Viagra in oncology
Erectile dysfunction drugs increase the sensitivity of esophageal cancer to chemotherapy
Elina Stoyanova, PCR.news
A new potential target for the fight against esophageal adenocarcinoma has been found — the PDE5 enzyme. Inhibitors of this enzyme are widely used for the treatment of erectile dysfunction. In experiments on mice, this drug in combination with chemotherapy led to a reduction in the volume of the tumor.
The staff of the University of Southampton, together with other researchers from the UK and the USA, began a thorough study of the cells that surround the tumor to find a potential target for treatment. Scientists have found that in mutant fibroblasts, compared with normal tissues, the expression of the enzyme phosphodiesterase type 5 (PDE5) is increased. This enzyme plays a significant role in the cardiovascular system, controlling vascular tone. For cancer research, this fact is noteworthy, since the features of the vascular network around the tumor can cause its rapid growth.
After scientists found a potential therapeutic target, the PDE5 enzyme, they began testing already known PDE5 inhibitors (PDE5i) on tumor—associated fibroblasts.
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Phosphodiesterase type 5 (PDE5i) inhibitors, due to their vasodilating effect, were first approved for the treatment of erectile dysfunction — Viagra (sildenafil) belongs to this group of drugs. Recently, high doses of PDE5i have been approved for the treatment of pulmonary arterial hypertension and lower urinary tract diseases. There are results that suggest that PDE5i may be prescribed for the treatment of cancer or lung diseases. It has also been shown that PDE5i reverse the differentiation of prostate fibroblasts into myofibroblasts, which suggests that they may affect the inflammatory microenvironment of solid tumors.
When tumor-associated fibroblasts were placed in a gel and treated with PDE5i or miRNA inhibiting PDE5 expression, the cells showed a decrease in tumor-promoting characteristics. Proteomic analysis and RNA sequencing of single cells confirmed that signaling pathways associated with cancer development are modulated in such fibroblasts.
For further analysis, the researchers took tumor tissue samples from eight patients with esophageal adenocarcinoma and grew them in vitro as three-dimensional models of the neoplasm. The PDE5i inhibitor contributed to the return of mutant fibroblasts to normal functional activity, while 9 out of 12 samples insensitive to standard chemotherapy became sensitive to it.
The next stage of the study was an experiment with model organisms: scientists implanted tumor cells resistant to chemotherapy into mice. Combination therapy using PDE5i proved to be more effective than chemotherapy alone, and no additional side effects were detected.
Since PDE5 enzyme inhibitors are widely used in the treatment of erectile dysfunction and have proven their safety, this should accelerate clinical trials. "Developing new cancer drugs is incredibly important, but doing it from scratch is difficult, and many potentially effective drugs are eliminated at different stages. We sought to find out whether existing drugs licensed for other diseases could be effective against cancer. If successful, they will also be more accessible, and patients will be able to get them faster," says Michelle Mitchell, executive director of Cancer Research UK (the study was carried out with the support of this organization).
Article by Sharpe et al. Phosphodiesterase type 5 inhibitors enhance chemotherapy in preclinical models of esophageal adenocarcinoma by targeting cancer-associated fibroblasts is published in the journal Cell Reports Medicine.
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