Tumor killing by a dietary curcumin mono-carbonyl analog that works as a selective ROS generator via TrxR inhibition

Li, Xuefeng; Cui, Hongmei; Li, Mi; Chai, Zuo-Hu; Wang, Haibo; Jin, Xiaojie; Dai, Fang; Liu, Yongqi; Zhang, Bo

doi:10.1016/j.ejmech.2023.115191

Cited by 9 publications

(7 citation statements)

References 48 publications

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“…Remarkably, 2c demonstrates robust in vivo antitumor efficacy against NCI‐H460 tumors in mice, surpassing the effectiveness of both curcumin and 5‐FU, all while maintaining a favorable safety profile. These findings underscore the pivotal role of TrxR in orchestrating the selective induction of ferroptotic cell death by 2c in lung cancer cells through the targeted generation of ROS (Liu, Cui, et al, 2023).…”

Section: Curcumin and Ferroptosis In Cancermentioning

confidence: 72%

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Induction of ferroptosis by natural phenols: A promising strategy for cancer therapy

Zhang,

Xie

2024

Phytotherapy Research

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In recent years, heightened interest surrounds the exploration of natural phenols as potential agents for cancer therapy, specifically by inducing ferroptosis, a unique form of regulated cell death characterized by iron‐dependent lipid peroxidation. This review delves into the roles of key natural phenols, flavonoids, phenolic acids, curcumin, and stilbenes, in modulating ferroptosis and their underlying mechanisms. Emphasizing the significance of amino acid, lipid, and iron metabolism, the study elucidates the diverse pathways through which these phenols regulate ferroptosis. Notably, curcumin, a well‐known polyphenol, exhibits multifaceted interactions with cellular components involved in ferroptosis regulation, providing a distinctive therapeutic avenue. Stilbenes, another phenolic class, demonstrate promising potential in influencing lipid metabolism and iron‐dependent processes, contributing to ferroptotic cell death. Understanding the intricate interplay between these natural phenols and ferroptosis not only illuminates complex cellular regulatory networks but also unveils potential avenues for novel cancer therapies. Exploring these compounds as inducers of ferroptosis presents a promising strategy for targeted cancer treatment, capitalizing on the delicate balance between cellular metabolism and regulated cell death mechanisms. This article synthesizes current knowledge, aiming to stimulate further research into the therapeutic potential of natural phenols in the context of ferroptosis‐mediated cancer therapy.

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Section: Curcumin and Ferroptosis In Cancermentioning

confidence: 72%

“…The curcumin mono-carbonyl analog, denoted as 2c, exhibits potent induction of ferroptosis in large-cell lung cancer, with its primary mode of action involving the selective targeting of thioredoxin reductase (TrxR). This compound Cui, et al, 2023).…”

Section: Gpx4mentioning

confidence: 97%

Induction of ferroptosis by natural phenols: A promising strategy for cancer therapy

Zhang,

Xie

2024

Phytotherapy Research

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“…Non-small cell lung cancer cell lines showed marked increases in apoptosis and ferroptosis driven by the analogs ability to generate ROS through TrxR inhibition. 65 The analog WZ26 increased ROS and cell death in cholangiocarcinoma via STAT3 inhibition and L48H37 was found to have similar results and induced ER-stress in human lung cancer cells. 66 , 67 An allylated mono-carbonyl Cur analog (CA6) showed effectiveness against gastric cancer cells through TrxR1 inhibition and ROS-dependent apoptotic death.…”

Section: Curcumin In Cancer Therapymentioning

confidence: 90%

Oxidative Stress and Cancer: Harnessing the Therapeutic Potential of Curcumin and Analogues Against Cancer

Lambring,

Chen,

Nelson

et al. 2023

ejb

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Reactive oxygen species (ROS) are a class of bioactive molecules that are the by-products of many cellular functions. These molecules are present in normal cells at homeostatic levels but have been studied extensively in cancer due to their dysregulation resulting in pro- and anti-tumorigenic environments. Completely understanding the paradoxical nature of ROS in cancer is imperative to fully realize its modulation as cancer therapy. Studies into ROS have shown far-reaching effects in cancer, including how ROS levels regulate signaling, response to treatment, drug resistance, etc. Many drugs were studied with the hopes of regulating the ROS levels in cancer; however, patient response varied. Plant-derived medications offered new avenues of drug treatment over the last few decades, and the phytochemical Curcumin gained ground as an interesting cancer therapeutic. Curcumin is an active phenolic compound used in traditional medicine around the world. Although it suffers from a poor pharmacokinetic profile, Curcumin exerts anti-tumorigenic, as well as ROS-modulating activities. Analogs and derivatives of Curcumin are under development to improve upon its anti-cancer properties and enhance its bioavailability, currently a major limitation of its usage. This review highlights ROS function in cancer treatment focused on ROS, including Curcumin and its analogs.

