2024-08-02 16:53:43
Once drugs enter the body, apart from performing their therapeutic function, they are biochemically transformed by the action of the metabolic machinery, a process that facilitates their expulsion.
This biotransformation results in a gradual disappearance of the drug, which is converted into its metabolites. These, in turn, can reach high concentrations in the body and also show a biological activity that may be different from that of the original drug. That is, the metabolites and the drug coexist in the body, and can cause effects different from those obtained with the individual molecules.
This is the case of Rucaparib, a drug used in chemotherapy for ovarian cancer, breast cancer and, more recently, prostate cancer, and its metabolite, the molecule M324. Rucaparib is part of a group of drugs designed to treat various types of cancer that show alterations in DNA repair. Specifically, they are inhibitors of the enzyme PARP1, involved, precisely, in the process of repairing mutations in genetic material.
A study conducted by a team comprising, among others, Albert A. Antolin, from the Oncobell programme of the Bellvitge Biomedical Research Institute (IDIBELL) and ProCure of the Catalan Institute of Oncology (ICO), Amadeu Llebaria, from the Institute of Advanced Chemistry of Catalonia (IQAC) affiliated with the Spanish National Research Council (CSIC) and Huabin Hu, from the Institute of Cancer Research in London, United Kingdom, has shown that Rucaparib and its main metabolite M324 exhibit differential activities.
Researchers have analyzed Rucaparib and M324, making a computational prediction of the metabolite’s activity. They have described the synthesis of M324 and performed a biological assay, demonstrating that the drug and its metabolite have differentiated activities and act synergistically in some prostate cancer cell lines.
And, surprisingly, M324 reduces the accumulation of the protein alpha-synuclein (an important component of Lewy bodies) in neurons derived from Parkinson’s patients, a neurodegenerative disease characterized by a movement disorder, and in which neurons do not produce sufficient amounts of the neurotransmitter dopamine.
Specifically, the synergy demonstrated between Rucaparib and M324 in prostate cancer cell lines could have an impact on clinical trials for advanced stages of this type of cancer. Furthermore, the fact that M324 is able to reduce the abnormal accumulation of α-synuclein in neurons derived from stem cells of a Parkinson’s patient, highlights the therapeutic potential of this metabolite and its possible pharmacological application for the treatment of this disease. These results have been obtained thanks to the collaboration of the IDIBELL and ICO groups led by Miquel Àngel Pujana, Álvaro Aytés and the group of Antonella Consiglio, from IDIBELL and the University of Barcelona (UB).
By: Science News.com / Amazings.com