Inhibition of the NLRP3 inflammasome using MCC950 reduces vincristine-induced adverse effects in an acute lymphoblastic leukemia patient-derived xenograft model

Hana Starobova; Hannah McCalmont; Svetlana Shatunova; Nicolette Tay; Christopher M Smith; Avril Robertson; Ingrid Winkler; Richard B Lock; Irina Vetter

doi:10.1002/hem3.70092

Inhibition of the NLRP3 inflammasome using MCC950 reduces vincristine-induced adverse effects in an acute lymphoblastic leukemia patient-derived xenograft model

Hemasphere. 2025 Mar 18;9(3):e70092. doi: 10.1002/hem3.70092. eCollection 2025 Mar.

Authors

Affiliations

¹ Institute for Molecular Bioscience, The University of Queensland St Lucia Queensland Australia.
² Children's Cancer Institute, Lowy Cancer Research Centre, School of Clinical Medicine, UNSW Medicine & Health, UNSW Centre for Childhood Cancer Research, UNSW Sydney Sydney New South Wales Australia.
³ Mater Research Institute, The University of Queensland South Brisbane Queensland Australia.
⁴ School of Chemistry and Molecular Biosciences The University of Queensland St Lucia Queensland Australia.
⁵ School of Pharmacy and Pharmaceutical Sciences The University of Queensland Woolloongabba Queensland Australia.

Abstract

Vincristine is one of the most important chemotherapeutic drugs used to treat acute lymphoblastic leukemia (ALL). Unfortunately, vincristine often causes severe adverse effects, including sensory-motor neuropathies, weight loss, and overall decreased well-being, that are difficult to control and that decrease the quality of life and survival of patients. Recent studies demonstrate that sensory-motor adverse effects of vincristine are driven by neuroinflammatory processes, including the activation of the Nod-like receptor 3 (NLRP3) inflammasome. In this study, we aimed to test the effects of MCC950, a specific NLRP3 inhibitor, on the prevention of vincristine-induced adverse effects as well as tumor progression and vincristine efficacy in NOD/SCID/interleukin-2 receptor γ-negative mice patient-derived xenografts of ALL. We demonstrate that co-administration of MCC950 effectively prevented the development of mechanical allodynia, motor impairment, and weight loss and significantly improved the overall well-being of the animals without negatively impacting the in vivo efficacy of vincristine as a single agent or in combination with standard-of-care drugs. These results provide proof of principle that the adverse effects of vincristine chemotherapy can be prevented using NLRP3 inflammasome inhibitors and provide new options for the development of effective treatment strategies.