RhoA/ROCK pathway inhibitor ameliorates erectile dysfunction induced by radiation therapy in rats

• Published in: Radiotherapy and oncology Vol. 150; pp. 174 - 180
• Main Authors: Mahmood, Javed, Pandita, Ravina, Zhang, Angel, Kamlapurkar, Shriya, Saeed, Ali, Chen, Minjie, Staats, Paul N., Shukla, Hem D., Anvari, Akbar, Sawant, Amit, Vujaskovic, Zeljko
• Format: Journal Article
• Language: English
• Published: Ireland Elsevier B.V 01.09.2020
• Subjects: Animals; Disease Models, Animal; Erectile dysfunction; Erectile Dysfunction - drug therapy; Erectile Dysfunction - etiology; Humans; Hydroxyfasudil; Male; Penile Erection; Penis; Prostate cancer; Quality of Life; Radiation; Rats; Rats, Sprague-Dawley; rhoA GTP-Binding Protein; RhoA/ROCK pathway; Treatment side-effects; RhoA/ROCK pathway; Radiation; Erectile dysfunction; Hydroxyfasudil; Treatment side-effects; Prostate cancer; Quality of life
• ISSN: 0167-8140; 1879-0887
• DOI: 10.1016/j.radonc.2020.06.021

Prostate cancer (PCa) treatment with radiation therapy (RT) has an excellent cure rate. However, Radiation-induced Erectile Dysfunction (RiED) is a common and irreversible toxicity impacting quality of life, and there is no FDA approved specific drug for RiED. We previously showed that prostate RT increased RhoA/ROCK signaling in the cavernous nerve (CN) and penile tissues, which may lead to RiED in rats. In this study, we investigated whether RhoA/ROCK pathway inhibition by a specific inhibitor called Hydroxyfasudil (HF) can improve RiED in our well-established rat model. Male Sprague-Dawley rats were randomized to the following groups: sham-RT, HF-only, RT-only, and RT + HF. Rats were either exposed to a single dose of 25 Gy prostate-confined RT or a sham procedure. 10 mg/kg HF or normal saline was injected intraperitoneally. Erectile function was evaluated by intracavernosal pressure (ICP) and mean arterial pressure (MAP) measurements at week 14 post-RT. Cavernous nerve (CN) injury was evaluated by transmission electron microscopy (TEM), and penile tissue fibrosis by Masson trichrome staining (MT). We have found that the HF treatment prior to RT showed significant (p < 0.001) improvement in ICP/MAP ratio, area under the curve, and maximum ICP value, compared to RT-alone rats. Furthermore, RT + HF treated rats exhibited increased CN myelination and decreased axonal atrophy, comparted to RT-only. HF treatment showed significantly decreased penile tissue fibrosis (p < 0.05) compared to RT-alone treated rats. Our results provide the first preclinical evidence that targeting RhoA/ROCK pathway by HF may provide a novel therapeutic option for the treatment of RiED.