Asian Journal of Pharmaceutical Sciences
·
2021
·
IF 6.598
Yinxian Yang,Shiyi Zuo,Linxiao Li,Xiao Kuang,Jinbo Li,Bingjun Sun,Shujun Wang,Zhonggui He,Jin Sun
Ferroptosis is a new mode of cell death, which can be induced by Fenton reaction-mediated lipid peroxidation. However, the insufficient H 2 O 2 and high GSH in tumor cells restrict the efficiency of Fenton reaction-dependent ferroptosis. Herein, a self-supplying lipid peroxide nanoreactor was developed to co-delivery of doxorubicin (DOX), iron and unsaturated lipid for efficient ferroptosis. By leveraging the coordination effect between DOX and Fe 3+ , trisulfide bond-bridged DOX dimeric prodrug was actively loaded into the core of the unsaturated lipids-rich liposome via iron ion gradient method. First, Fe 3+ could react with the overexpressed GSH in tumor cells, inducing the GSH depletion and Fe 2+ generation. Second, the cleavage of trisulfide bond could also consume GSH, and the released DOX induces the generation of H 2 O 2, which would react with the generated Fe 2+ in step one to induce efficient Fenton reaction-dependent ferroptosis. Third, the formed Fe 3+ /Fe 2+ couple could directly catalyze peroxidation of unsaturated lipids to boost Fenton reaction-independent ferroptosis. This iron-prodrug liposome nanoreactor precisely programs multimodal ferroptosis by integrating GSH depletion, ROS generation and lipid peroxidation, providing new sights for efficient cancer therapy.
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高影响因子
IUBMB LIFE
·
2021
·Vol. 73
·期 9
·1180-1190
·
IF 3.885
Jing Wang,Tao Wang,Yang Zhang,Jiaqi Liu,Jie Song,Yanlong Han,Lihong Wang,Shuang Yang,Lili Zhu,Rui Geng,Weimin Li,Xiaoguang Yu
The induction of ferroptosis is considered a new strategy for cancer treatment. Cytoplasmic polyadenylation element binding protein 1 (CPEB1) is a post-transcriptional regulatory factor, whose low expression has been reported to link to the enhanced metastasis and angiogenesis of gastric cancer (GC). In this study, to explore the role of CPEB1 in ferroptosis, GC cells with overexpressed or silenced CPEB1 expression were treated with erastin, a classic ferroptosis inducer. The results showed that erastin dose-dependently decreased the viability of four GC cell lines (AGS, SNU-1, Hs-746 T, and HGC-27), suggesting that ferroptosis could be triggered in these GC cells. Interestingly, HGC-27 cells overexpressing CPEB1 were more sensitive to erastin, generated more lipid reactive oxygen species (ROS) and malondialdehyde (MDA), and their glutathione peroxidase 4 (Gpx4) expression and GSH content were reduced. Contrarily, CPEB1-silenced AGS cells were more resistant to erastin. Mechanically, we demonstrated that CPEB1 overexpression reduced the expression of twist1, an inhibitor of activating transcription factor 4 (ATF4), thereby activating the ATF4/ChaC Glutathione Specific Gamma-Glutamylcyclotransferase 1 (CHAC1) pathway (CHAC1, a molecule known to induce GSH degradation). Furthermore, re-expression of twist1 in GC cells impaired the effects of CPEB1 overexpression in presence of erastin. Additionally, similar to the in vitro results, the growth-inhibiting effects of erastin on GC xenografted tumors were also augmented by CPEB1 overexpression in vivo. Collectively, we demonstrate that CPEB1 facilitates erastin-induced ferroptosis by inhibiting twist1.
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JOURNAL OF CONTROLLED RELEASE
·
2020
·
IF 7.727
Qingqing Guan,Ruomi Guo,Shihui Huang,Fan Zhang,Jie Liu,Zhiyong Wang,Xi Yang,Xintao Shuai,Zhong Cao
Iron-based nanomaterials as the main ferroptosis-inducing platforms are more promising because iron itself is a key component in the Fenton reaction to produce ROS . However, the Fe dose needs to be very high in order to induce ferroptosis-based cancer treatment using the SPIO NPs. Therefore, it is still of great challenge to enhance the efficacy of ferroptosis-based cancer therapy by associating the iron-based nanomaterials with other components and therapeutic modalities. In this study, sorafenib (SRF) and ultrasmall SPIO nanoparticles were loaded into the mesopores and onto the surface of MPDA NPs to form [email protected] nanoparticles. SPIO loading endowed the system with iron-supply for ferroptosis and made the system MRI-visible. Meanwhile, SRF was able to induce ferroptosis in cancer cells with lower Fe dose. Furthermore, the heat generated by MPDA NPs upon laser irradiation offered a moderate PTT to boost the ferroptosis effect. The [email protected] exhibited biocompatibility highly desirable for in vivo application and superior anticancer therapy via the combination of ferroptosis and photothermal therapy.