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“…It is imperative to utilize a more specific TrxR inhibitor, such as TRi-1 [ 81 ], to validate the selectivity of TRFS-green [ 79 , 80 , 82 ]. While TRFS-green has been prevalently applied in many studies to probe the cellular status of TrxR [ 83 , 84 , 85 , 86 , 87 , 88 , 89 , 90 , 91 , 92 , 93 , 94 , 95 ], caution and reevaluation are warranted in interpreting these findings. This is due to the seminal work by Thorn-Seshold and colleagues, which unequivocally demonstrates the significant contributions of Trxs, Grxs, and TRP14 to the signal generation observed from TRFS-green, in addition to TrxR [ 80 ].…”

Section: The Mammalian Trxr Probesmentioning

confidence: 99%

“…Compounds containing α,β-unsaturated ketone moieties have long been documented as TrxR inhibitors, due to their potential to undergo the Michael addition with reactive Sec residue in the C-terminal active site of TrxR under physiological conditions [ 84 , 130 , 131 , 132 , 133 , 134 , 135 , 136 , 137 , 138 , 139 , 140 ]. Inspired by this interesting chemistry, the Bu group developed an α,β-unsaturated ketone-based fluorogenic probe for the covalent labelling of TrxR ( Figure 9 , TR-green, probe 12) [ 141 ].…”

Section: The Mammalian Trxr Probesmentioning

confidence: 99%

Fluorescent Probes for Mammalian Thioredoxin Reductase: Mechanistic Analysis, Construction Strategies, and Future Perspectives

et al. 2023

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The modulation of numerous signaling pathways is orchestrated by redox regulation of cellular environments. Maintaining dynamic redox homeostasis is of utmost importance for human health, given the common occurrence of altered redox status in various pathological conditions. The cardinal component of the thioredoxin system, mammalian thioredoxin reductase (TrxR) plays a vital role in supporting various physiological functions; however, its malfunction, disrupting redox balance, is intimately associated with the pathogenesis of multiple diseases. Accordingly, the dynamic monitoring of TrxR of live organisms represents a powerful direction to facilitate the comprehensive understanding and exploration of the profound significance of redox biology in cellular processes. A number of classic assays have been developed for the determination of TrxR activity in biological samples, yet their application is constrained when exploring the real-time dynamics of TrxR activity in live organisms. Fluorescent probes offer several advantages for in situ imaging and the quantification of biological targets, such as non-destructiveness, real-time analysis, and high spatiotemporal resolution. These benefits facilitate the transition from a poise to a flux understanding of cellular targets, further advancing scientific studies in related fields. This review aims to introduce the progress in the development and application of TrxR fluorescent probes in the past years, and it mainly focuses on analyzing their reaction mechanisms, construction strategies, and potential drawbacks. Finally, this study discusses the critical challenges and issues encountered during the development of selective TrxR probes and proposes future directions for their advancement. We anticipate the comprehensive analysis of the present TrxR probes will offer some glitters of enlightenment, and we also expect that this review may shed light on the design and development of novel TrxR probes.

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Tumor killing by a dietary curcumin mono-carbonyl analog that works as a selective ROS generator via TrxR inhibition

Cited by 9 publications

References 48 publications

Induction of ferroptosis by natural phenols: A promising strategy for cancer therapy

Induction of ferroptosis by natural phenols: A promising strategy for cancer therapy

Oxidative Stress and Cancer: Harnessing the Therapeutic Potential of Curcumin and Analogues Against Cancer

Fluorescent Probes for Mammalian Thioredoxin Reductase: Mechanistic Analysis, Construction Strategies, and Future Perspectives

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