In this revised Program Project renewal application, the applicant group is representative of three primary institutions. The Ohio State University (OSU), the University of Illinois at Chicago (UIC), and the University of North Carolina at Greensboro (UNCG). The participants have combined their vast experience in the isolation, structure elucidation, and biological evaluation of natural products, to continue the development of a consolidated, integrated program for the discovery of novel anticancer agents of diverse origin for development as cancer chemotherapeutic agents. Plant materials to be studied in Project 1 (OSU) will be collected by established botanists located in tropical countries with the assistance of the NAPRALERT database (Project 2;UIC), and cyanobacteria (Project 2) and filamentous fungi (Project 3 UNCG) will also be accessed. Organisms acquired will be extracted and evaluated in a diverse battery of relevant mechanism-based, cell-based, and tumor-growth related assays currently operational at OSU (Project 1), UIC (Core A), Columbia University (through Project 3), and a new pharmaceutical company partner, Eisai Inc., Andover, MA (through Core C at OSU). Dereplication of known active compounds will be accomplished at OSU, UIC, and UNCG using computerized literature surveys and LC-MS coupled to bioassays. Bioassay-directed fractionation will be employed in Projects 1-3, for the elucidation of active principles. Lead development of active natural products via medicinal chemistry and pharmacokineticsrelated studies will be conducted at OSU (Core B), facilitated by the OSU Biostatistics group (Core C). Novel, active compounds thus discovered will be further evaluated in our panel of in vitro and in vivo bioassays (Projects 1 and 3, Cores A and Eisai). Group decisions will be made regarding the further development of agents for potential use as anticancer agents. The more advanced states of biological and toxicological testing, as well as the procurement of larger quantities of lead compounds will be sponsored by Eisai (through Core C). The Consortium will work with the involvement of the NCI Program Director in the discovery process, and plans to hold regular meetings of key scientific personnel (inclusive of our External and OSU Internal Advisory panels) to enhance communication and decision-making processes, to be organized by Core C. Excellent facilities for the isolation, structure determination, chemical modification, synthesis, and in vitro and in vivo biological evaluation, and overall project data management are available.

Public Health Relevance

Cancer is responsible for about one in every four deaths in the United States, and new treatments are urgently needed. It is the overall goal of the integrated studies in this renewal application to discover novel chemicals from selected tropical rainforest plants, as well as cyanobacteria and fungi, for development as cancer chemotherapeutic agents, particularly for tumors not cured by present treatment methods.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
2P01CA125066-06A1
Application #
8608726
Study Section
Special Emphasis Panel (ZCA1-RPRB-C (O1))
Program Officer
Fu, Yali
Project Start
2006-12-01
Project End
2019-04-30
Budget Start
2014-06-06
Budget End
2015-04-30
Support Year
6
Fiscal Year
2014
Total Cost
$1,484,104
Indirect Cost
$247,118
Name
Ohio State University
Department
Type
Schools of Pharmacy
DUNS #
832127323
City
Columbus
State
OH
Country
United States
Zip Code
43210
May, Daniel S; Kang, Hahk-Soo; Santarsiero, Bernard D et al. (2018) Ribocyclophanes A-E, Glycosylated Cyclophanes with Antiproliferative Activity from Two Cultured Terrestrial Cyanobacteria. J Nat Prod 81:572-578
Oblinger, Janet L; Burns, Sarah S; Huang, Jie et al. (2018) Overexpression of eIF4F components in meningiomas and suppression of meningioma cell growth by inhibiting translation initiation. Exp Neurol 299:299-307
Amrine, Chiraz Soumia M; Raja, Huzefa A; Darveaux, Blaise A et al. (2018) Media studies to enhance the production of verticillins facilitated by in situ chemical analysis. J Ind Microbiol Biotechnol 45:1053-1065
Young, Alexandria N; Herrera, Denisse; Huntsman, Andrew C et al. (2018) Phyllanthusmin Derivatives Induce Apoptosis and Reduce Tumor Burden in High-Grade Serous Ovarian Cancer by Late-Stage Autophagy Inhibition. Mol Cancer Ther 17:2123-2135
Acuña, Ulyana Muñoz; Mo, Shunyan; Zi, Jiachen et al. (2018) Hapalindole H Induces Apoptosis as an Inhibitor of NF-?B and Affects the Intrinsic Mitochondrial Pathway in PC-3 Androgen-insensitive Prostate Cancer Cells. Anticancer Res 38:3299-3307
Al-Huniti, Mohammed H; Rivera-Chávez, José; Colón, Katsuya L et al. (2018) Development and Utilization of a Palladium-Catalyzed Dehydration of Primary Amides To Form Nitriles. Org Lett 20:6046-6050
Crnkovic, Camila M; Krunic, Aleksej; May, Daniel S et al. (2018) Calothrixamides A and B from the Cultured Cyanobacterium Calothrix sp. UIC 10520. J Nat Prod 81:2083-2090
Wilson, Tyler A; Tokarski 2nd, Robert J; Sullivan, Peter et al. (2018) Total Synthesis of Scytonemide A Employing Weinreb AM Solid-Phase Resin. J Nat Prod 81:534-542
Lu, Chunwan; Yang, Dafeng; Sabbatini, Maria E et al. (2018) Contrasting roles of H3K4me3 and H3K9me3 in regulation of apoptosis and gemcitabine resistance in human pancreatic cancer cells. BMC Cancer 18:149
El-Elimat, Tamam; Rivera-Chávez, José; Burdette, Joanna E et al. (2018) Cytotoxic homoisoflavonoids from the bulbs of Bellevalia flexuosa. Fitoterapia 127:201-206

Showing the most recent 10 out of 144 publications