Experimental treatment of pancreatic cancer with two novel histone deacetylase inhibitors.
OBJECTIVE
To investigate in vitro and in vivo treatment with histone deacetylase inhibitors NVP-LAQ824 and NVP-LBH589 in pancreatic cancer.


METHODS
Cell-growth inhibition by NVP-LAQ824 and NVP-LBH589 was studied in vitro in 8 human pancreatic cancer cell lines using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. In addition, the anti-tumoral effect of NVP-LBH589 was studied in a chimeric mouse model. Anti-tumoral activity of the drugs was assessed by immunoblotting for p21(WAF-1), acH4, cell cycle analysis, TUNEL assay, and immunohistochemistry for MIB-1.


RESULTS
In vitro treatment with both compounds significantly suppressed the growth of all cancer cell lines and was associated with hyperacetylation of nucleosomal histone H4, increased expression of p21(WAF-1), cell cycle arrest at G2/M-checkpoint, and increased apoptosis. In vivo, NVP-LBH589 alone significantly reduced tumor mass and potentiated the efficacy of gemcitabine. Further analysis of the tumor specimens revealed slightly increased apoptosis and no significant reduction of cell proliferation.


CONCLUSIONS
Our findings suggest that NVP-LBH589 and NVP-LAQ824 are active against human pancreatic cancer, although the precise mechanism of in vivo drug action is not yet completely understood. Therefore, further preclinical and clinical studies for the treatment of pancreatic cancer are recommended.
Haefner
Martin
M
Department of Internal Medicine II, University of Leipzig, Philipp-Rosenthal-Str. 27, Leipzig 04103, Germany.
Bluethner
Thilo
T
Niederhagen
Manuel
M
Moebius
Christian
C
Wittekind
Christian
C
Mossner
Joachim
J
Caca
Karel
K
Wiedmann
Marcus
M
D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D003841:Deoxycytidine / Q000031:analogs & derivatives / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005260:Female; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases / Q000378:metabolism; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology*; D015151:Immunoblotting; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D007211:Indoles; D019394:Ki-67 Antigen / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D000077767:Panobinostat; D013997:Time Factors; D000093542:Gemcitabine
D000964:Antimetabolites, Antineoplastic; D000970:Antineoplastic Agents; C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D007211:Indoles; D019394:Ki-67 Antigen; C477361:LAQ824; D003841:Deoxycytidine; D000077767:Panobinostat; D006655:Histone Deacetylases; D000093542:Gemcitabine