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JOURNAL OF CELLULAR PHYSIOLOGY
·
2020
·
IF 5.546
Tao Bai,Ruopeng Liang,Rongtao Zhu,Weijie Wang,Lin Zhou,Yuling Sun
Primary liver cancer is the second most frequent cause of cancer-related deaths. Ferroptosis, a recognized form of regulated cell death, recently gains attention. MicroRNA-214-3p (miR-214) plays a regulatory role in hepatocarcinogenesis. However, the role of miR-214 in cellular ferroptosis is unclear. This study aimed at elucidating whether miR-214 could regulate ferroptosis of liver cancer. In vitro, HepG2 and Hep3B cancer cells were treated with erastin, a ferroptosis inducer, and then erastin was demonstrated to suppress the cell viability. Moreover, pre-miR-214 overexpression caused that HepG2 and Hep3B cells were more susceptible to erastin, whereas anti-miR-214 sponge showed the opposite effect. Additionally, pre-miR-214 overexpression increased the malondialdehyde and reactive oxygen species levels, upregulated Fe 2+ concentration, and decreased glutathione levels in cancer cells exposed to erastin. Further, erastin enhanced the activation of transcription factor 4 (ATF4) in HepG2 and Hep3B cells, and pre-miR-214 overexpression inhibited ATF4 expression. The luciferase reporter data validated ATF4 as a direct target of miR-214. Cancer cells transfected with ATF4 overexpression plasmid rendered lower susceptible to miR-214-induced ferroptotic death. In vivo, erastin significantly reduced the size and weight of xenografted tumors, and miR-214 elevated the ferroptosis-promoting effects of erastin and decreased ATF4 expression. In summary, our study demonstrates that the ferroptosis-promoting effects of miR-214 in hepatoma cells are attributed at least to its inhibitory effects on ATF4, which may provide a new target for therapy of hepatoma regarding ferroptosis.
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高影响因子
MOLECULAR AND CELLULAR BIOCHEMISTRY
·
2020
·Vol. 473
·期 1
·217-228
·
IF 2.795
Wu Xinghan,Liu Chuanliang,Li Zihaoran,Gai Chengcheng,Ding Dejun,Chen Weijuan,Hao Fengyun,Li Wentong
Ferroptosis is a newly discovered form of regulated cell death and characterized by an iron-dependent accumulation of lethal lipid reactive oxygen species (ROS), ferroptosis may exhibit a novel spectrum of clinical activity for cancer therapy. However, the significance of ferroptosis in the context of carcinoma biology is still emerging. Glycogen synthase kinase-3β (GSK-3β) has been found to be a fundamental element in weaking antioxidant cell defense by adjusting the nuclear factor erythroid 2-related factor 2 (Nrf2). In our study, decreased expression of GSK-3β was observed in the cancer tissues of breast cancer patients, results of immunohistochemistry indicated that Nrf2 was highly expressed in low-GSK-3β-expressed breast cancer tissues. The contributions of aberrant expression of GSK-3β and Nrf2 to the erastin-induced ferroptosis in breast cancer were further assessed, silence of GSK-3β blocked erastin-induced ferroptosis with less production of ROS and malondialdehyde (MDA) via upregulation of GPX4 and downregulation of arachidonate 15-lipoxygenase (Alox15), overexpression of GSK-3β enhanced erastin-triggered ferroptosis with elevated ROS and MDA. Enhanced erastin-induced ferroptosis by overexpression of GSK-3β was blocked by activating Nrf2. We further confirmed that overexpression of GSK-3β strengthened erastin-induced tumor growth inhibition in breast cancer xenograft models in vivo. In summary, our findings conclude that modulation the balance between GSK-3β/Nrf2 is a promising therapeutic approach and probably will be important targets to enhance the effect of erastin-induced ferroptosis in breast cancer.
