An approved treatment for amyotrophic lateral sclerosis (ALS), called riluzole, may be an effective option for people with aggressive prostate cancer because of its ability to induce androgen receptor degradation, according to a study.
The study, “Riluzole induces AR degradation via endoplasmic reticulum stress pathway in androgen‐dependent and castration‐resistant prostate cancer cells” was published in the journal The Prostate.
The relationship between prostate cancer and androgen is well-known, and many treatments against this disease focus on the direct inhibition of the androgen receptor, a molecule that activates prostate cancer-related genes.
Androgen deprivation therapies, which directly target the androgen receptor, are the mainstay of advanced prostate cancer treatment. But despite initial responses, almost all patients progress to castration-resistant prostate cancer (CRPC) — an aggressive cancer that keeps growing even with low levels of testosterone, the major androgen in men.
A strategy that cells use to create resistance is to produce variants (mutants or splice variants) of the androgen receptor that are not recognized by the common inhibitors. New medications to target prostate cancer are necessary.
In a previous study, researchers at the Roswell Park Comprehensive Cancer Center observed that treating CRPC cells with riluzole — approved to treat ALS in 1995 — decreased cell growth and migration capacity, while inducing cell death.
Riluzole was the first FDA approved medication to treat ALS, under the brand name Rilutek. It is an oral treatment that helps reduce disease progression.
To clarify the mechanism by which riluzole combats prostate cancer cells, the investigators treated different androgen-dependent and CRPC cells lines with the compound and assessed their response.
They observed that treatment with riluzole reduced the levels of the androgen receptor in both cell types, and that CRPC cell lines were especially susceptible.
But riluzole did not directly inhibit, or block, the production of this receptor. Instead, it activated two general cell mechanisms that degrade newly synthesized proteins that are not correctly folded or are produced in excess: endoplasmic reticulum stress pathway and selective autophagy. These pathways, in turn, degraded the androgen receptor.
The pathways activated by riluzole also caused the degradation of the most relevant splice variant (AR-V7) and some receptor mutants.
“To our knowledge, our study is the first to show that this [androgen receptor] degradation mechanism also occurs in CR-PCa cells and is not limited to AR-FL (the original androgen receptor), but extends to AR-V7,” the researchers said.
They also noted that, consistent with lower androgen receptor levels, riluzole reduced the production of some androgen receptor-target genes.
Other drugs that reduce levels of the androgen receptor and its AR-V7 variant, such as galeterone and niclosamide, are now in clinical trials as potential treatments for prostate cancer. The researchers think that riluzole could be an even better alternative.
“The findings suggest that riluzole should be investigated clinically for prostate cancer and predict that it may be effective for both early stage and advanced disease,” Shahriar Koochekpour, with the Roswell Park Comprehensive Cancer Center and the study’s senior author, said in a press release.