Drug discovery has a habit of rewarding researchers for finding exactly what they weren’t looking for. From hair-loss treatments to anxiety medications, pharmacy shelves are lined with myriad remedies whose rises to success were serendipitous. One of the happiest accidents birthed Viagra®, the Little Blue Pill that revolutionized bedrooms across the world. But before it rose to fame as the frisky first-line treatment for erectile dysfunction, Viagra® had humble beginnings as a candidate therapy for heart disease.
From Bench to Bedroom
In the late 1980s, a group of British chemists led by Sir Simon Campbell conceived a compound called sildenafil, which they hoped might help treat high blood pressure and angina, a type of chest pain that can arise when heart muscles are not receiving enough oxygenated blood. Backed by Pfizer, Campbell’s team conducted rounds upon rounds of clinical trials in the early 1990s. As time passed without any promising results, confidence in the new drug fell limp. Pfizer was on the cusp of abandoning the project altogether. But in 1993, a glimmer of hope appeared when one trial participant had the courage to report a rather awkward side effect: while sildenafil did little to alleviate his angina, it instead aroused a series of prolonged erections that persisted throughout the entire overnight study. This observation, subsequently echoed by many other male participants in the trial, prompted the researchers to pivot. Despite its impotence at treating heart disease, a new set of clinical trials found that sildenafil was incredibly effective at managing erectile dysfunction. By 1998, sildenafil was launched commercially as Viagra® and has earned its keep as the so-called “Pfizer Riser” by becoming one of the most prescribed and most profitable drugs in history.
Viagra® is a vasodilator, meaning it can widen the walls of blood vessels to allow more blood to flow through. In healthy people, a molecule called cGMP helps keep muscle cells, including those surrounding blood vessels, relaxed. Normally, cGMP will naturally be recycled by another enzyme called phosphodiesterase-5 (PDE5) once its job is done. Balancing the amount of cGMP available to use allows blood vessels to dilate or constrict as needed. Sildenafil works by inhibiting PDE5, which permits the dilatory effect of cGMP to last longer within muscle cells so its user can last longer too. This property is initially what made the drug so attractive as a heart disease therapy, since increasing the ease and amount of blood flow would, on paper, help relieve high blood pressure and chest pain. In practice, Viagra® dilates arteries throughout the body too weakly to allow for any improvement in cardiovascular symptoms as a whole; where it excels instead is as an extra boost to help people with erectile dysfunction rise to the occasion. Sildenafil augments the existing physiological response associated with sexual arousal, which focuses the muscle-relaxing effect specifically on the small blood vessels within the erectile tissue of the penis.
The Bedside
Since its 1998 debut, Viagra® has been used by over 64 million men worldwide and has brought in tens of billions of dollars for Pfizer. Encouraged by its excellent safety profile and tolerability, Viagra®’s vasodilatory capacity has already been further repurposed to treat pulmonary hypertension by relaxing the arteries in the lungs. Off-label, it can even be used to manage Raynaud’s disease, a condition where the muscles of blood vessels in the fingers and toes spasm in response to cold temperatures. But the story of Viagra® is far from finished: for a drug best known for helping things rise, its legacy still has plenty of room to grow.
Viagra® and other PDE5 inhibitors may be the next big thing in the realm of cancer therapy. With over a decade of research across myriad pre-clinical and clinical trials, the wonder pill is emerging as a hard-hitting drug against a variety of different malignancies, including those of the colorectum, breast, prostate, pancreas, and liver, which are among the most common and most fatal types.
One study following a cohort of Swedish gastric cancer patients found that post-diagnosis treatment with PDE5 inhibitors was associated with significantly lower cancer-specific mortality. Many gastric and other solid cancers overexpress PDE5, which reduces the amount of cGMP available within tumour cells. The researchers found that, by limiting cGMP, tumour cells can hijack a gene called c-myc, which keeps many cell signalling pathways in check – including those controlling cell survival and proliferation. Loosening the reins on c-myc expression permits the uncontrolled growth characteristic of tumours. To add insult to injury, overactive c-myc also allows these tumour cells to abuse IL-6, a pro-inflammatory chemical messenger usually used to fight off infections. In addition to further promoting unbridled growth and survival directly, IL-6 also helps protect cancer cells against damage inflicted by drugs or the immune system. Just like they do in blood vessel walls, PDE5 inhibitors increase cGMP in tumours too to stabilize c-myc. This can help wrangle the cancer cells into submission by slowing their growth and making them more vulnerable to attack.
Other trials are further investigating the ability of sildenafil to enhance the efficacy of concurrent chemo- or immunotherapies. PDE5 inhibitors can help deliver cancer-killing drugs to tumour sites more efficiently, manipulate properties of cancerous cells to make those drugs more effective, and stimulate immune cells to mount more potent and longer-lasting attacks. One group showed in mice that sildenafil can counteract the immune suppression within the tumour environment upheld by myeloid-derived suppressor cells (MDSCs). MDSCs, which are immune cells themselves, treacherously protect cancer cells from recognition by the rest of the immune system in a PDE5-dependent manner. When PDE5 is blocked in MDSCs, they drop their guard, allowing killer T cells to penetrate the tumour and mount a stronger attack.
And Beyond?
After thirty years, Viagra® has proved its versatility from the bench to bedroom to bedside. With its rising popularity among practitioners, patients, paramours, and pharmacological pundits alike, sildenafil’s story surely has yet to reach its climax.
Victoria Sephton
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