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RSC Advances
·
2020
·Vol. 10
·期 52
·31171-31179
·
IF 3.119
Xiaojian Ouyang,Xican Li,Jie Liu,Yangping Liu,Yulu Xie,Zhongcun Du,Hong Xie,Ban Chen,Wenbiao Lu,Dongfeng Chen
Erastin-treated bone marrow-derived mesenchymal stem cells (bmMSCs) were prepared and used to compare the ferroptosis inhibitory bioactivities of four monostilbenes, including rhapontigenin (1a), isorhapontigenin (1b), piceatannol-3′-O-glucoside (1c), and rhapontin (1d). Their relative levels were 1c ≈ 1b > 1a ≈ 1d in 4,4-difluoro-5-(4-phenyl-1,3-butadienyl)-4-bora-3a,4a-diaza-s-indacene-3-undecanoic acid (C11-BODIPY), 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), and flow cytometric assays. The comparison highlighted two 4′-OH-containing monostilbenes (1c and 1b) in ferroptosis inhibitory bioactivity. Similar structure–activity relationships were also observed in antioxidant assays, including 1,1-diphenyl-2-picryl-hydrazl radical (DPPH˙)-trapping, 2-phenyl-4,4,5,5-tetramethylimidazoline-1-oxyl 3-oxide radical (PTIO˙)-trapping, and Fe3+-reducing assays. UPLC-ESI-Q-TOF-MS analysis of the DPPH˙-trapping reaction of the monostilbenes revealed that they can inhibit ferroptosis in erastin-treated bmMSCs through a hydrogen donation-based antioxidant pathway. After hydrogen donation, these monostilbenes usually produce the corresponding stable dimers; additionally, the hydrogen donation potential was enhanced by the 4′-OH. The enhancement by 4′-OH can be attributed to the transannular resonance effect. This effect can be used to predict the inhibition potential of other π–π conjugative phenolics.
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高影响因子
BIOMATERIALS
·
2022
·
IF 15.304
Qunfang Yang,Tao Liu,Haiping Zheng,Zechen Zhou,Yan Huang,Honglin Jia,Shixiang Fu,Xuan Zhang,Haigang Zhang,Ya Liu,Xiaohong Chen,Wenjun Shan
The efficacy of immunotherapy combined with other therapeutic modalities in the management of cancer has been extensively studied. However, no effective strategy to improve the antitumor effects of immunotherapy at the tumor site has been developed. In this study, we describe a nanoformulation (CP) that integrates ferroptosis-inducing cannabinoid nanoparticles with immunostimulatory Poly(I:C) to enhance antitumor immune responses by activating ferroptosis-immunotherapy pathways. The results indicated that CP nanoformulation effectively induced ferroptosis , cellular immunogenic death, and anti-tumor immune responses which initiate T cell responses leading to the inhibition of established tumors. In addition, CP nanoformulations reversed the tumor immunosuppressive microenvironment and promoted tumor ferroptosis. These results indicated that the self-amplifying nanoformulation may be an effective strategy for broad-spectrum cancer immunotherapy .
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FASEB JOURNAL
·
2022
·Vol. 36
·期 12
·e22665
·
IF 5.834
Yang Zheng,Tiejian Zhao,Jiaru Wang,Ruizhu Jiang,Jinbiao Huang,Weimin Li,Jiahui Wang
To explore the effect of curcumol on autophagy and ferroptosis of hepatic stellate cells, and to clarify the molecular mechanism of its anti-hepatic fibrosis. In the present study, we report that curcumol promotes the death of activated HSCs and reduces the deposition of extracellular matrix. Interestingly, curcumol treatment can trigger ferroptosis to eliminate activated HSCs characterized by iron overload, lipid ROS accumulation, glutathione depletion, and lipid peroxidation. Curcumol promotes HSC autophagy, which may be the key mechanism for its induction of ferroptosis. It is worth noting that the upregulation of nuclear receptor coactivator 4 (NCOA4) may play a key molecular mechanism. NCOA4 mediates the release of iron ions and induces the occurrence of ferroptosis. Overall, curcumol promotes autophagy in hepatic stellate cells, mediates the degradation of NCOA4 and FTH1 complexes, releases iron ions, leads to iron overload, and induces ferroptosis, which may be an important mechanism for its anti-hepatic fibrosis effect.
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高影响因子
Small
·
2022
·Vol. 19
·期 2
·2205024
·
IF 15.153
Jundong Lin,Huikang Yang,Yixun Zhang,Fen Zou,Huichan He,Wenjie Xie,Zhihao Zou,Ren Liu,Qianfeng Xu,Jie Zhang,Guowei Zhong,Yuejiao Li,ZhenFeng Tang,Yulin Deng,Shanghua Cai,Linyao Wang,Yugang Huang,Yangjia Zhuo,Xinqing Jiang,Weide Zhong
Mono-chemotherapy has significant side effects and unsatisfactory efficacy, limiting its clinical application. Therefore, a combination of multiple treatments is becoming more common in oncotherapy. Chemotherapy combined with the induction of ferroptosis is a potential new oncotherapy. Furthermore, polymeric nanoparticles (NPs) can improve the antitumor efficacy and decrease the toxicity of drugs. Herein, a polymeric NP, mPEG -b- PPLGFc@Dox, is synthesized to decrease the toxicity of doxorubicin (Dox) and enhance the efficacy of chemotherapy by combining it with the induction of ferroptosis. First, mPEG -b- PPLGFc@Dox is oxidized by endogenous H 2 O 2 and releases Dox, which leads to an increase of H 2 O 2 by breaking the redox balance. The Fe(II) group of ferrocene converts H 2 O 2 into ·OH, inducing subsequent ferroptosis. Furthermore, glutathione peroxidase 4, a biomarker of ferroptosis, is suppressed and the lipid peroxidation level is elevated in cells incubated with mPEG -b- PPLGFc@Dox compared to those treated with Dox alone, indicating ferroptosis induction by mPEG -b- PPLGFc@Dox. In vivo, the antitumor efficacy of mPEG -b- PPLGFc@Dox is higher than that of free Dox. Moreover, the loss of body weight in mice treated mPEG -b- PPLGFc@Dox is lower than in those treated with free Dox, indicating that mPEG -b- PPLGFc@Dox is less toxic than free Dox. In conclusion, mPEG -b- PPLGFc@Dox not only has higher antitumor efficacy but it reduces the damage to normal tissue.
