AUTHOR=Bloomingdale Peter , Meregalli Cristina , Pollard Kevin , Canta Annalisa , Chiorazzi Alessia , Fumagalli Giulia , Monza Laura , Pozzi Eleonora , Alberti Paola , Ballarini Elisa , Oggioni Norberto , Carlson Louise , Liu Wensheng , Ghandili Mehrnoosh , Ignatowski Tracey A. , Lee Kelvin P. , Moore Michael J. , Cavaletti Guido , Mager Donald E. TITLE=Systems Pharmacology Modeling Identifies a Novel Treatment Strategy for Bortezomib-Induced Neuropathic Pain JOURNAL=Frontiers in Pharmacology VOLUME=12 YEAR=2022 URL=https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2021.817236 DOI=10.3389/fphar.2021.817236 ISSN=1663-9812 ABSTRACT=

Chemotherapy-induced peripheral neurotoxicity is a common dose-limiting side effect of several cancer chemotherapeutic agents, and no effective therapies exist. Here we constructed a systems pharmacology model of intracellular signaling in peripheral neurons to identify novel drug targets for preventing peripheral neuropathy associated with proteasome inhibitors. Model predictions suggested the combinatorial inhibition of TNFα, NMDA receptors, and reactive oxygen species should prevent proteasome inhibitor-induced neuronal apoptosis. Dexanabinol, an inhibitor of all three targets, partially restored bortezomib-induced reduction of proximal action potential amplitude and distal nerve conduction velocity in vitro and prevented bortezomib-induced mechanical allodynia and thermal hyperalgesia in rats, including a partial recovery of intraepidermal nerve fiber density. Dexanabinol failed to restore bortezomib-induced decreases in electrophysiological endpoints in rats, and it did not compromise bortezomib anti-cancer effects in U266 multiple myeloma cells and a murine xenograft model. Owing to its favorable safety profile in humans and preclinical efficacy, dexanabinol might represent a treatment option for bortezomib-induced neuropathic pain.