Abstract
Cancer patients often use dietary supplements while on therapy, but little is known about interactions of supplements with cancer chemotherapy. Black raspberries (BRB) have anti-cancer effects, but have not been evaluated for interference with chemotherapy for castrate-resistant prostate cancer (CRPC). Here we studied whether BRB and some of their constituents interact with docetaxel and cabazitaxel on CRPC cells in culture and implanted into nude mice. Ellagic acid increased, but BRB extract inhibited, microtubule assembly. Ellagic acid decreased tubulin polymerization by cabazitaxel and bound to tubulin. Ellagic acid, its metabolite urolithin A, BRB extract, and the anthocyanin metabolite protocatechuic acid (PCA) did not alter cytotoxicity of taxanes. Ellagic acid inhibited drug efflux in CRPC cells, but BRB extract and PCA did not. None of these compounds altered CYP3A4 activity. Although dietary ellagic acid did not alter the tumor growth inhibition by docetaxel of xenografted 22Rv1 cells, ellagic acid has the potential to interfere with taxane chemotherapy by reducing tubulin polymerization while inhibiting P-glycoprotein drug efflux. These data are cause for concern of consuming ellagic acid during treatment for CRPC and indicate need for further research, but BRB consumption appears safe.
Highlights
We evaluated the effects on castrate-resistant prostate cancer (CRPC) cells of combining docetaxel and cabazitaxel with Black raspberries (BRB) extract, ellagic acid and its metabolite urolithin A, and protocatechuic acid (PCA) which is a major metabolite of BRB anthocyanins
We investigated the effects of BRB extract, PCA, ellagic acid, and urolithin A on tubulin polymerization using an cell-free assay
Tubulin polymerization was slightly reduced by BRB extract at concentrations of 10 μg/mL and higher (Fig. 1A) By contrast, 10 μM ellagic acid significantly increased the amount of polymerized tubulin compared to control (Fig. 1E), as did 10 μg/mL PCA this effect was not significant (Fig. 1C)
Summary
BRB target similar pathways as do chemotherapeutic drugs, it is a plausible that adding BRB supplementation to chemotherapy could result in enhanced drug efficacy and reduced resistance. We hypothesized that treatment of prostate cancer cells with BRB extract and BRB compounds would improve effectiveness of the standard chemotherapeutics docetaxel and cabazitaxel, resulting in decreased growth of CRPC cells and increased sensitivity of these cells to chemotherapeutic agents. A secondary objective was to rule out possible adverse interactions, i.e., reduction in cytotoxic efficacy of docetaxel and cabazitaxel by BRB that may lead to harmful effects for patients who are consuming such supplements while on chemotherapy. We evaluated the effects on CRPC cells of combining docetaxel and cabazitaxel with BRB extract, ellagic acid and its metabolite urolithin A, and protocatechuic acid (PCA) which is a major metabolite of BRB anthocyanins
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