Formononetin ameliorates oxaliplatin-induced peripheral neuropathy via the KEAP1-NRF2-GSTP1 axis

Abstract

Management of oxaliplatin-induced peripheral neuropathy (OIPN) has proven challenging owing to the concern that any OIPN-preventing agents may also decrease the efficacy of the chemotherapeutic agent and fail to reverse established neuronal damage. Nevertheless, targeting redox signaling pathways constitutes a promising therapy in OIPN and we have previously demonstrated the protective role of nuclear factor erythroid-2 related factor 2 (NRF2) in this disorder. Here, we investigated the protective properties of formononetin (FN), a clinical preparation extract, in OIPN. RNA interference experiments revealed that FN protects against OIPN directly through activation of the NRF2 pathway. Further expression profile sequencing showed that FN exerts its protective effect via the NRF2 downstream-oxaliplatin metabolism enzyme, GSTP1. We also demonstrated that FN does not influence the chemotherapeutic function of oxaliplatin, as NRF2 exhibits a different drug metabolic enzyme activation state downstream in colorectal cell lines than that in neurons. Following synthesis of Bio-FN to screen the target binding proteins, we found that FN selectively binds to His129 and Lys131 in the BTB domain of KEAP1. In vivo experiments revealed that FN-induced activation of the NRF2 signaling pathway alleviated the nociceptive sensations in mice. Our findings highlight a new binding mechanism between KEAP1 and isoflavones for activation of the NRF2 system and suggest that pharmacological or therapeutic activation of the NRF2-GSTP1 axis may serve as an effective strategy to prevent or attenuate the progression of OIPN.

Nrf2 Signaling Pathway in Chemoprotection and Doxorubicin Resistance: Potential Application in Drug Discovery

“…It has been reported that activation of Nrf2/HO-1 signaling is in favor of enhancing cell survival upon chemotherapy [75]. What is noteworthy is that phytochemicals such as curcumin [76] and formononetin [77] induce Nrf2/HO-1 signaling in reducing toxicity of oxaliplatin against liver and brain cells. These studies clearly demonstrate that Nrf2 signaling is of importance for alleviation of chemotherapy-mediated side effects.…”

The potential roles of Nrf2/Keap1 signaling in anticancer drug interactions

“…These mechanisms include upregulation of antioxidant and detoxification enzymes, activation of drug efflux transporters, inhibition of drug-induced cellular apoptotic responses and induction of Nrf2-dependent proteasome activity ( Rojo de la Vega et al., 2018 ; Panieri et al., 2020 ). On the other hand, adverse events resulted from anticancer drugs could also be affected by Nrf2/Keap1 signaling in normal tissues ( Yarmohammadi et al., 2020 ; Fang et al., 2020 ). Due to the broad participation of Nrf2/Keap1 signaling in the metabolism of and cellular defense against anticancer drugs in both cancerous and normal cells, it is expected that more and more anticancer drugs would be identified to be sensitive to Nrf2/Keap1 signaling.…”

Herbal formula Huangqi Guizhi Wuwu decoction attenuates paclitaxel-related neurotoxicity via inhibition of inflammation and oxidative stress

“…For instance, paeoniflorin exerts neuroprotective effect by attenuating oxidative stress through Nrf2 activation in diabetic peripheral neuropathy mice [ 24 ]. 6-Gingerol, cinnamic acid, and formononetin have been shown to play antioxidant and anti-inflammatory roles in several neurological diseases, such as ischemic brain damage, Alzheimer’s disease, and oxaliplatin-induced peripheral neuropathy [ 25 – 27 ]. Both KEGG pathway enrichment and network analyses predicted the PI3K-Akt and Toll-like receptor pathways as the key signalling pathways that mediate the protective effect of HGWD against PIPN (Fig.…”