Quercetin as a JAK–STAT inhibitor: a potential role in solid tumors and neurodegenerative diseases

Abstract

The Janus kinase–signal transducer and activator of transcription (JAK–STAT) pathway is involved in many immunological processes, including cell growth, proliferation, differentiation, apoptosis, and inflammatory responses. Some of these processes can contribute to cancer progression and neurodegeneration. Owing to the complexity of this pathway and its potential crosstalk with alternative pathways, monotherapy as targeted therapy has usually limited long-term efficacy. Currently, the majority of JAK–STAT-targeting drugs are still at preclinical stages. Meanwhile, a variety of plant polyphenols, especially quercetin, exert their inhibitory effects on the JAK–STAT pathway through known and unknown mechanisms. Quercetin has shown prominent inhibitory effects on the JAK–STAT pathway in terms of anti-inflammatory and antitumor activity, as well as control of neurodegenerative diseases. This review discusses the pharmacological effects of quercetin on the JAK–STAT signaling pathway in solid tumors and neurodegenerative diseases.

Identification and Validation of RNA Methylation-Related Related Alternative Splicing Gene Signature for Low Grade Glioma to Predict Survival and Immune Landscapes

“…JAK-STAT pathway is constitutively activated in multiple cancers and is connected to cancer progression and antitumor immunity (Brooks and Putoczki 2020; Owen et al 2019). Numerous inhibitors targeting members of the JAK-STAT pathway have been developed (Rah et al 2022;Zalpoor et al 2022). Quercetin acted as a blocker of STAT3 activation pathway and inhibited the growth and migration of glioblastoma (Michaud-Levesque et al 2012).…”

Apoptotic Mechanisms of Quercetin in Liver Cancer: Recent Trends and Advancements

“…It reduced the expression of p-JAK1 and p-STAT3 while it decreased STAT3-dependent activity in many hepato-cancerous cells [ 66 ]. Treatment of cancer cells with 25, 50, and 100 µM doses of quercetin, led to dose-dependent apoptosis of cell lines, which resulted in decreased STAT3 phosphorylation levels [ 67 ]. Similar effects were observed in Huh7 cells where STAT1 levels were regulated by quercetin treatment [ 64 , 67 ].…”

“…Treatment of cancer cells with 25, 50, and 100 µM doses of quercetin, led to dose-dependent apoptosis of cell lines, which resulted in decreased STAT3 phosphorylation levels [ 67 ]. Similar effects were observed in Huh7 cells where STAT1 levels were regulated by quercetin treatment [ 64 , 67 ]. It potentiated the inhibitory effect of IFN-α on hepato-cancer cell proliferation by activating JAK/STAT pathway signaling through inhibiting SHP2 [ 64 ].…”

The Role of Natural Products as Inhibitors of JAK/STAT Signaling Pathways in Glioblastoma Treatment

“…Quercetin (chemically known as 3,3′,4′,5,7-pentahydroxy flavone) is a polyphenolic flavonoid found in a variety of fruits and vegetables [ 104 ]. Because of its anti-inflammatory, antioxidant, and antitumor effects, quercetin has been extensively studied in vitro and in vivo in multiple cancer models including lung, gastric, cervical, breast, prostate, and colon [ 105 – 108 ]. Quercetin has the ability to impact apoptosis and arrest phase G1 cell cycle in tumor cells, through its interaction with cell cycle regulators, including cyclin-dependent kinase- (CDK-) 4 and cyclin D1, activating p53, cytochrome c release, and also inducing caspase 9 and caspase 3 release [ 109 ].…”