A new study has found that a compound created by the body’s breakdown of a cancer drug has therapeutic properties. When combined with the original drug, the by-product produced a synergistic effect to inhibit prostate cancer cells; when used alone, it reduced the buildup of a toxic protein in the brain associated with Parkinson’s disease.
After medications are consumed, they’re absorbed and distributed around the body. When they’ve produced their therapeutic effect, they’re broken down – metabolized – by various organs into by-products called metabolites, compounds that are more easily eliminated from the body.
The potential therapeutic effects of drug metabolites are often overlooked, even though they are present at high concentrations in the plasma and can be pharmacologically active. However, a new study by the Spanish National Research Council (CSIC) has found that a metabolite produced by the breakdown of a cancer drug may have value as a therapeutic agent in its own right.
Rucaparib, a drug used to treat recurrent ovarian, breast and, more recently, prostate cancers, is broken down to its major metabolite, M324, which can be detected in several species, including mice and humans. M324 can reach higher plasma concentrations in animals than the parent drug and can enter tumor cells; in humans, the metabolite’s plasma concentration is around 40% of rucaparib’s concentration.
Using four different computational approaches, the researchers comprehensively characterized the profile of M324, enabling them to predict the potential ‘off-targets’ of rucaparib and its metabolite. They identified targets that were shared by the pair and those that were exclusive to either.
Moving on to experiments on lab cell lines to validate their computational findings, the researchers tested whether M324 had anti-cancer properties. They screened rucaparib and a synthesized version of M324 across a panel of 20 human cancer cell lines that included prostate, breast, ovarian, and pancreatic cancers. In nine cell lines, combining the parent drug and its metabolite increased cancer cell inhibition more than using either compound singly. The biggest difference was seen in the prostate cancer cell line, with a difference in inhibition exceeding 30%.
Having observed synergy but not independent activity in prostate cancer cell line models, the researchers wondered whether the metabolite could, by itself, have activity in another cellular context. Differentiating Parkinson’s disease dopamine neurons from induced pluripotent stem cells (iPSCs) obtained from a patient with the condition, they treated the neurons with M324. They found that the metabolite effectively reduced the accumulation of ⍺-synuclein, a protein that, when misfolded into aggregates, causes neuroinflammation, neurodegeneration and cell death. It’s been linked genetically and neuropathologically to Parkinson’s disease.
The researchers say their findings could have significant clinical impact. First, the synergistic effect seen with rucaparib and M324 could impact clinical trials for advanced stages of prostate cancer, as combining both could be advantageous compared to other cancer drugs used in this setting. It could also have implications for the drug’s safety and efficacy and warrants further research. Concerning Parkinson’s, the study showed that the metabolite is pharmacologically active and has the potential to be repurposed, representing a new way to treat the disease.
“Overall, we demonstrate that drug metabolites can have a different polypharmacology than their parent drugs, highlighting the importance of making drug metabolites commercially available, incorporating them in preclinical studies, and characterizing them more thoroughly during drug discovery and development to comprehensively understand the effect of drugs in the clinic and better tailor drugs to patients in precision medicine,” said the researchers.
The study was published in the journal Cell Chemical Biology.
Source: CSIC
