Abstract
Pancreatic cancer is an aggressive neoplasm, with a mortality rate close to 100%. The most successful agent for pancreatic cancer treatment is gemcitabine, although the overall effect in terms of patient survival remains very poor. This study was initiated to evaluate a novel class of anticancer agents against pancreatic cancer. This group of compounds belongs to the dipyridyl thiosemicarbazone class that have been shown to have potent and selective activity against a range of different neoplasms in vitro and in vivo. We demonstrate for the first time in pancreatic cancer that these agents increase the expression of the growth and metastasis suppressor N-myc downstream-regulated gene 1 and its phosphorylation at Ser330 and Thr346 that is important for its activity against this tumor. In addition, these agents increased expression of the cyclin-dependent kinase inhibitor p21CIP1/WAF1, whereas decreasing cyclin D1 in pancreatic cancer cells. Together, these molecular alterations account, in part, for the pronounced antitumor activity observed. Indeed, these agents had significantly higher antiproliferative activity in vitro than the established treatments for pancreatic cancer, namely gemcitabine and 5-fluorouracil. Studies in vivo demonstrated that a novel thiosemicarbazone, namely di-2-pyridylketone 4-cyclohexyl-4-methyl-3-thiosemicarbazone hydrochloride, completely inhibited the growth of pancreatic cancer xenografts with no evidence of marked alterations in normal tissue histology. Together, our studies have identified molecular effectors of a novel and potent antitumor agent that could be useful for pancreatic cancer treatment.
Footnotes
↵ The online version of this article (available at http://molpharm.aspetjournals.org) contains supplemental material.
This work was supported by the National Health and Medical Research Council Australia [Grant 632778; Senior Principal Research Fellowship 571123]; the Cancer Institute of New South Wales [Grant 06/RSA/1-12]; and the Australian Rotary Health Research Fund.
Article, publication date, and citation information can be found at http://molpharm.aspetjournals.org.
doi:10.1124/mol.111.073627.
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ABBREVIATIONS:
- NDRG1
- N-myc downstream-regulated gene 1
- Bax
- Bcl-2-associated X protein
- Bcl-2
- B-cell CLL/lymphoma 2
- DFO
- desferrioxamine
- DpC
- di-2-pyridylketone 4-cyclohexyl-4-methyl-3-thiosemicarbazone hydrochloride
- Dp44mT
- di-2-pyridylketone 4,4-dimethyl-3-thiosemicarbazone
- HIF-1
- hypoxia-inducible factor-1
- MTD
- maximum tolerated dose
- PARP
- poly(ADP-ribose) polymerase
- 3-AP
- 3-aminopyridine-2-carboxaldehyde thiosemicarbazone
- 311
- 2-hydroxy-1-naphthaldehyde isonicotinoyl hydrazone
- AV
- Annexin V
- MTT
- 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium
- PI
- propidium iodide
- ROS
- reactive oxygen species.
- Received May 18, 2011.
- Accepted June 30, 2011.
- Copyright © 2011 The American Society for Pharmacology and Experimental Therapeutics
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