SNX-2112, an Hsp90 inhibitor, induces apoptosis and autophagy via degradation of Hsp90 client proteins in human melanoma A-375 cells

Kaisheng, Liu; Liu, Hui; Qi, Jinhuan; Liu, Qiuyun; Liu, Zhong; Xia, Min; Xing, Guo‐wen; Wang, Shao-Xiang; Wang, Yifei

doi:10.1016/j.canlet.2011.12.015

Cited by 52 publications

(47 citation statements)

References 50 publications

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“…SNX-2112 was synthesized as previously described in our lab with >98.0% purity; we stored 10 mM SNX-2112 stock solution in dimethyl sulfoxide (DMSo) at -20˚C (18). We purchased 5-FU, 3-(4, 5-diethylthiazol-2-yl)-2, 5-diphenyl tetrazolium bromide (MTT) from Sigma-Aldrich (St. Louis, Mo, USA).…”

Section: Methodsmentioning

confidence: 99%

“…Previously, we found that SNX-2112 caused depletion of Hsp90 client proteins such as Akt, p-Akt, IKK, ERK 1/2 , and GSK-3β (18). To determine whether 5-FU antago-nized the anticancer effect of SNX-2112 on Hsp90 client proteins, we investigated the expression of these proteins following SNX-2112 and 5-FU treatment.…”

Section: -Fu Inhibits Snx-2112-induced Downregulation Of Hsp90 Clienmentioning

confidence: 99%

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Combination of SNX-2112 with 5-FU exhibits antagonistic effect in esophageal cancer cells

Liu

Xiao

Wang

et al. 2014

International Journal of Oncology

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The low efficacy of single-drug chemotherapy forms the basis for combination therapy in esophageal squamous cell carcinoma. SNX-2112, a selective heat shock protein 90 (Hsp90) inhibitor, was recently reported as being effective in combination with cisplatin and paclitaxel. In this study, we investigated the effect of SNX-2112 in combination with 5-fluorouracil (5-FU), another first-line anticancer drug, in esophageal cancer. Unexpectedly, tetrazolium assay revealed that the combination of SNX-2112 with 5-FU exhibited antagonistic effect. Flow cytometry revealed that the SNX-2112 and 5-FU combination greatly decreased the number of G2/M cells compared to SNX-2112-only treatment in Eca‑109 cells. This effect might be related to the altered mRNA level of cyclin-related genes including cyclin D1, Chk2 and Cdk4. Further, 5-FU attenuated SNX-2112-induced apoptosis by decreasing poly(ADP-ribose) polymerase (PARP) cleavage and inactivating caspase-3, -8 and -9. Additionally, 5-FU suppressed the SNX-2112-induced decrease of mitochondrial membrane potential. Moreover, 5-FU partly recovered Hsp90 client proteins, including Akt, p-Akt, inhibitor of κB kinase (IKK)α, extracellular signal-regulated kinase (ERK)1/2, and glycogen synthase kinase (GSK)-3β, which SNX-2112 had downregulated. Taken together, this is the first report that the combination of SNX-2112 with 5-FU exhibited antagonistic effect in esophageal cancer cells by affecting growth inhibition, cell cycle, apoptosis, and Hsp90 client proteins, suggesting that care is required in the clinical application of combined SNX-2112 and 5-FU.

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Section: Methodsmentioning

confidence: 99%

Section: -Fu Inhibits Snx-2112-induced Downregulation Of Hsp90 Clienmentioning

confidence: 99%

Combination of SNX-2112 with 5-FU exhibits antagonistic effect in esophageal cancer cells

Liu

Xiao

Wang

et al. 2014

International Journal of Oncology

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“…Many Hsp90 client proteins are degraded via the ubiquitin-proteasome pathway in the absence of Hsp90 (77)(78)(79), suggesting that proteasomal inhibitors might attenuate the effect of the Hsp90 inhibitor on EBV PK and/or HCMV UL97 expression. In addition to the ubiquitin-proteasome pathway, the autophagy pathway is another important protein degradation pathway and has been shown to mediate the degradation of a subset of Hsp90 client proteins (80)(81)(82)(83). To examine this in EBV-infected cells, AGS-Akata cells were treated with 17-DMAG or the DMSO control in the presence or absence of the proteasomal inhibitor lactacystin or an autophagy inhibitor, 3-methyladenine (3-MA).…”

Section: -Dmag Treatment Inhibits Intracellular Lytic Viral Replicamentioning

confidence: 99%

Hsp90 Inhibitor 17-DMAG Decreases Expression of Conserved Herpesvirus Protein Kinases and Reduces Virus Production in Epstein-Barr Virus-Infected Cells

