Terrestrial plants are a proven source for effective cancer chemotherapeutic agents. However, for novel drug discovery, major challenges include identification of correct starting materials and provision of a proper bioassay procedure for procurement of truly useful active principles. This project provides an experimental strategy and the where-with-all to meet these challenges. As a first level of selection, cytotoxic plant extracts will be identified in a panel of cultured mammalian cells. Of the 500 plant extracts to be evaluated each year, it is responsible to suggest 50 can be classified as active (cytotoxic) and the remaining 450 can be classified as inactive (non-cytotoxic). The 450 non- cytotoxic extracts will be evaluated in secondary models to assess anti- metastatic and anti-angiogenic potential. Specifically, potential to block cancer cell invasion will be determined with Matrigel cell migration test systems and growth inhibitory potential will be assessed with cultured human umbilical vein endothelial cells (HUVEC). We anticipate these evaluation procedures will identify 3-5 promising leads per year that will be subjected to bioassay-directed fractionation using the appropriate in vitro system as a monitor. For the 50 cytotoxic leads, a straight-forward preliminary fractionation will be performed (Project 2) to yield a cytotoxic fraction with enriched activity. These 50 susceptible cell lines, to provide an initial indication of anti-tumor potential. It is anticipated this will eliminate approximately one-half of the test materials, yielding 25 active leads. These 25 leads will be further assessed for potential to modulate gene expression. Using a susceptible cultured cell line and DNA array analyses, the effect of each lead material on the expression of approximately 1,000 cancer-related genes will be determined. Based on these data sets, a judicious decision can be made regarding our 3-5 best lead starting materials, which will be subjected to bioassay-directed fractionation (Project 2) using a susceptible as a monitor. The chemical isolates will be evaluated with the in vitro and animal models used to facilitate their discovery. As a consequence of this strategy, we anticipate virtually all resulting isolates will be clinical or mechanistic significance.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program--Cooperative Agreements (U19)
Project #
5U19CA052956-13
Application #
6591262
Study Section
Project Start
2002-05-15
Project End
2003-04-30
Budget Start
Budget End
Support Year
13
Fiscal Year
2002
Total Cost
Indirect Cost
Name
University of Illinois at Chicago
Department
Type
DUNS #
121911077
City
Chicago
State
IL
Country
United States
Zip Code
60612
Li, Jie; Pan, Li; Deng, Ye et al. (2013) Sphenostylisins A-K: bioactive modified isoflavonoid constituents of the root bark of Sphenostylis marginata ssp. erecta. J Org Chem 78:10166-77
Ren, Yulin; Acuña, Ulyana Muñoz; Jiménez, Francisco et al. (2012) Cytotoxic and NF-?B inhibitory sesquiterpene lactones from Piptocoma rufescens. Tetrahedron 68:2671-2678
Pan, Li; Chai, Hee-Byung; Kinghorn, Alan Douglas (2012) Discovery of new anticancer agents from higher plants. Front Biosci (Schol Ed) 4:142-56
Pan, Li; Yong, Yeonjoong; Deng, Ye et al. (2012) Isolation, structure elucidation, and biological evaluation of 16,23-epoxycucurbitacin constituents from Eleaocarpus chinensis. J Nat Prod 75:444-52
Ren, Yulin; Matthew, Susan; Lantvit, Daniel D et al. (2011) Cytotoxic and NF-?B inhibitory constituents of the stems of Cratoxylum cochinchinense and their semisynthetic analogues. J Nat Prod 74:1117-25
Kinghorn, A Douglas; Pan, Li; Fletcher, Joshua N et al. (2011) The relevance of higher plants in lead compound discovery programs. J Nat Prod 74:1539-55
Deng, Ye; Chin, Young-Won; Chai, Hee-Byung et al. (2011) Phytochemical and Bioactivity Studies on Constituents of the Leaves of Vitex Quinata. Phytochem Lett 4:213-217
Gupta, Sneha V; Sass, Ellen J; Davis, Melanie E et al. (2011) Resistance to the translation initiation inhibitor silvestrol is mediated by ABCB1/P-glycoprotein overexpression in acute lymphoblastic leukemia cells. AAPS J 13:357-64
Pan, Li; Chai, Heebyung; Kinghorn, A Douglas (2010) The continuing search for antitumor agents from higher plants. Phytochem Lett 3:1-8
Pan, Li; Lantvit, Daniel D; Riswan, Soedarsono et al. (2010) Bioactivity-guided isolation of cytotoxic sesquiterpenes of Rolandra fruticosa. Phytochemistry 71:635-40

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