The Anticancer Effect And Mechanism Of Sildenafil In Colorectal Cancer

Objective: Colorectal cancer is one of the three most common malignant tumors. Recently, with the improvement of people’s living standard, the change of dietary structure and environmental factors, there is an escalating trend in colorectal cancer incidence and mortality, which severely debilitate people’s health. Because the etiology and specific molecular mechanism of colorectal cancer are not clear, lack of effective prevention and treatment measures, drug resistance, recurrence and metastasis lead to the poor survival rate. Therefore, it urges us to further understanding the molecular mechanism of colorectal cancer and to find novel treatment protocols and new therapeutic targets. Sildenafil is a potent and selective inhibitor of the type 5 cGMP-specific phosphodiesterase that is used clinically to treat erectile dysfunction and pulmonary arterial hypertension,this study shows that the anti-cancer effect and mechanism of sildenafil in colorectal cancer. Methods: The effect of sildenafil on colorectal cancer cells was measured by MTT assay in vitro and xenografts nude mouse model in vivo. The cell cycle distribution and apoptosis of colorectal cancer cells were analyzed by flow cytometry. The levels of intracellular ROS were detected with DHE staining. The levels of proteins were detected with Western Blot. Results: 1. Sildenafil inhibited the proliferation of colorectal cancer cells in vitro. 2. Sildenafil induced cell cycle arrest and apoptosis. 3. Sildenafil induced the intercellular accumulation of ROS in colorectal cancer cells, and NAC could reverse the level of ROS and apoptosis effectively. 4. KT-5823, a PKG inhibitor, enhanced sildenafil-induced apoptosis in colorectal cancer cells. 5. Sildenafil inhibited the growth of SW480 and HCT116 xenografts in nude mice. Conclusions: The data here demonstrated that sildenafil, a PDE5 inhibitor, could induce growth inhibition, cell cycle arrest and apoptosis of human colorectal cancer lines in vitro. Additionally, sildenafil also inhibited the growth of SW480 and HCT116 xenografts in nude mice in vivo.