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INFLAMMATION
·
2023
·
IF 5.1
Ji Hongfei,Zhao Yanyan,Ma Xiaojun,Wu Lina,Guo Feng,Huang Fengjuan,Song Yi,Wang Jiao,Qin Guijun
Diabetic nephropathy (DN) is a common diabetic complication. Studies show that mitophagy inhibition induced-ferroptosis plays a crucial role in DN progression. UHRF1 is associated with mitophagy and is highly expression in DN patients, however, the effect of UHRF1 on DN is still unclear. Thus, in this study, we aimed to investigate whether UHRF1 involves DN development by the mitophagy/ferroptosis pathway. We overexpressed UHRF1 using an adeno-associated virus 9 (AAV9) system in high-fat diet/streptozotocin-induced diabetic mice. Renal function index, pathological changes, mitophagy factors, and ferroptosis factors were detected in vivo . High-glucose cultured human renal proximal tubular (HK-2) cells were used as in vitro models to investigate the mechanism of UHRF1 in DN. We found that diabetic mice exhibited kidney damage, which was alleviated by UHRF1 overexpression. UHRF1 overexpression promoted PINK1-mediated mitophagy and inhibited the expression of thioredoxin interacting protein (TXNIP), a factor associated with mitochondrial dysfunction. Additionally, UHRF1 overexpression alleviated lipid peroxidation and free iron accumulation, and upregulated the expression of GPX4 and Slc7a11, indicating the inhibition effect of UHRF1 overexpression on ferroptosis. We further investigated the mechanism of UHRF1 in the mitophagy/ferroptosis pathway in DN. We found that UHRF1 overexpression promoted PINK1-mediated mitophagy via inhibiting TXNIP expression, thus suppressing ferroptosis. These findings confirmed that upregulation of UHRF1 expression alleviates DN, indicating that UHRF1 has a reno-protective effect against DN.
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高影响因子
NEW JOURNAL OF CHEMISTRY
·
2023
·
IF 3.3
Guili Ge,Hanyu Tu,Dan Wang,Mingjian Chen,Zhaoyang Zeng,Can Guo,Xu Wu,Wei Xiong
Fe-CDs-PEG, leading to the occurrence of excess iron, iron metabolism disorder, GSH consumption, reactive oxygen species (ROS) accumulation, and activated the ferroptosis pathway, can enhance radiotherapy sensitivity by inducing ferroptosis in lung cancer cells. This study provides a new idea for effective therapy of lung cancer.
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EUROPEAN JOURNAL OF PHARMACOLOGY
·
2023
·
IF 5
Jiangbo Nie,Yuhang Ling,Mingchao Jin,Zhuo Chen,Wei Liu,Weiyun Shen,Tianshun Fang,Jianyou Li,Ying He
Osteosarcoma (OS) is a highly fatal bone tumor characterized by high degree of malignancy and early lung metastasis. Traditional chemotherapy fails in improving the efficacy and survival rate of patients with OS. Butyrate (NaBu) has been reported as a new antitumor drug for inhibiting proliferation and inducing apoptosis in various cancer cells. However, the effect of NaBu on the ferroptosis of osteosarcoma is still unknown. This study aimed to investigate whether NaBu promotes erastin-induced ferroptosis in OS cells and to uncover the underlying mechanism. Here, we found that NaBu significantly enhanced erastin-induced ferroptosis in vitro . Compared with the group that erastin used alonely, pre-treating with NaBu exacerbated erastin-meditated GSH depletion, lipid peroxidation, and mitochondrial morphologic changes in OS cells. In a subcutaneous OS model, NaBu combined with erastin significantly reduced tumor growth and increased the levels of 4-HNE. Mechanistically, NaBu downregulated SLC7A11 transcription via regulating ATF3 expression. Overexpression of ATF3 facilitated erastin to induce ferroptosis, while ATF3 knockdown attenuated NaBu-induced ferroptosis sensitivity. In conclusion, our findings revealed a previously unidentified role of NaBu in erastin-induced ferroptosis by regulating SLC7A11, suggesting that NaBu may be a potential therapeutic agent for OS treatment.
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