Dimeric naphthoquinones, a novel class of compounds with prostate cancer cytotoxicity
Authors: Ross Ashley E. , Emadi Ashkan , Marchionni Luigi , Hurley Paula J. , Simons Brian W. , Schaeffer Edward M. , Vuica‐Ross Milena 
Published: December 2010

What’s known on the subject? and What does the study add? Sexual function is often impaired after radical prostatectomy (RP) resulting in reduced sexual activity and sexual bother. The main focus in the literature concerning sexual adverse effects has been on erectile dysfunction and impairment of sexual function rather than the actual sexual bother it causes, although the sexual bother is most important to the individual patient’s quality of life. The relation between these measures, and in particular pre‐operative prediction of post‐operative sexual bother, has only been studied limitedly and with varying results. Some studies have found good mental health, low levels of pre‐operative sexual bother, and higher education to be associated with absence of post‐operative sexual bother, but another study could not identify any pre‐operative predictors of a post‐operative sexual bother. Severe sexual bother after RP were reported by 64% to 95% of the patients three years after operation, and the prevalence was associated with the level of pre‐treatment sexual bother and pre‐operative nerve‐preservation. On the other hand, others have reported that only 43% of men have sexual bother 2 years after RP. However, none of these studies stratified patients according to their pre‐operative sexual activity and most of them were American. It has been shown that American findings concerning sexual bother may not always be valid for non‐American patients due to differing sex role expectations thus warranting the need for more non‐American studies.This study has shown that two thirds of patients experienced sexual bother one year after RP. We have identified patients with increased risk of experiencing overall sexual bother post‐operatively: those who report pre‐operative sexual bother, those who are sexually active before RP, and those who display neurotic personality‐traits. Another important finding was that the proportion of patients who experienced bother relevant to having impaired post‐operative SF was significantly higher among pre‐operatively sexually active patients than those who had been inactive. This study adds knowledge that patients’ pre‐operative sexual activity, sexual bother and personality should be taken into account to be able to give individualized information about the risk of getting sexual bother after RP.OBJECTIVES

To evaluate the cytotoxicity of dimeric naphthoquinones (BiQs) in prostate cancer cells.
To assess the interaction of dimeric naphthoquinones with common therapies including radiation and docetaxel.

MATERIALS AND METHODS

The cytotoxicity of 12 different dimeric naphthoquinones was assessed in androgen‐independent (PC‐3, DU‐145) and androgen‐responsive (LNCaP, 22RV1) prostate cancer cell lines and in prostate epithelial cells (PrECs).
BiQ2 and BiQ11 were selected for determination of dose response, effects on colony formation and initial exploration into mechanism of action.
Synergistic effects with radiation and docetaxel were explored using colony‐forming and MTT assays.

RESULTS

At concentrations of 15µM, BiQ2, BiQ3, BiQ11, BiQ12, and BiQ15 demonstrated cytotoxicity in all prostate cancer cell lines.
Treatment with BiQs limited the ability of prostate cancer cells to form colonies in clonogenic assays.
Exposure of prostate cancer to BiQs increased cellular reactive oxygen species (ROS), decreased ATP production, and promoted apoptosis.
BiQ cytotoxicity was independent of NADP(H):quinone oxidoreductase 1 (NQO1) activity in PrECs, PC‐3 and 22RV1, but not DU‐145 cells.
Exposure of prostate cancer cells to radiation before treatment with BiQs increased their activity allowing for inhibitory effects well below the IC50s of these compounds in PrECs.
Co‐administration of BiQs with docetaxel had minimal additive effects.

CONCLUSIONS

Dimeric naphthoquinones represent a new class of compounds with prostate cancer cytotoxicity and synergistic effects with radiation. The cytotoxic effect of these agents is probably contributed to by the accumulation of ROS and mitochondrial dysfunction.
Further studies are warranted to better characterize this class of potential chemo‐therapeutics.