Introduction
Colorectal cancer (CRC) is one of the most commonly diagnosed and
represents approximately 8% of all cancer deaths due to the late stage
at diagnosis when treatments are ineffective. The primary prevention of
CRC is therefore very important for high-risk patients. The average
lifetime risk for developing sporadic CRC is about 1 in 23, but there
are millions at 3-5 fold higher risk, including those with recurrent
polypectomy and those with first-person relatives with an early
diagnosis (Roos et al., 2019). The typical recommendations for these
high-risk patients include lifestyle modifications that have a marginal
effect, and colonoscopy with polypectomy to detect and remove
precancerous polyps (Oruc et al. , 2019; Yao et al. , 2017).
Colonoscopy is the most effective approach to CRC prevention, but there
are many cultural, geographic and economic barriers that limit the
availability of this invasive procedure (Sachdev et al. , 2019;
Wagner et al. , 2019; Zhao et al. , 2019). Chemoprevention
agents are needed for CRC, but apart from NSAIDs that have significant
side effects (Veettil et al., 2017), nothing has been approved for this
purpose.
A large body of preclinical evidence has highlighted the potential use
of cGMP-elevating agents to prevent colon cancer (Islam et al. ,
2018). Uroguanylin and guanylin are peptide hormones that trigger
intracellular cGMP production by activating epithelial guanylyl cyclase
C receptors (GC-C) (Forte, 2004). In vivo studies using knockout
mice with defective cGMP signaling have shown that cGMP controls
intestinal homeostasis by slowing epithelial turnover (Li et al. ,
2007; Steinbrecher et al. , 2002; Wang et al. , 2012). GC-C
knockout mice also exhibit increased tumorigenesis in both AOM andApc Min/+ mouse models of colon cancer (Li et
al., 2007; Lin et al., 2010). Moreover, increasing cGMP in wild type
mice using exogenous GC-C agonists inhibits tumorigenesis inApc Min/+ mice (Chang et al., 2017; Shailubhai
et al., 2000; Sharman et al., 2018). Phosphodiesterase 5 is expressed in
the intestinal epithelium, and antagonizes the effects of GC-C agonists
by degrading cGMP (Bakre et al. , 2000). Phosphodiesterase 5
inhibitors (PDE5i) such as sildenafil amplify the effect of endogenous
GC-C agonists and suppress proliferation in the colon (Sharman et al.,
2018; Sharman et al., 2017; Wang et al., 2014). Landmark studies showed
that a clinically relevant dose of PDE5i can block tumorigenesis by 50%
in both AOM/DSS and Apc Min/+ mouse models of
CRC (Islam et al., 2017; Sharman et al., 2018). Sildenafil reduced polyp
multiplicity in these studies but did not affect the size of the
initiated polyps, indicating that the central effect of cGMP is to
suppress tumor initiation (Browning, 2019; Islam et al. , 2018).
Two recent large cohort retrospective studies suggest that PDE5i might
also prevent CRC in humans. The first report used the Swedish Hospital
Discharge Register to show that polypectomy patients who had taken PDE5i
had 36% less incidence of CRC compared to those who had never been
exposed to PDE5i (Huang et al. , 2019). The second report
interrogated the Veterans Affairs Database, and found that patients
taking PDE5i over the long term had up to 50% reduction in CRC
incidence (Lilley et al. , 2020). Prospective clinical studies are
needed to support the repurposing PDE5i for CRC chemoprevention.
Conventional PDE5i (e.g. sildenafil, tadalifil) that are most widely
prescribed for erectile dysfunction, have also been safely used to treat
chronic diseases including pulmonary arterial hypertension and benign
prostate hyperplasia (Cohen et al. , 2019; Hatzimouratidis, 2014).
However, side effects of these drugs such as headache, flushing and
dyspepsia, would be less tolerated by otherwise healthy patients using
them to reduce their risk of CRC. Moreover, due to common predisposing
factors, many high-risk CRC patients also take nitroglycerin to treat
ischemic heart disease (Boden et al. , 2015). Due to drug-drug
interactions, these patients could not benefit from PDE5i for CRC
prevention. PDE5i that avoid systemic delivery would therefore be a
major advantage as an agent for CRC chemoprevention. The present study
has designed an analog of sildenafil that exhibits poor membrane
permeability, and we show that it avoids systemic delivery while
retaining the anti-proliferative ability of PDE5i in the colon
epithelium.