Abstract
Compounds derived from natural products are becoming promising alternative drugs/tools in Alzheimer's disease (AD) therapeutics. From an in-house natural products library, seventeen hits were selected for their inhibitory effect on the production of amyloid-β (Aβ) with IC50 lower than 10 μM without causing obvious toxicity. Among these compounds, camptothecin (CPT) and its analogs showed inhibitory effects on amyloid-β 1-42 (Aβ42) with the IC50 value in the nanomolar range in HEKsw cells and SHSY5Ysw cells. Further studies showed that CPT and its analogs inhibited Aβ42 via a p53 dependent pathway. Meanwhile, CPT and its analogs could also inhibit Aβ42 induced IL-1β production in the THP-1 cells. Taken together, our results indicate that CPT and its analogs would be a promising therapeutic candidates for AD.
Keywords:
Alzheimer's disease; IL-1β; amyloid-β; camptothecin; p53.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Amyloid Precursor Protein Secretases / metabolism
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Amyloid beta-Peptides / metabolism*
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Amyloid beta-Peptides / pharmacology
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Amyloid beta-Protein Precursor / genetics
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Aspartic Acid Endopeptidases / metabolism
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Camptothecin / analogs & derivatives*
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Camptothecin / chemistry
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Camptothecin / pharmacology*
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Caspases
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Cell Line
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Cell Survival / drug effects
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Cell Survival / genetics
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Chromatography, High Pressure Liquid
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Dose-Response Relationship, Drug
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Gene Expression Regulation / drug effects
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Gene Expression Regulation / genetics
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HEK293 Cells
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Humans
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Inhibitory Concentration 50
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Interleukin-1beta / metabolism*
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Mass Spectrometry
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Mutation / genetics
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Neuroblastoma / pathology
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Peptide Fragments / metabolism
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Peptide Fragments / pharmacology*
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Transfection
Substances
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Amyloid beta-Peptides
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Amyloid beta-Protein Precursor
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Interleukin-1beta
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Peptide Fragments
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amyloid beta-protein (1-40)
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amyloid beta-protein (1-42)
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Amyloid Precursor Protein Secretases
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Caspases
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Aspartic Acid Endopeptidases
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BACE1 protein, human
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Camptothecin