Sildenafil

Sildenafil is a selective inhibitor of phosphodiesterase type 5 (PDE5) with an IC₅₀ value of 5.22nM^[1]. By inhibiting PDE5, Sildenafil regulates the NO-cGMP pathway, increasing the cGMP level in the penile corpus cavernosum, causing relaxation of the penile arteries and the smooth muscles of the penile corpus cavernosum, thereby improving the erectile function of patients with erectile dysfunction^[2]. Sildenafil has been widely used to regulate hemodynamic balance, reduce arterial resistance and increase venous compliance^[3].

In vitro, Sildenafil treatment for 72 hours significantly inhibited the proliferation of HT-29, SW480 and SW620 cells, with IC₅₀ values of 190μM, 217μM and 205μM, respectively^[4]. Treatment with 50μM Sildenafil for 72 hours significantly inhibited the proliferation of MDA-MB-231 cells and induced cell apoptosis^[5]. Treatment with 100nM sildenafil for 72 hours significantly inhibited the proliferation of hypoxia-induced human pulmonary artery smooth muscle cells (PASMCs), and prevented the upregulation of TRPC1 expression as well as the nuclear translocation of NFATc3^[6].

In vivo, Sildenafil treatment via intraperitoneal injection at a dose of 15mg/kg/day for 5 days significantly restored the cognitive function of the Alzheimer's disease mouse model without affecting the β-amyloid protein load^[7]. Oral administration of 5.7mg/kg dose of Sildenafil daily for 12 weeks significantly inhibited the formation of intestinal polyps and inflammation in mice induced by azoxymethane/dextran sulfate sodium (AOM/DSS) ^[8].

References:
[1] Wang Z, Zhu D, Yang X, et al. The selectivity and potency of the new PDE5 inhibitor TPN729MA[J]. The journal of sexual medicine, 2013, 10(11): 2790-2797.
[2] Zusman R M, Morales A, Glasser D B, et al. Overall cardiovascular profile of sildenafil citrate[J]. The American journal of cardiology, 1999, 83(5): 35-44.
[3] Jackson G, Benjamin N, Jackson N, et al. Effects of sildenafil citrate on human hemodynamics[J]. The American journal of cardiology, 1999, 83(5): 13-20.
[4] Mei X L, Yang Y, Zhang Y J, et al. Sildenafil inhibits the growth of human colorectal cancer in vitro and in vivo[J]. American journal of cancer research, 2015, 5(11): 3311.
[5] Chen L, Liu Y, Becher A, et al. Sildenafil triggers tumor lethality through altered expression of HSP90 and degradation of PKD2[J]. Carcinogenesis, 2020, 41(10): 1421-1431.
[6] Wang C, Li J F, Zhao L, et al. Inhibition of SOC/Ca2+/NFAT pathway is involved in the anti-proliferative effect of sildenafil on pulmonary artery smooth muscle cells[J]. Respiratory research, 2009, 10(1): 123.
[7] Cuadrado‐Tejedor M, Hervias I, Ricobaraza A, et al. Sildenafil restores cognitive function without affecting β‐amyloid burden in a mouse model of Alzheimer's disease[J]. British journal of pharmacology, 2011, 164(8): 2029-2041.
[8] Islam B N, Sharman S K, Hou Y, et al. Sildenafil suppresses inflammation-driven colorectal cancer in mice[J]. Cancer Prevention Research, 2017, 10(7): 377-388.