitors such as 17-AAG exert promising antitumor effects in clinical trials, current efforts focus on developing agents targeting Hsp90 with improved efficacy and lower toxicity. Using a fluorescence polarization assay, we screened over a hundred of synthetic small molecules and identified a resorcinol derivative LD053 that bound the Hsp90 ATP-binding pocket. The binding of LD053 to Hsp90 dissociated the co-chaperone protein cdc37 from Hsp90, resulting in destabilization of Akt and c-Raf and subsequent inhibition of PI3K/Akt and c-Raf/Mek/Erk signaling in BGC823 gastric cancer cells. As a consequence, LD053 decreased cancer cell viability and induced apoptosis evidenced by increased subG0/G1 cell population and increased cleavage of caspase 3 and PARP. Interestingly, normal human cells appeared insensitive to LD053 treatments. Consistent with its in vitro anticancer activities, LD053 significantly inhibited growth of BGC823 xenografts in nude mice without apparent body weight loss. These results thus demonstrate that LD053 is a novel Hsp90 inhibitor and has potential to be used to treat gastric cancer.
journal_name
Biochem Pharmacoljournal_title
Biochemical pharmacologyauthors
Lu C,Liu D,Jin J,Deokar H,Zhang Y,Buolamwini JK,Yu X,Yan C,Chen Xdoi
10.1016/j.bcp.2013.02.003subject
Has Abstractpub_date
2013-05-01 00:00:00pages
1246-56issue
9eissn
0006-2952issn
1873-2968pii
S0006-2952(13)00089-0journal_volume
85pub_type
杂志文章abstract：:In model experiments using human erythrocytes, glycochenodeoxycholate caused extensive membrane damage (as judged by release of membrane phospholipid and acetylcholinesterase and by cell lysis) at approximately 10-fold lower concentrations than glycocholate. Chenodeoxycholate feeding had no effect upon the total prote...
journal_title：Biochemical pharmacology
pub_type： 杂志文章
doi：10.1016/0006-2952(84)90660-9
更新日期：1984-07-15 00:00:00
abstract：:The role of calcium in the stimulation of phosphoinositide (PIn) hydrolysis by norepinephrine and the calcium ionophore A23187 was investigated in chopped cerebral cortex in which the PIns had been labeled previously with ([3H]myo-inositol. The accumulation of the newly formed [3H]inositol phosphate ([3H]IPs) was used...
journal_title：Biochemical pharmacology
pub_type： 杂志文章
doi：10.1016/0006-2952(87)90222-x
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journal_title：Biochemical pharmacology
pub_type： 杂志文章
doi：10.1016/j.bcp.2010.05.024
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journal_title：Biochemical pharmacology
pub_type： 杂志文章
doi：10.1016/s0006-2952(01)00837-1
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journal_title：Biochemical pharmacology
pub_type： 杂志文章
doi：10.1016/j.bcp.2016.03.014
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journal_title：Biochemical pharmacology
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journal_title：Biochemical pharmacology
pub_type： 杂志文章
doi：10.1016/j.bcp.2006.11.020
更新日期：2007-03-15 00:00:00
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journal_title：Biochemical pharmacology
pub_type： 杂志文章
doi：10.1016/0006-2952(93)90268-2
更新日期：1993-03-09 00:00:00
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journal_title：Biochemical pharmacology
pub_type： 杂志文章
doi：10.1016/j.bcp.2011.11.030
更新日期：2012-02-15 00:00:00
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journal_title：Biochemical pharmacology
pub_type： 杂志文章
doi：10.1016/0006-2952(84)90344-7
更新日期：1984-06-01 00:00:00
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journal_title：Biochemical pharmacology
pub_type： 杂志文章
doi：10.1016/j.bcp.2005.03.008
更新日期：2005-06-01 00:00:00
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journal_title：Biochemical pharmacology
pub_type： 杂志文章
doi：10.1016/s0006-2952(97)00075-0
更新日期：1997-05-15 00:00:00
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journal_title：Biochemical pharmacology
pub_type： 杂志文章
doi：10.1016/s0006-2952(98)00191-9
更新日期：1998-11-01 00:00:00
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journal_title：Biochemical pharmacology
pub_type： 杂志文章
doi：10.1016/0006-2952(84)90127-8
更新日期：1984-11-01 00:00:00
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journal_title：Biochemical pharmacology
pub_type： 杂志文章
doi：10.1016/0006-2952(92)90502-a
更新日期：1992-03-17 00:00:00
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journal_title：Biochemical pharmacology
pub_type： 杂志文章
doi：10.1016/j.bcp.2018.03.031
更新日期：2018-06-01 00:00:00
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journal_title：Biochemical pharmacology
pub_type： 杂志文章
doi：10.1016/0006-2952(89)90095-6
更新日期：1989-08-01 00:00:00
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journal_title：Biochemical pharmacology
pub_type： 杂志文章
doi：10.1016/j.bcp.2012.09.032
更新日期：2012-12-15 00:00:00
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journal_title：Biochemical pharmacology
pub_type： 杂志文章
doi：10.1016/0006-2952(82)90341-0
更新日期：1982-03-15 00:00:00
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journal_title：Biochemical pharmacology
pub_type： 杂志文章
doi：10.1016/0006-2952(92)90501-9
更新日期：1992-03-17 00:00:00
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journal_title：Biochemical pharmacology
pub_type： 杂志文章
doi：10.1016/j.bcp.2003.08.007
更新日期：2003-12-01 00:00:00
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journal_title：Biochemical pharmacology
pub_type： 杂志文章
doi：10.1016/0006-2952(84)90510-0
更新日期：1984-04-01 00:00:00
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journal_title：Biochemical pharmacology
pub_type： 杂志文章
doi：10.1016/j.bcp.2009.05.026
更新日期：2009-09-15 00:00:00
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journal_title：Biochemical pharmacology
pub_type： 杂志文章
doi：10.1016/0006-2952(95)00035-x
更新日期：1995-05-11 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：2018-09-01 00:00:00
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journal_title：Biochemical pharmacology
pub_type： 杂志文章
doi：10.1016/0006-2952(90)90245-g
更新日期：1990-11-01 00:00:00
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journal_title：Biochemical pharmacology
pub_type： 杂志文章
doi：10.1016/s0006-2952(02)01656-8
更新日期：2003-03-15 00:00:00
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journal_title：Biochemical pharmacology
pub_type： 杂志文章
doi：10.1016/0006-2952(92)90138-9
更新日期：1992-06-23 00:00:00
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journal_title：Biochemical pharmacology
pub_type： 杂志文章
doi：10.1016/0006-2952(84)90055-8
更新日期：1984-12-01 00:00:00
abstract：:The molecular mechanism(s) underlying induction of the hepatic microsomal cytochrome P4502E1 (2E1) by xenobiotics (e.g. ethanol and acetone) is controversial. Proposed mechanisms include increased rates of enzyme synthesis due to elevated 2E1 mRNA levels, enhanced translation of pre-existing mRNA, or stabilization of ...
journal_title：Biochemical pharmacology
pub_type： 杂志文章
doi：10.1016/0006-2952(93)90049-3
更新日期：1993-04-06 00:00:00
