Hydroxylated Rotenoids Selectively Inhibit the Proliferation of Prostate Cancer Cells.
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Authors
Serreli, Riccardo
Kidd, Sarah L
Mateu, Natalia
Osberger, Thomas J
Sore, Hannah F
Publication Date
2020-06-26Journal Title
J Nat Prod
ISSN
0163-3864
Publisher
American Chemical Society (ACS)
Volume
83
Issue
6
Pages
1829-1845
Language
eng
Type
Article
This Version
AM
Physical Medium
Print-Electronic
Metadata
Show full item recordCitation
Russell, D. A., Bridges, H., Serreli, R., Kidd, S. L., Mateu, N., Osberger, T. J., Sore, H. F., et al. (2020). Hydroxylated Rotenoids Selectively Inhibit the Proliferation of Prostate Cancer Cells.. J Nat Prod, 83 (6), 1829-1845. https://doi.org/10.1021/acs.jnatprod.9b01224
Abstract
Prostate cancer is one of the leading causes of cancer-related death in men. The identification of new therapeutics to selectively target prostate cancer cells is therefore vital. Recently, the rotenoids rotenone (1) and deguelin (2) were reported to selectively kill prostate cancer cells, and the inhibition of mitochondrial complex I was established as essential to their mechanism of action. However, these hydrophobic rotenoids readily cross the blood-brain barrier and induce symptoms characteristic of Parkinson's disease in animals. Since hydroxylated derivatives of 1 and 2 are more hydrophilic and less likely to readily cross the blood-brain barrier, 29 natural and unnatural hydroxylated derivatives of 1 and 2 were synthesized for evaluation. The inhibitory potency (IC50) of each derivative against complex I was measured, and its hydrophobicity (Slog10P) predicted. Amorphigenin (3), dalpanol (4), dihydroamorphigenin (5), and amorphigenol (6) were selected and evaluated in cell-based assays using C4-2 and C4-2B prostate cancer cells alongside control PNT2 prostate cells. These rotenoids inhibit complex I in cells, decrease oxygen consumption, and selectively inhibit the proliferation of prostate cancer cells, leaving control cells unaffected. The greatest selectivity and antiproliferative effects were observed with 3 and 5. The data highlight these molecules as promising therapeutic candidates for further evaluation in prostate cancer models.
Keywords
Blood-Brain Barrier, Cell Line, Tumor, Animals, Cattle, Humans, Prostatic Neoplasms, Rotenone, Electron Transport Complex I, Antineoplastic Agents, Uncoupling Agents, Drug Screening Assays, Antitumor, Cell Division, Cell Proliferation, Cell Survival, Molecular Structure, Male, Mitochondrial Membranes
Sponsorship
MC_U105663141
MC_UU_00015/2
Funder references
Engineering and Physical Sciences Research Council (EP/P020291/1)
Medical Research Council (MC_U105663141)
MRC (MC_UP_1002/1)
MRC (MC_UU_00015/2)
European Commission (626191)
Identifiers
External DOI: https://doi.org/10.1021/acs.jnatprod.9b01224
This record's URL: https://www.repository.cam.ac.uk/handle/1810/308217
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