The prostate is a metabolically unusual gland. While benign prostate epithelial cells are glycolytic and energy-inefficient, malignant prostate epithelial cells are oxidative and energy-efficient, relying upon their mitochondria for growth and proliferation. This metabolic switch from glycolytic to oxidative metabolism suggests that malignant prostate epithelial cells may be uniquely susceptible to mitochondrial poisons.We aim to target mitochondria in prostate cancer by exploiting the rotenoid group of natural products, the parent compound of which, rotenone, is a well-known inhibitor of mitochondrial complex I and mitochondrial poison. Rotenone itself is unsuitable for use a drug due to its systemic toxicity, however other bioactive rotenoids, e.g. deguelin, have been shown to display markedly reduced toxicity in animals while retaining anticancer activity.We present the results of an SAR study based upon a library of rotenoids, accessed in optically active form from rotenone, in which compounds were evaluated using both in vitro and ex-vivo assays involving sub-mitochondrial particles and prostate cancer cell lines respectively. The structural requirements for anticancer activity are described and correlations are drawn between potency and toxicity, with a view to balancing these factors. In addition, and most importantly, we show that rotenoids display remarkable selectivity for malignant over benign prostate epithelial cells, in agreement of our initial hypothesis. Lastly, ongoing studies are presented aimed at identifying solubilising modifications that will enable the preparation of an orally bioavailable rotenoid for evaluation in mice models of prostate cancer.

Targeting mitochondria in prostate cancer with the rotenoid group of natural products

248th National Meeting (2014)

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