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Hydroxylated Rotenoids Selectively Inhibit the Proliferation of Prostate Cancer Cells.

Accepted version
Peer-reviewed

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Type

Article

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Authors

Bridges, Hannah R 
Serreli, Riccardo 
Kidd, Sarah L 
Mateu, Natalia 

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.

Description

Keywords

Animals, Antineoplastic Agents, Blood-Brain Barrier, Cattle, Cell Division, Cell Line, Tumor, Cell Proliferation, Cell Survival, Drug Screening Assays, Antitumor, Electron Transport Complex I, Humans, Male, Mitochondrial Membranes, Molecular Structure, Prostatic Neoplasms, Rotenone, Uncoupling Agents

Journal Title

J Nat Prod

Conference Name

Journal ISSN

0163-3864
1520-6025

Volume Title

83

Publisher

American Chemical Society (ACS)

Rights

All rights reserved
Sponsorship
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)
Medical Research Council (MC_UP_1002/1)
Medical Research Council (MC_UU_00015/7)
MC_U105663141 MC_UU_00015/2