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.
Highlights
Renal cell carcinoma (RCC) is the most common renal tumor with an incidence of 11.8 per 100,000 in industrialized nations [1]
Long-term application of valproic acid (VPA) resulted in significant inhibition of tumor cell growth in 50% of the mice
The remaining 50% did not respond to VPA at all
Summary
Renal cell carcinoma (RCC) is the most common renal tumor with an incidence of 11.8 per 100,000 in industrialized nations [1]. The majority of patients with clinically localized tumors can effectively be cured, those with metastatic RCC have a bleak prognosis. Epigenetic changes have been shown to be induced by abnormal histone deacetylase (HDAC) activity and to correlate with tumor development and progression. Immunohistologic assessment of 44 RCC cases have provided evidence that decreased histone acetylation is a common alteration in the malignant phenotype of this tumor entity [2]. Tissue microarray analysis carried out on 193 patients with RCC revealed an inverse correlation between histone acetylation and pT-stage, distant metastasis, Fuhrman grading and RCC progression [3]. It has been suggested that increasing the amount of acetylated histones by lowering HDAC might be a therapeutic option for RCC. In vitro and in vivo experiments point to distinct growth and invasion blocking properties of HDAC-
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