Fisetin attenuates doxorubicin‐induced cardiotoxicity by inhibiting the insulin‐like growth factor II receptor apoptotic pathway through estrogen receptor‐α/‐β activation

Abstract

Doxorubicin (DOX), an effective chemotherapeutic drug, has been used to treat various cancers; however, its cardiotoxic side effects restrict its therapeutic efficacy. Fisetin, a flavonoid phytoestrogen derived from a range of fruits and vegetables, has been reported to exert cardioprotective effects against DOX‐induced cardiotoxicity; however, the underlying mechanisms remain unclear. This study investigated fisetin's cardioprotective role and mechanism against DOX‐induced cardiotoxicity in H9c2 cardiomyoblasts and ovariectomized (OVX) rat models. MTT assay revealed that fisetin treatment noticeably rescued DOX‐induced cell death in a dose‐dependent manner. Moreover, western blotting and TUNEL‐DAPI staining showed that fisetin significantly attenuated DOX‐induced cardiotoxicity in vitro and in vivo by inhibiting the insulin‐like growth factor II receptor (IGF‐IIR) apoptotic pathway through estrogen receptor (ER)‐α/‐β activation. The echocardiography, biochemical assay, and H&E staining results demonstrated that fisetin reduced DOX‐induced cardiotoxicity by alleviating cardiac dysfunction, myocardial injury, oxidative stress, and histopathological damage. These findings imply that fisetin has a significant therapeutic potential against DOX‐induced cardiotoxicity.

Sensitizing Chemotherapy for Glioma with Fisetin mediated by Microenvironment-responsive Nano-drug Delivery System

“…Although setin has a variety of pharmacological activities, the bioavailability of setin is severely limited due to its hydrophobicity, and no clinical applications for setin combination therapy were reported. Lin K. et al proved that avonoids, including setin, could alleviate cardiotoxicity caused by doxorubicin [40]. These ndings indicate that setin has potential bene ts for reducing DOX-induced cardiac toxicity, making this combinational strategy promising to increase therapeutic effects while decreasing adverse reactions.…”

Sensitizing chemotherapy for glioma with fisetin mediated by a microenvironment-responsive nano-drug delivery system

“…K. H. Lin et al proved that flavonoids, including fisetin, could alleviate cardiotoxicity caused by doxorubicin. 18 These findings indicate that fisetin has potential benefits for reducing DOX-induced cardiac toxicity, making this combinational strategy promising to increase therapeutic effects while decreasing adverse reactions. Therefore, the combination of chemotherapeutic drugs with fisetin could hopefully become a novel strategy in enhancing chemotherapy and solving drug resistance.…”