Repurposing azithromycin for improvement of radiation therapy of prostate cancer

Aggressive prostate cancer (PCa) is highly unpredictable and its treatment has been ineffective. Previously, we have demonstrated an increase of oxidative stress in aggressive PCa, thus we hypothesize that selectively inducing oxidative stress beyond the antioxidant capacity of cancers is a logical approach to treat aggressive PCa. We have identified Azithromycin (AZM), a macrolide antibiotic, as a potential novel drug for treating PCa based on its ability to increase ROS production and enhance sensitivity of PCa to radiation. AZM-generated ROS production could lead to modification of mitochondrial HSP90 (mtHSP90), a key protein that controls and maintains numerous cancer features. Moreover, our results from high Gleason score PCa tissues demonstrated an increase in mtHSP90 protein levels when compared with benign epithelial tissues, providing a promising rationale for AZM targeting mtHSP90. Hence, Specific Aim 1 will investigate if AZM down regulates mtHSP90 via H2O2-mediated posttranslational modifications using aggressive PCa cancer models. Specific Aim 2 will investigate if mtHSP90 is a marker for PCa progression, tumor microarrays with different pathological stages of PCa will be analyzed for HSP90 subcellular localization, and the patient’s serum will be measured for HSP90. The findings from this proposed pilot have immediate cancer relevance because 1) AZM has a good safety record, thus co-treatment of AZM with RAD or chemotherapy will improve the efficacy of aggressive PCa treatment, and 2) high expression of mtHSP90 may associate with aggressive PCa, thus allowing for mtHSP90 or serum HSP90 to be applied to personalized cancer therapy and/or to be used complementarily with other markers.