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Critical analysis of simultaneous blockage of histone deacetylase and multiple receptor tyrosine kinase in the treatment of prostate cancer
Author(s) -
Wedel Steffen,
Hudak Lukasz,
Seibel JensMichael,
Juengel Eva,
Oppermann Elsie,
Haferkamp Axel,
Blaheta Roman A.
Publication year - 2010
Publication title -
the prostate
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.295
H-Index - 123
eISSN - 1097-0045
pISSN - 0270-4137
DOI - 10.1002/pros.21288
Subject(s) - prostate cancer , prostate , medicine , tyrosine kinase , cancer research , histone deacetylase , receptor tyrosine kinase , oncology , receptor , cancer , histone , biology , genetics , gene
BACKGROUND The concept of molecular tumor targeting might be an innovative option to treat advanced prostate cancer. We analyzed the effect of combining the multiple receptor tyrosine kinase inhibitor AEE788 and the histone deacetylase (HDAC) inhibitor valproic acid (VPA) on adhesion and growth properties of prostate cancer cell lines. METHODS PC‐3, DU‐145, and LNCaP cells were treated with AEE788, VPA or with an AEE788–VPA combination, and cell cycle progression investigated. Furthermore, tumor cell adhesion to vascular endothelium or to immobilized extracellular matrix proteins was evaluated, and integrin α and β subtypes were analyzed. Finally, effects of drug treatment on cell signaling pathways were determined. RESULTS AEE788 moderately and VPA strongly reduced tumor cell adhesion and growth. VPA impaired cell cycle progression and altered the expression level of the cell cycle regulating proteins cdk1, cdk2, cdk4, cyclin B, D1, cyclin E, p21, and p27. VPA also acted on the membranous, cytoplasmic, and gene expression pattern of various integrin α and β subtypes. AEE788 acted likewise, but more moderately. Combining AEE788 and VPA did not result in an additive anti‐tumor effect. Signaling analysis revealed that the EGFr downstream target Akt was similarly modified in the presence of VPA or the VPA–AEE788 combination, but not influenced by AEE788 alone. CONCLUSIONS The AEE788–VPA combination has no advantage over VPA monotreatment in vitro. The non‐responsiveness of Akt towards AEE788 might be one reason for this phenomenon. Prostate 71:722–735, 2011. © 2010 Wiley‐Liss, Inc.