title: Deguelins, Natural Product Modulators of NF1-Defective Astrocytoma Cell Growth Identified by High-Throughput Screening of Partially Purified Natural Product Extracts.
abstract: A high-throughput screening assay for modulators of Trp53/NF1 mutant astrocytoma cell growth was adapted for use with natural product extracts and applied to a novel collection of prefractionated/partially purified extracts. Screening 68 427 samples identified active fractions from 95 unique extracts, including the terrestrial plant Millettia ichthyotona. Only three of these extracts showed activity in the crude extract form, thus demonstrating the utility of a partial purification approach for natural product screening. The NF1 screening assay was used to guide purification of active compounds from the M. ichthyotona extract, which yielded the two rotenones deguelin (1) and dehydrodeguelin (2). The deguelins have been reported to affect growth of a number of cancer cell lines. They potently inhibited growth of only one of a panel of NF1/Trp53 mutant murine astrocytoma cell lines, possibly related to epigenetic factors, but had no effect on the growth of normal astrocytes. These results suggest the potential utility of deguelins as tools for further investigating NF1 astrocytoma cell growth. These bioprobes were identified only as a result of screening partially purified natural product extracts.
authors.affiliation: Basic Science Program, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research , Frederick, Maryland 21702-1201, United States.
authors.forename: Curtis J
authors.initials: CJ
authors.lastname: Henrich
authors.affiliation: Basic Science Program, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research , Frederick, Maryland 21702-1201, United States.
authors.forename: Laura K
authors.initials: LK
authors.lastname: Cartner
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Wilson
authors.forename: Richard W
authors.initials: RW
authors.lastname: Fuller
authors.forename: Anthony E
authors.initials: AE
authors.lastname: Rizzo
authors.forename: Karlyne M
authors.initials: KM
authors.lastname: Reilly
authors.forename: James B
authors.initials: JB
authors.lastname: McMahon
authors.forename: Kirk R
authors.initials: KR
authors.lastname: Gustafson
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism; D001254:Astrocytoma / Q000188:drug therapy*; D001688:Biological Products / Q000737:chemistry / Q000302:isolation & purification* / Q000494:pharmacology*; D002453:Cell Cycle / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D007887:Fabaceae / Q000737:chemistry*; D006801:Humans; D051379:Mice; D033641:Millettia / Q000737:chemistry*; D015394:Molecular Structure; D012402:Rotenone / Q000031:analogs & derivatives* / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology
chemical_list: D001688:Biological Products; D012402:Rotenone; C107676:deguelin