Alterperylenol as a Novel Thioredoxin Reductase Inhibitor Induces Liver Cancer Cell Apoptosis and Ferroptosis

Abstract

Natural products are a rich resource for discovering innovational drugs. Herein, we isolated and characterized two compounds dihydroalterperylenol (DAP) and alterperylenol (AP) from Alternaria sp. MG1, an endophytic fungus isolated from Vitis quinquangularis, and investigated the underlying antitumor mechanism of AP. Mechanistically, AP inhibits the growth of HepG2 cells by targeting the selenoprotein thioredoxin reductase (TrxR) and ultimately induces cell apoptosis and ferroptosis. Compared to DAP, the α,β-unsaturated carbonyl structure of AP is an indispensable moiety for its antitumor activity and TrxR inhibition. Specifically, inhibition of TrxR causes the extensive reactive oxygen species and consequently results in DNA damage, G2/M cell cycle arrest, and mitochondrial fission. Furthermore, ferroptosis is driven via excess toxic lipid peroxidation and elevation of intracellular iron levels via regulating iron-related proteins. In vivo validation also shows that AP owns anticancer activity in xenograft mice. Collectively, our results disclose a novel natural TrxR inhibitor AP exerting the antitumor effect via inducing cell apoptosis and ferroptosis and evidence that AP is a promising candidate agent for liver carcinoma therapy. The link of TrxR inhibition to ferroptosis further highlights the physiological importance of TrxR in regulating ferroptosis.

Recent progress in biomaterials-driven ferroptosis for cancer therapy

“…This resulted in mitochondrial and DNA damage, induction of endoplasmic reticulum stress, and ultimately autophagy-dependent ferroptosis, while also eliminating gemcitabine-resistant pancreatic cancer. 112 In addition to traditional first-line cancer treatment drugs, researchers have also focused on identifying potential ferroptosis inducers to induce Fenton-like reactions for cancer cell eradication, such as cystathionine β-synthase, 113 corosolic acid (CA), 114 dihydroa-rtemisinin, 115 natural polyketone compounds dihydroxyisoben-zofuran (DAP) and hydroxyisobenzofuran (AP), 116 and indirubin. 117 Lu et al prepared a biodegradable, glutathione-consuming manganese oxide nanomaterial rich in Mn( iii ) and utilized photosynthetic cyanobacteria as an efficient co-therapy platform to increase oxygen content and reduce GSH levels, thereby enhancing the anti-tumour effect.…”

Natural Flavonoids and Ferroptosis: Potential Therapeutic Opportunities for Human Diseases

“…Meanwhile, more attention should be paid to the pharmacokinetic study of natural flavonoids in vivo , and clinical trials should be carried out to further explore their dosage, efficacy, and safety. Interestingly, other bioactive natural products, such as gingerenone A, chlorogenic acid, and alterperylenol, can also serve as regulators of ferroptosis to alleviate various pathological processes. − Overall, natural products, especially flavonoids, show broad application prospects in ferroptosis-related human diseases.…”

Ferroptosis: Potential opportunities for natural products in cancer therapy

“…In addition, natural polyphenols such as alterperylenol, curcumin, and quercetin could enhance ferroptosis in cancer cells by promoting iron overload (H. Chen, Li, et al, 2023;Z. X. Wang, Ma, et al, 2021;J. Xi, Tian, et al, 2022).…”

“…For example, alterperylenol not only increased iron import by increasing TFR1 expression but also decreased iron export via decreasing ferroportin (Fpn) expression, thereby elevating intracellular iron levels and resulting in ferroptosis in liver cancer cells (J. Xi, Tian, et al, 2022).…”

“…Meanwhile, low expression of NEAT1 also induced autophagy by activating the adenosine monophosphate‐activated protein kinase (AMPK)/mammalian target of rapamycin (mTOR) pathway, indicating that gambogenic acid might be an effective inducer of ferroptosis and autophagy. In addition, natural polyphenols such as alterperylenol, curcumin, and quercetin could enhance ferroptosis in cancer cells by promoting iron overload (H. Chen, Li, et al, 2023; Z. X. Wang, Ma, et al, 2021; J. Xi, Tian, et al, 2022). For example, alterperylenol not only increased iron import by increasing TFR1 expression but also decreased iron export via decreasing ferroportin (Fpn) expression, thereby elevating intracellular iron levels and resulting in ferroptosis in liver cancer cells (J. Xi, Tian, et al, 2022).…”