RESUMO
Rationale: Oxaliplatin-induced peripheral neuropathy (OIPN) is a common adverse effect that causes delayed treatment and poor prognosis among colorectal cancer (CRC) patients. However, its mechanism remains elusive, and no effective treatment is available. Methods: We employed a prospective cohort study of adult patients with pathologically confirmed stage III CRC receiving adjuvant chemotherapy with an oxaliplatin-based regimen for investigating OIPN. To further validate the clinical manifestations and identify a potential therapeutic strategy, animal models, and in vitro studies on the mechanism of OIPN were applied. Results: Our work found that (1) consistent with clinical findings, OIPN was observed in animal models. Targeting the enzymatic activity of cathepsin S (CTSS) by pharmacological blockade and gene deficiency strategy alleviates the manifestations of OIPN. (2) Oxaliplatin treatment increases CTSS expression by enhancing cytosol translocation of interferon response factor 1 (IRF1), which then facilitates STIM-dependent store-operated Ca2+ entry homeostasis. (3) The cytokine array demonstrated an increase in anti-inflammatory cytokines and suppression of proinflammatory cytokines in mice treated with RJW-58. (4) Mechanistically, inhibiting CTSS facilitated olfactory receptors transcription factor 1 release from P300/CBP binding, which enhanced binding to the interleukin-10 (IL-10) promoter region, driving IL-10 downstream signaling pathway. (5) Serum CTSS expression is increased in CRC patients with oxaliplatin-induced neurotoxicity. Conclusions: We highlighted the critical role of CTSS in OIPN, which provides a therapeutic strategy for the common adverse side effects of oxaliplatin.
Assuntos
Catepsinas/genética , Neurônios/metabolismo , Animais , Antineoplásicos/efeitos adversos , Antineoplásicos/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Catepsinas/antagonistas & inibidores , Catepsinas/efeitos dos fármacos , Quimioterapia Adjuvante , Estudos de Coortes , Neoplasias Colorretais/tratamento farmacológico , Citocinas/metabolismo , Modelos Animais de Doenças , Inibidores Enzimáticos , Feminino , Fluoruracila/uso terapêutico , Gânglios Espinais , Humanos , Técnicas In Vitro , Leucovorina/uso terapêutico , Masculino , Camundongos , Camundongos Knockout , Microglia/efeitos dos fármacos , Microglia/metabolismo , Terapia de Alvo Molecular , Condução Nervosa , Neurônios/efeitos dos fármacos , Compostos Organoplatínicos/uso terapêutico , Oxaliplatina/efeitos adversos , Oxaliplatina/farmacologia , Doenças do Sistema Nervoso Periférico/induzido quimicamente , Estudos ProspectivosRESUMO
A new lignan glycoside, 4-O-alpha-L-arabinopyranosyl-(1' "-->2' ')-beta-D-apiofuranosyldiphyllin (2), named procumbenoside A, and 11 known compounds were isolated from the whole plant of Justicia procumbens. The structure of 2 was established by spectral analysis and chemical methods. The known compounds justicidin A (1), diphyllin (3), and tuberculatin (4) showed potent cytotoxic effects against a number of cancer cells in vitro. Compounds 1 and 4 also strongly enhanced tumor-necrosis factor-alpha (TNF-alpha) generation from mouse macrophage-like RAW 264.7 cells stimulated with lipopolysaccharide (LPS).