title: Impact of combined HDAC and mTOR inhibition on adhesion, migration and invasion of prostate cancer cells.
abstract: The concept of molecular tumor targeting might provide new hope in the treatment of advanced prostate cancer. We evaluated metastasis blocking properties of the histone deacetylase (HDAC) inhibitor valproic acid (VPA) and the mammalian target of rapamycin (mTOR) inhibitor RAD001 on prostate cancer cell lines. RAD001 or VPA were applied to PC-3 or LNCaP cells, either separately or in combination. Adhesion to vascular endothelium or to immobilized collagen, fibronectin or laminin was quantified. Migration and invasion were explored by a modified Boyden chamber assay. Integrin α and β subtypes were analyzed by flow cytometry, western blotting and RT-PCR. Effects of drug treatment on integrin related signaling, Akt and p70S6kinase activation, histone H3 and H4 acetylation were also determined. Separate application of RAD001 or VPA distinctly reduced tumor cell adhesion, migration and invasion, accompanied by elevated Akt activation and p70S6kinase de-activation. Integrin subtype expression was altered significantly by both compounds (VPA > RAD001). When both drugs were used in concert additive effects were observed on the migratory and invasive behavior but not on tumor-endothelium and tumor-matrix interaction. Separate mTOR or HDAC inhibition slows processes related to tumor metastasis. The RAD001-VPA combination showed advantage over VPA monotreatment with particular respect to migration and invasion. Ongoing studies are required to assess the relevance of VPA monotherapy versus VPA-RAD001 combination on tumor cell motility.
authors: Department of Urology, Johann Wolfgang Goethe-University, Theodor-Stern-Kai 7, 60590, Frankfurt am Main, Germany.
authors: Steffen
authors: S
authors: Wedel
authors: Lukasz
authors: L
authors: Hudak
authors: Jens-Michael
authors: JM
authors: Seibel
authors: Jasmina
authors: J
authors: Makarević
authors: Eva
authors: E
authors: Juengel
authors: Igor
authors: I
authors: Tsaur
authors: Christoph
authors: C
authors: Wiesner
authors: Axel
authors: A
authors: Haferkamp
authors: Roman A
authors: RA
authors: Blaheta
mesh_terms: D002448:Cell Adhesion / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects*; D004359:Drug Therapy, Combination; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D000068338:Everolimus; D006655:Histone Deacetylases / Q000378:metabolism*; D006801:Humans; D008297:Male; D009361:Neoplasm Invasiveness; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology*; D020123:Sirolimus / Q000031:analogs & derivatives / Q000494:pharmacology; D013329:Structure-Activity Relationship; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D014407:Tumor Cells, Cultured; D014635:Valproic Acid / Q000494:pharmacology
chemical_list: D004791:Enzyme Inhibitors; D014635:Valproic Acid; D000068338:Everolimus; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases; D006655:Histone Deacetylases; D020123:Sirolimus