Modulation of adhesion and growth of colon and pancreatic cancer cells by the histone deacetylase inhibitor valproic acid.
Histone deacetylase (HDAC) inhibitors belong to a promising class of antineoplastic agents which affect tumor growth, differentiation and invasion. The effects of the HDAC inhibitor valproic acid (VPA) were tested in vitro on preclinical colon and pancreatic cancer models. Human colon adenocarcinoma HT-29 and pancreatic carcinoma DanG cells were treated with 1 mM VPA for different time periods during cell proliferation MTT assays, and to evaluate the tumor cell adhesion to endothelial cell monolayers. Alterations of beta1 integrin subunits alpha1-6) were analyzed by flow cytometry and RT-PCR. VPA significantly caused growth arrest in tumor cells and prevented tumor cell attachment to the endothelium. HT-29 cell adhesion was blocked to a higher extent than the adhesion of DanG cells. VPA modified membranous integrin beta1 expression, quantity and quality (up- or down-regulation) which depended on the tumor type investigated. Furthermore, VPA diminished integrin coding mRNA in HT-29 but not in DanG cells. We conclude that VPA shifts the integrin beta1 subunit balance from a 'pathological' towards a 'physiological' expression pattern leading to reduced tumor growth and invasion. Further study is required to elucidate the molecular background of the post-transcriptional modifications of VPA in order to exploit the potential of this agent in the treatment of colon and pancreatic cancer.
Jones
Jon
J
Klinik für Urologie und Kinderurologie, Zentrum der Chirurgie, Johann Wolfgang Goethe-Universität; Frankfurt am Main, Germany.
Bentas
Wassilios
W
Blaheta
Roman A
RA
Makarevic
Jasmina
J
Hudak
Lukasz
L
Wedel
Steffen
S
Probst
Michael
M
Jonas
Dietger
D
Juengel
Eva
E
D002448:Cell Adhesion / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D003110:Colonic Neoplasms / Q000201:enzymology* / Q000473:pathology*; D015536:Down-Regulation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases / Q000378:metabolism; D006801:Humans; D016023:Integrins / Q000235:genetics; D010190:Pancreatic Neoplasms / Q000201:enzymology* / Q000473:pathology*; D012333:RNA, Messenger / Q000235:genetics; D014635:Valproic Acid / Q000494:pharmacology*
D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D016023:Integrins; D012333:RNA, Messenger; D014635:Valproic Acid; D006655:Histone Deacetylases