Renin-Angiotensin-Aldosterone System Inhibitors Prevent the Onset of Oxaliplatin-Induced Peripheral Neuropathy: A Retrospective Multicenter Study and in Vitro Evaluation

Mami Uchida, Soichiro Ushio, Takahiro Niimura, Kenshi Takechi, Hitoshi Kawazoe, Noriaki Hidaka, Akihiro Tanaka, Hiroaki Araki, Yoshito Zamami, Keisuke Ishizawa, Yoshihisa Kitamura, Toshiaki Sendou, Hiromu Kawasaki, Hiroyuki Namba, Kazuhiko Shibata, Mamoru Tanaka, Shingo Takatori

Research output: Contribution to journalArticlepeer-review

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, 10µM OXA suppressed the neurite length; treatment with 1µM aliskiren, spironolactone, 10µM candesartan, and enalapril significantly restored neurite length to the control level. Moreover, 1µM SCH772984 (a selective inhibitor of extracellular signal-regulated kinase, ERK1/2) and 500µM SQ22536 (a cell-permeable adenylate cyclase (AC) inhibitor) markedly abolished neurite-extending effects of candesartan and enalapril. These results indicate that RAASIs possess preventive or therapeutic effects in acute and chronic OIPN, candesartan and enalapril may increase in the activity of ERK1/2 and AC in PC12 cells.

Original languageEnglish
Pages (from-to)226-234
Number of pages9
JournalBiological and Pharmaceutical Bulletin
Volume45
Issue number2
DOIs
Publication statusPublished - 2022 Feb

Keywords

  • Adenylate cyclase
  • Extracellular signal-regulated kinase 1/2
  • Oxaliplatin-induced peripheral neuropathy
  • PC12 cell
  • Renin-angiotensin-aldosterone system inhibitor

ASJC Scopus subject areas

  • Pharmacology
  • Pharmaceutical Science

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