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Inhibition of gastric tumor growth by a novel Hsp90 inhibitor.

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.

SUBMITTER: Lu C

PROVIDER: S-EPMC3617064 | biostudies-literature | 2013 May

REPOSITORIES: biostudies-literature

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Inhibition of gastric tumor growth by a novel Hsp90 inhibitor.

Lu Chunwan C Liu Di D Jin Jing J Deokar Hemantkumar H Zhang Yi Y Buolamwini John K JK Yu Xiaoming X Yan Chunhong C Chen Xiaoguang X

Biochemical pharmacology 20130213 9

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 th ...[more]

PMID: 23415900

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Project description:Purpose:Currently, the paucity of classical effective pharmacological drugs to treat esophageal squamous cell carcinoma (ESCC) is a major problem. The c-Myc (MYC) protein is a promising target as it is overexpressed in ESCC. MYC is a sensitive client protein of the heat shock protein 90 (HSP90) and, therefore, targeting the HSP90-MYC axis by inhibition of HSP90 is a potential therapeutic strategy for ESCC. Here, we evaluated the clinical application value of the HSP90 inhibitor (Ganetespib, STA-9090) as an anti-cancer agent for MYC-positive ESCC. Materials and Methods:We first analyzed ESCC tissue microarrays and clinical tissue samples to determine MYC expression. The relationship between MYC and HSP90 was analyzed by co-immunoprecipitation assays and immunofluorescence. In in vitro cell models, cell growth was analyzed using the CCK-8 kit, and MYC protein expression was analyzed by Western blot. The in vivo antitumor activity of STA-9090 was assessed in two xenograft animal models. Results:We demonstrated that MYC-overexpressing ESCC cells were highly sensitive to STA-9090 treatment through suppressing ESCC cell proliferation, cell cycle progression and survival. Moreover, STA-9090 treatment decreased MYC expression, reducing the half-life of the MYC protein. We further established two xenograft mouse models using ESCC cells and clinical ESCC samples to validate the effectiveness of STA-9090 in vivo. In both xenograft models, STA-9090 substantially inhibited the growth of MYC-positive ESCC tumors in vivo. In contrast, STA-9090 treatment demonstrated no bene?cial effects in mice with low-MYC expressing ESCC tumors. Conclusion:In conclusion, our data support that the HSP90 inhibitor, STA-9090, suppresses the expression of the MYC protein and interferes with HSP90-MYC protein-protein interaction. This, in turn, leads to inhibition of ESCC cell proliferation and promotion of apoptosis in ESCC cells in vitro and reduction of ESCC tumors in vivo. We propose, based on our findings, that STA-9090 is a potential novel therapeutic target for MYC-positive ESCC.

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Inhibition of gastric tumor growth by a novel Hsp90 inhibitor.

Publications

Inhibition of gastric tumor growth by a novel Hsp90 inhibitor.

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