Resistance after chronic application of the HDAC-inhibitor valproic acid is associated with elevated Akt activation in renal cell carcinoma in vivo.
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.
Department of Urology, Johann Wolfgang Goethe-University, Frankfurt am Main, Germany.
Eva
E
Juengel
Jasmina
J
Makarević
Igor
I
Tsaur
Georg
G
Bartsch
Karen
K
Nelson
Axel
A
Haferkamp
Roman A
RA
Blaheta
D000107:Acetylation / Q000187:drug effects; D000818:Animals; D002292:Carcinoma, Renal Cell / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D018844:Cyclin-Dependent Kinases / Q000235:genetics / Q000378:metabolism; D004334:Drug Administration Schedule; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006655:Histone Deacetylases / Q000235:genetics* / Q000378:metabolism; D006657:Histones / Q000235:genetics / Q000378:metabolism; D007680:Kidney Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D009368:Neoplasm Transplantation; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D047368:Tumor Burden / Q000187:drug effects; D014635:Valproic Acid / Q000494:pharmacology*
D056572:Histone Deacetylase Inhibitors; D006657:Histones; D014635:Valproic Acid; D051057:Proto-Oncogene Proteins c-akt; D018844:Cyclin-Dependent Kinases; D006655:Histone Deacetylases