RRC ID 68769
Author Uchida M, Ushio S, Niimura T, Takechi K, Kawazoe H, Hidaka N, Tanaka A, Araki H, Zamami Y, Ishizawa K, Kitamura Y, Sendou T, Kawasaki H, Namba H, Shibata K, Tanaka M, Takatori S.
Title Renin-Angiotensin-Aldosterone System Inhibitors Prevent the Onset of Oxaliplatin-Induced Peripheral Neuropathy: A Retrospective Multicenter Study and in Vitro Evaluation.
Journal Biol Pharm Bull
Abstract Oxaliplatin (OXA) is used in chemotherapy for various cancer types and is associated with acute and chronic neurotoxicity. However, a preventive strategy for OXA-induced peripheral neuropathy (OIPN) and its underlying mechanism remain unclear. We examined the effects of renin-angiotensin-aldosterone system inhibitors (RAASIs) on OIPN by performing a retrospective multicenter study and an in vitro assay. We retrospectively evaluated electronic medical records of 976 patients who underwent one or more courses of OXA-containing regimens at Ehime, Okayama, and Tokushima University Hospitals. The primary endpoint was the incidence of OIPN during or after OXA administration. The effects of RAASIs and OXA on the neurite length in PC12 cells were determined. The combined administration of an OXA-containing regimen and RAASI significantly inhibited the cumulative incidence grade-2 or higher OIPN (log-rank test; P=0.0001). RAASIs markedly suppressed the development of both acute and chronic OIPN (multivariate analysis; P=0.017 and P=0.011). In an in vitro assay, 10 µM OXA suppressed the neurite length; treatment with 1 μM aliskiren, spironolactone, 10 μM candesartan, and enalapril significantly restored neurite length to the control level. Moreover, 1 μM SCH772984 (a selective inhibitor of extracellular signal-regulated kinase, ERK1/2) and 500 μM SQ22536 (a cell-permeable adenylate cyclase [AC] inhibitor) markedly abolished neuroprotective effects of candesartan and enalapril. These results indicate that RAASIs possess preventive or therapeutic effects in acute and chronic OIPN, candesartan and enalapril may directly increase in the activity of ERK1/2 and AC in PC12 cells.
Volume 45(2)
Pages 226-234
Published 2022-2-1
DOI 10.1248/bpb.b21-00852
PMID 34803077
MeSH Angiotensin II Type 1 Receptor Blockers / pharmacology Angiotensin II Type 1 Receptor Blockers / therapeutic use Angiotensin-Converting Enzyme Inhibitors / pharmacology Angiotensin-Converting Enzyme Inhibitors / therapeutic use Animals Antihypertensive Agents / pharmacology Antihypertensive Agents / therapeutic use Antineoplastic Agents / adverse effects* Calcium Channel Blockers / pharmacology Calcium Channel Blockers / therapeutic use Female Humans Male Neuroprotective Agents / pharmacology Neuroprotective Agents / therapeutic use* Oxaliplatin / adverse effects* PC12 Cells Peripheral Nervous System Diseases / chemically induced* Peripheral Nervous System Diseases / prevention & control* Proportional Hazards Models Rats Renin-Angiotensin System* Retrospective Studies
IF 1.863
Human and Animal Cells PC-12(RCB0009)