Deguelins, Natural Product Modulators of NF1-Defective
Astrocytoma Cell Growth Identified by High-Throughput Screening of
Partially Purified Natural Product Extracts
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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 <i>Millettia
ichthyotona</i>. 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 <i>M. ichthyotona</i> extract, which yielded the two rotenones
deguelin (<b>1</b>) and dehydrodeguelin (<b>2</b>). 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