Inhibition of human pancreatic cell line MIA PaCa2 proliferation by HA-But, a hyaluronic butyric ester: a preliminary report.
OBJECTIVE
Inhibition of histone deacetylase activity is one of the epigenetic mechanisms in the regulation of the cellular gene expression. We investigated the antitumor effect of HA-But, a new histone deacetylase inhibitor, in which hyaluronic acid is esterified with butyric acid residues and selectively bind to CD44, overexpressed in most human cancers, including pancreatic cancer.


METHODS
We analyzed the effect of HA-But on the expression level of some cell cycle (p21 waf1/cip1, p27 kip1, p53, and cyclin D1), apoptosis (BAX, caspase-7, Bcl-2, and survivin), and angiogenesis-related (vascular endothelial growth factor [VEGF] A165, VEGF-C, and VEGF-D) proteins on MIA PaCa-2, a pancreas carcinoma cell line that expressed CD44 in a high percentage (99%) of cells.


RESULTS
HA-But was 7-fold more effective than sodium butyrate in inhibiting cell proliferation; it induced p21 waf1/cip1, p27 kip1, p53, and cyclin D1 modulation, resulting in a block of the cell cycle at G0/G1 and G2/M phases. Moreover, Ha-But induced apoptosis, affecting the expression level of either proapoptotic or antiapoptotic factors, reduced the expression level of VEGF-A165 and VEGF-D, and inhibited the angiogenesis process in vitro.


CONCLUSIONS
On the basis of these results, which demonstrated an interesting antiproliferative, proapoptotic, and antiangiogenic activity, Ha-But could be a promising candidate for the treatment of pancreatic cancer.
Pellizzaro
Cinzia
C
Experimental Department, Fondazione IRCCS Istituto Nazionale Tumori, Milano, Italy.
Speranza
Annalisa
A
Zorzet
Sonia
S
Crucil
Ilaria
I
Sava
Gianni
G
Scarlata
Ignazio
I
Cantoni
Silvia
S
Fedeli
Maya
M
Coradini
Danila
D
D002087:Butyrates / Q000494:pharmacology*; D002453:Cell Cycle / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects*; D002460:Cell Line; D006801:Humans; D006820:Hyaluronic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology*; D007700:Kinetics; D010179:Pancreas / Q000166:cytology* / Q000187:drug effects; D010190:Pancreatic Neoplasms / Q000188:drug therapy; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
D002087:Butyrates; D042461:Vascular Endothelial Growth Factor A; D006820:Hyaluronic Acid