β-AR agonist therapy may prevent metastasis in oral squamous cell carcinoma

Affecting almost 600,000 people worldwide every year, and with only a 50% survival rate, oral squamous cell carcinoma (OSCC) is one of the more common and deadly forms of cancer. The poor prognosis of OSCC patients is mainly attributed to a lack of therapies that block the metastasis, or spread, of cancer cells from the primary tumor to other sites in the body.

Prior to metastasis, cancer cells undergo a series of changes that cause them to become motile and more invasive. This process, called epithelial-mesenchymal transition (EMT), equips cancer cells with everything they need to travel through the lymphatic system and form secondary tumors. Furthermore, recent reports imply that EMT also confers cancer cells with tumor initiation activity and drug resistance.

Working on the theory that disrupting EMT should prevent cancer progression and therefore reduce OSCC mortality rates, researchers from Tokyo Medical and Dental University (TMDU) screened a panel of small chemical compounds for their ability to reverse the process of EMT in oral cancer cells. The results, published this month in Cancer Science, may represent an exciting new avenue for the treatment of OSCC.

We identified a β2‐adrenergic receptor (β2‐AR)  agonist called isoxsuprine that effectively interfered with EMT. Interestingly, previous studies have provided conflicting results regarding the involvement of β-ARs in tumorigenesis--some reports suggest that β-AR signaling is important in tumor progression, while others point to a protective role for β-AR induction."

Shintaro Sakakitani, lead author of the study

After treating a range of oral cancer cell types with isoxsuprine, the researchers found that the resulting increase in β2-AR expression significantly impaired EMT and reduced cell motility. A non-selective agonist called isoprenaline, which enhances the expression of all types of β?adrenergic receptor not just β2, produced a similar result.

Confirming the protective role of β-AR activation, the researchers then pre-treated cells with a chemical that prevents receptor expression, resulting in enhanced EMT. Further, deletion of the gene coding for β2-AR completely abolished the protective effects of isoxsuprine.

As a further test of treatment efficacy, the researchers established tumors in mice and provided daily treatment with either isoxsuprine or a placebo. Not surprisingly, at the end of the treatment period, mice that received isoxsuprine had significantly smaller tumors compared with the placebo group, confirming the tumor-suppressive effects of isoxsuprine.

"These results are hugely encouraging," says senior author Katarzyna Anna Podyma-Inoue. "The efficacy of β-AR-agonist therapy in both the in vitro and in vivo models suggests that this group of compounds may be the answer to preventing metastasis in OSCC and could potentially even inhibit tumor growth, offering a much better prognosis for OSCC patients worldwide."

Source:
Journal reference:

Sakakitani, S., et al. (2020) Activation of β2‐adrenergic receptor signals suppresses mesenchymal phenotypes of oral squamous cell carcinoma cells. Cancer Science. doi.org/10.1111/cas.14670.

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