Molsidomine provides neuroprotection against vincristine-induced peripheral neurotoxicity through soluble guanylyl cyclase activation
Peripheral neurotoxicity is a dose-limiting adverse reaction of primary frontline chemotherapeutic agents, including vincristine. Neuropathy can be so disabling that patients drop out of potentially curative therapy, negatively impacting cancer prognosis. The hallmark of vincristine neurotoxicity is axonopathy, yet its underpinning mechanisms remain uncertain. We developed a comprehensive drug discovery platform to identify neuroprotective agents against vincristine-induced neurotoxicity. Among the hits identified, SIN-1-an active metabolite of molsidomine-prevents vincristine-induced axonopathy in both motor and sensory neurons without compromising vincristine anticancer efficacy. Mechanistically, we found that SIN-1's neuroprotective effect is mediated by activating soluble guanylyl cyclase. We modeled vincristine-induced peripheral neurotoxicity in rats to determine molsidomine therapeutic potential in vivo. Vincristine administration induced severe nerve damage and mechanical hypersensitivity that were attenuated by concomitant treatment with molsidomine. This study provides evidence of the neuroprotective properties of molsidomine and warrants further investigations of this drug as a therapy for vincristine-induced peripheral neurotoxicity.
Authors
- A Chiorazzi (ORCID: https://orcid.org/0000-0002-3469-1829)
- Charles Karan (ORCID: https://orcid.org/0000-0003-4012-8677)
- L Monza (ORCID: https://orcid.org/0000-0002-7992-047X)
- A Canta (ORCID: https://orcid.org/0000-0003-4946-647X)
- Paola Alberti (ORCID: https://orcid.org/0000-0001-6106-6183)
- Yalda Moayedi (ORCID: https://orcid.org/0000-0002-0600-1253)
- Valentina Carozzi (ORCID: https://orcid.org/0000-0003-0963-7107)
- Serge Przedborski (ORCID: https://orcid.org/0000-0002-7283-3883)
- Francesco Lotti (ORCID: https://orcid.org/0000-0002-5104-9088)
- Mariangels De Planell-Saguer
- Irina Utkina-Sosunova (ORCID: https://orcid.org/0000-0002-5352-5797)
- Guido Cavaletti (ORCID: https://orcid.org/0000-0003-4128-2406)
- C Meregalli (ORCID: https://orcid.org/0000-0002-4281-4577)
- G Fumagalli (ORCID: https://orcid.org/0000-0002-3999-0123)
- E Pozzi (ORCID: https://orcid.org/0000-0001-6438-286X)
- Hai Li (ORCID: https://orcid.org/0000-0002-3304-1429)
Institutions
- Columbia University Irving Medical Center (US)
- Azienda Ospedaliera San Gerardo (IT)
- High Throughput Biology (United States) (US)
- Istituti di Ricovero e Cura a Carattere Scientifico (IT)
- University of Milano-Bicocca (IT)
- Columbia University (US)
Publication Details
- Journal
- Scientific Reports
- Published
- 2024-08-20
- DOI
- https://doi.org/10.1038/s41598-024-70294-w
- Citations
- 5
- Primary Topic
- Cancer Treatment and Pharmacology
- Type
- article
- Field-Weighted Citation Impact
- 1.41
Funders
- Fondazione Cariplo
- Associazione Italiana per la Ricerca sul Cancro