ArticlePloS one2013
Resistance after chronic application of the HDAC-inhibitor valproic acid is associated with elevated Akt activation in renal cell carcinoma in vivo.
Article in PloS one, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 29 papers.
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Who cites it
29 citing papers in PubMed, 42 citations in OpenAlex.
- HDAC inhibitors in cancer therapy: sensitization mechanisms, combination strategies, and translational challenges.Frontiers in cell and developmental biology · 2026Review
- Histone deacetylases and their inhibitors in kidney diseases.Molecular therapy : the journal of the American Society of Gene Therapy · 2025Review
- Structural Modifications and Prospects of Histone Deacetylase (HDAC) Inhibitors in Cancer.Current medicinal chemistry · 2025Review
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- Article
- Advances in Renal Cell Carcinoma Drug Resistance Models.Frontiers in oncology · 2022Review
- Upregulation of ERK-EGR1-heparanase axis by HDAC inhibitors provides targets for rational therapeutic intervention in synovial sarcoma.Journal of experimental & clinical cancer research : CR · 2021Article
- Molecular and Functional Analysis of Sunitinib-Resistance Induction in Human Renal Cell Carcinoma Cells.International journal of molecular sciences · 2021Article
- Article
- Chronic Sulforaphane Administration Inhibits Resistance to the mTOR-Inhibitor Everolimus in Bladder Cancer Cells.International journal of molecular sciences · 2020Article
- Article
- Valproic acid treatment response in vitro is determined by TP53 status in medulloblastoma.Child's nervous system : ChNS : official journal of the International Society for Pediatric Neurosurgery · 2018Article
- Polydatin exerts anti-tumor effects against renal cell carcinoma cells via induction of caspase-dependent apoptosis and inhibition of the PI3K/Akt pathway.OncoTargets and therapy · 2018Article
- HDAC inhibition as a treatment concept to combat temsirolimus-resistant bladder cancer cells.Oncotarget · 2017Article
- Molecular, biological characterization and drug sensitivity of chidamide-resistant non-small cell lung cancer cells.Oncology letters · 2017Article
- Inhibition of HDAC3 prevents diabetic cardiomyopathy in OVE26 mice via epigenetic regulation of DUSP5-ERK1/2 pathway.Clinical science (London, England : 1979) · 2017Article
- SAHA and/or MG132 reverse the aggressive phenotypes of glioma cells: An in vitro and vivo study.Oncotarget · 2017Article
- Synergistic effect of cytokine-induced killer cell with valproate inhibits growth of hepatocellular carcinoma cell in a mouse model.Cancer biology & therapy · 2017Article
- Anticancer effects of valproic acid on oral squamous cell carcinoma via SUMOylationExperimental and therapeutic medicine · 2016Article
- Deciphering mechanisms of drug sensitivity and resistance to Selective Inhibitor of Nuclear Export (SINE) compounds.BMC cancer · 2015Article
Corrections and comments
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Authors and funding
7 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Targeted drugs have significantly improved the therapeutic options for advanced renal cell carcinoma (RCC). However, resistance often develops, negating the benefit of these agents. In the present study, the molecular mechanisms of acquired resistance towards the histone deacetylase (HDAC) inhibitor valproic acid (VPA) in a RCC in vivo model were investigated. NMRI:nu/nu mice were transplanted with Caki-1 RCC cells and then treated with VPA (200 mg/kg/day). Controls remained untreated. Based on tumor growth dynamics, the mice were divided into "responders" and "non-responders" to VPA. Histone H3 and H4 acetylation and expression of cell signaling and cell cycle regulating proteins in the RCC mouse tumors were evaluated by Western blotting. Tumor growth of VPA responders was significantly diminished, whereas that of VPA non-responders even exceeded control values. Cdk1, 2 and 4 proteins were strongly enhanced in the non-responders. Importantly, Akt expression and activity were massively up-regulated in the tumors of the VPA non-responders. Chronic application (12 weeks) of VPA to Caki-1 cells in vitro evoked a distinct elevation of Akt activity and cancer cells no longer responded with cell growth reduction, compared to the short 2 week treatment. We assume that chronic use of an HDAC-inhibitor is associated with (re)-activation of Akt, which may be involved in resistance development. Consequently, combined blockade of both HDAC and Akt may delay or prevent drug resistance in RCC.
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