Abstract

The overall objective of the proposed project is to discover novel agents with utility in the treatment of pancreatic cancer. A two-fold approach will be used. The first approach will investigate the potential clinical utility of three classes of natural products (dictyostatin-1, the lasonolides and the batzellines, all of which we have shown have excellent activity against MDR resistant pancreatic tumor cell lines. Mechanism of action studies as well as in vivo profiling of these compounds will be undertaken. The second approach will allow us to discover new compounds, which are active in MDR resistant tumors. The focus will be on the discovery of cell cycle specific agents. Compounds will be identified by screening marine-derived extracts through a panel of pancreatic tumor cell lines and the phosphonucleolin cytoblot assay which detects compounds which block mitotic cell proliferation of human pancreatic cancer cells (PANC-1). Bioassay-guided fractionation, followed by spectroscopic analysis will identify the structures of the new active metabolites. For the three year period we propose to: Evaluate the in vitro and in vivo spectrum of antitumor activity in human pancreatic cell lines and in experimental models of pancreatic cancer for three series of marine derived compounds: the dictyostatins; the lasonolides and the batzellines as well as for compounds discovered during Years 1-3 of the grant period. Isolate and determine the structures of the active compounds of five extracts recently identified to be cytotoxic towards pancreatic tumor cells and determine their in vitro and in vivo antitumor activities. Screen marine extracts using a panel of human pancreatic cancer cell lines and the phosphonucleolin cytoblot assay in order to discover novel compounds with antitumor activity towards pancreatic cancer. Isolate and determine the structures of the active compounds. Successful completion of the proposed research will serve to identify new marine derived compounds as potential licensing candidates to pharmaceutical companies for development as antitumor agents effective against pancreatic cancer.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
1R01CA093455-01A1
Application #
6572826
Study Section
Bio-Organic and Natural Products Chemistry Study Section (BNP)
Program Officer
Fu, Yali
Project Start
2003-07-01
Project End
2006-06-30
Budget Start
2003-07-01
Budget End
2004-06-30
Support Year
1
Fiscal Year
2003
Total Cost
$329,300
Indirect Cost

  Institution

Name
Harbor Branch Oceanographic Institute, Inc.
Department
Type
DUNS #
072224280
City
Fort Pierce
State
FL
Country
United States
Zip Code
34946

  Publications

Wright, Amy E; Roberts, Jill C; Guzmán, Esther A et al. (2017) Analogues of the Potent Antitumor Compound Leiodermatolide from a Deep-Water Sponge of the Genus Leiodermatium. J Nat Prod 80:735-739
Guzmán, Esther A; Harmody, Dedra; Pitts, Tara P et al. (2017) Inhibition of IL-8 secretion on BxPC-3 and MIA PaCa-2 cells and induction of cytotoxicity in pancreatic cancer cells with marine natural products. Anticancer Drugs 28:153-160
Guzmán, Esther A; Xu, Qunli; Pitts, Tara P et al. (2016) Leiodermatolide, a novel marine natural product, has potent cytotoxic and antimitotic activity against cancer cells, appears to affect microtubule dynamics, and exhibits antitumor activity. Int J Cancer 139:2116-26
Guzmán, Esther A; Maers, Kelly; Roberts, Jill et al. (2015) The marine natural product microsclerodermin A is a novel inhibitor of the nuclear factor kappa B and induces apoptosis in pancreatic cancer cells. Invest New Drugs 33:86-94
Guzmán, Esther; Maher, Michael; Temkin, Alexis et al. (2013) Spongiatriol inhibits nuclear factor kappa B activation and induces apoptosis in pancreatic cancer cells. Mar Drugs 11:1140-51
Russell, Floyd; Harmody, Dedra; McCarthy, Peter J et al. (2013) Indolo[3,2-a]carbazoles from a deep-water sponge of the genus Asteropus. J Nat Prod 76:1989-92
Kallifatidis, Georgios; Hoepfner, Dominic; Jaeg, Tiphaine et al. (2013) The marine natural product manzamine A targets vacuolar ATPases and inhibits autophagy in pancreatic cancer cells. Mar Drugs 11:3500-16
Guzmán, Esther A; Johnson, Jacob D; Linley, Patricia A et al. (2011) A novel activity from an old compound: Manzamine A reduces the metastatic potential of AsPC-1 pancreatic cancer cells and sensitizes them to TRAIL-induced apoptosis. Invest New Drugs 29:777-85
Winder, Priscilla L; Baker, Heather L; Linley, Patricia et al. (2011) Neopetrosiquinones A and B, sesquiterpene benzoquinones isolated from the deep-water sponge Neopetrosia cf. proxima. Bioorg Med Chem 19:6599-603
Paterson, Ian; Naylor, Guy J; Gardner, Nicola M et al. (2011) Total synthesis and biological evaluation of a series of macrocyclic hybrids and analogues of the antimitotic natural products dictyostatin, discodermolide, and taxol. Chem Asian J 6:459-73

Showing the most recent 10 out of 18 publications