Sun

Bristol

Iwahori

et al. 2013

J Virol

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H uman herpesviruses are enveloped viruses containing relatively large, double-stranded DNA genomes. Although all herpesviruses experience both latent and lytic stages of infection, they are grouped into three separate families (alpha-, beta-, and gammaherpesviruses) according to differences in sequence homology and cellular tropisms. The alphaherpesviruses, which comprise herpes simplex virus 1 (HSV-1), HSV-2, and varicella-zoster virus (VZV), cause recurrent skin lesions and meningitis (1, 2). Human cytomegalovirus (HCMV), human herpesviruses 6A and 6B (HHV6), and human herpesvirus 7 (HHV7) are betaherpesviruses, which cause severe disease in patients with compromised immune function (3, 4). The gammaherpesviruses are Epstein-Barr virus (EBV) and Kaposi's sarcoma-associated herpesvirus (KSHV), which are causally associated with mononucleosis (EBV) as well as a variety of human cancers (5, 6).Each of the eight human herpesviruses encodes a protein kinase (PK) with discernible homology in amino acid sequences and positional similarity in their respective viral genomes. These related protein kinases, termed the conserved herpesvirus protein kinases (CHPKs), are important for viral replication and infection (7-13). They play important roles in multiple processes, including gene expression (8,11,14), viral DNA replication (11,(15)(16)(17), capsid nuclear egress (7,11,18,19), and the DNA damage response (20, 21). For example, EBV PK (the product of the BGLF4 gene) phosphorylates a number of different viral and cellular proteins, including the viral DNA polymerase processivity factor BMRF1 (7,(22)(23)(24); the latent viral proteins EBNA1 (25), EBNA2 (26), and EBNA LP (27); the EBV immediate early (IE) protein BZLF1 (28); the cell cycle regulatory proteins p27 (29) and pRB (30); nuclear lamin A/C (7, 31); and interferon regulatory factor 3 (IRF3) (32). In addition, EBV PK may upregulate the expression of two viral proteins important for nuclear egress, BFRF1 and BFLF2 (11,33). Both EBV PK and the homologous HCMV kinase, UL97, greatly enhance but are not absolutely required for the release of infectious viral particles in vitro and appear to be intimately involved in the pathogenesis associated with viral infections in vivo (34,35). Although maribavir, an inhibitor of HCMV UL97, failed a phase III clinical trial in bone marrow transplant patients (36) (possibly due to insufficient dosing), CHPKs nevertheless remain very promising targets for development of novel antiviral therapeutics.Two guanine nucleoside analogues, ganciclovir (GCV) and acyclovir (ACV), have been used frequently to inhibit replication of various human herpesviruses by targeting viral DNA polymerases (37-40). UL97 mediates the first step of GCV and ACV phosphorylation (41-43). Since the triphosphorylated forms of GCV and ACV are much better substrates for herpesvirus DNA polymerases than cellular DNA polymerases, GCV and ACV inhibit viral DNA replication more effectively than cellular DNA replication (44,45). It was recently found that EBV PK is req...

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“…PCR was carried out for human "Alu" sequences. a pro-death pathway post treatment (30)(31)(32)(33)(34)(35). Several lines of evidence indicate that ER stress leads to autophagy (36)(37)(38), and recent studies have highlighted a prominent role between autophagic cell death induced by Akt-mTOR signaling triggered by ER stress (37,38).…”

Section: Discussionmentioning

confidence: 99%

Reovirus as a Viable Therapeutic Option for the Treatment of Multiple Myeloma

Thirukkumaran

Zhong

Luider

et al. 2012

Clinical Cancer Research

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Purpose: Despite the recent advances made in the treatment of multiple myeloma, the disease still remains incurable. The oncolytic potential of reovirus has previously been shown and is currently in phase III clinical trials for solid tumors. We tested the hypothesis that reovirus can successfully target human multiple myeloma in vitro, ex vivo, and in vivo without affecting human hematopoietic stem cell (HHSC) repopulation/differentiation in a murine model that partially recapitulates human multiple myeloma.Experimental Design: Human myeloma cell lines and ex vivo tumor specimens were exposed to reovirus and oncolysis and mechanisms of cell death were assessed. RPMI 8226GFPþ cells were injected intravenously to non-obese diabetic/severe combined immune deficient (NOD/SCID) mice and treated with live reovirus (LV) or dead virus (DV). Multiple myeloma disease progression was evaluated via whole-body fluorescence and bone marrow infiltration. HHSCs exposed to LV/DV were injected to NOD/SCID mice and repopulation/differentiation was monitored.Results: A total of six of seven myeloma cell lines and five of seven patient tumor specimens exposed to reovirus showed significant in vitro sensitivity. Tumor response of multiple myeloma by LV, but not DV, was confirmed by comparison of total tumor weights (P ¼ 0.05), and bone marrow infiltration (1/6, LV; 5/6, DV). Mice injected with LV-or DV-exposed HHSCs maintained in vivo re-population/lineage differentiation showing a lack of viral effect on the stem cell compartment. Reovirus oncolysis was mediated primarily by activation of the apoptotic pathways.Conclusions: The unique ability of reovirus to selectively kill multiple myeloma while sparing HHSCs places it as a promising systemic multiple myeloma therapeutic for clinical testing.

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SNX-2112, an Hsp90 inhibitor, induces apoptosis and autophagy via degradation of Hsp90 client proteins in human melanoma A-375 cells

Cited by 52 publications

References 50 publications

Combination of SNX-2112 with 5-FU exhibits antagonistic effect in esophageal cancer cells

Combination of SNX-2112 with 5-FU exhibits antagonistic effect in esophageal cancer cells

Hsp90 Inhibitor 17-DMAG Decreases Expression of Conserved Herpesvirus Protein Kinases and Reduces Virus Production in Epstein-Barr Virus-Infected Cells

Reovirus as a Viable Therapeutic Option for the Treatment of Multiple Myeloma

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