%0 Journal Article
%T Molecular targeting of prostate cancer cells by a triple drug combination down-regulates integrin driven adhesion processes, delays cell cycle progression and interferes with the cdk-cyclin axis
%A Steffen Wedel
%A Lukasz Hudak
%A Jens-Michael Seibel
%A Jasmina Makarevi£¿
%A Eva Juengel
%A Igor Tsaur
%A Ana Waaga-Gasser
%A Axel Haferkamp
%A Roman A Blaheta
%J BMC Cancer
%D 2011
%I BioMed Central
%R 10.1186/1471-2407-11-375
%X PC-3, DU-145 and LNCaP cells were treated with RAD001, AEE788 or VPA or with a RAD-AEE-VPA combination. Tumor cell growth, cell cycle progression and cell cycle regulating proteins were then investigated by MTT-assay, flow cytometry and western blotting, respectively. Furthermore, tumor cell adhesion to vascular endothelium or to immobilized extracellular matrix proteins as well as migratory properties of the cells was evaluated, and integrin ¦Á and ¦Â subtypes were analyzed. Finally, effects of drug treatment on cell signaling pathways were determined.All drugs, separately applied, reduced tumor cell adhesion, migration and growth. A much stronger anti-cancer effect was evoked by the triple drug combination. Particularly, cdk1, 2 and 4 and cyclin B were reduced, whereas p27 was elevated. In addition, simultaneous application of RAD001, AEE788 and VPA altered the membranous, cytoplasmic and gene expression pattern of various integrin ¦Á and ¦Â subtypes, reduced integrin-linked kinase (ILK) and deactivated focal adhesion kinase (FAK). Signaling analysis revealed that EGFr and the downstream target Akt, as well as p70S6k was distinctly modified in the presence of the drug combination.Simultaneous targeting of several key proteins in prostate cancer cells provides an advantage over targeting a single pathway. Since strong anti-tumor properties became evident with respect to cell growth and adhesion dynamics, the triple drug combination might provide progress in the treatment of advanced prostate cancer.Prostate cancer (PC) is a major medical problem facing the male population. It has become the second most common cause of cancer death in men in the United States [1]. In the western world it is the most common solid tumor in men, followed by lung and colorectal cancer. Although PC is highly curable when diagnosed early, 10 to 15% of patients present with metastases at diagnosis [2-4]. Another 30% develop metastases after initially seemingly curative local treatment fails [5
%U http://www.biomedcentral.com/1471-2407/11/375