ROS-responsive fluorinated polyethyleneimine vector to co-deliver shMTHFD2 and shGPX4 plasmids induces ferroptosis and apoptosis for cancer therapy

Yang, Shuaijun; Wong, Ka Hong; Hua, Peng; He, Chengwei; Yu, Hua; Shao, Dan; Shi, Zhi; Chen, Meiwan

doi:10.1016/j.actbio.2021.11.042

Cited by 59 publications

(28 citation statements)

References 29 publications

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“…Chemotherapy is the principal treatment modality for malignant tumors in clinic, and most of chemotherapeutic drugs exert their anticancer efficacy by activating caspase‐related apoptotic pathways. [ 1 ] However, its curative effect is often unsatisfactory due to the intrinsic or acquired resistance of tumor cells to apoptosis. For example, in malignant cells, the overexpressed anti‐apoptotic protein always causes poor response to apoptotic cell death, and the multi‐drug resistance effect frequently occurs as a self‐defense means to combat cellular apoptosis.…”

Section: Introductionmentioning

confidence: 99%

A Hollow Amorphous Bimetal Organic Framework for Synergistic Cuproptosis/Ferroptosis/Apoptosis Anticancer Therapy via Disrupting Intracellular Redox Homeostasis and Copper/Iron Metabolisms

Qian

Hou

et al. 2022

Adv Funct Materials

140

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Cuproptosis is a very newly recognized regulated cell death modality that is distinct from known death mechanisms and shows enormous prospect in cancer treatment. However, its efficacy is copper-dependent and restricted by strictly regulated copper metabolism. Herein, a novel copper/iron hybrid hollow amorphous metal organic framework (HaMOF) is developed as an oxidative stress amplifier and copper/iron metabolic disrupter for synergistic cuproptosis/ferroptosis/apoptosis anticancer therapy. The HaMOF is fabricated from Cu 2+ , 3,3′-dithiobis(propionohydrazide) and Fe 3+ via an unsaturated coordination-etching integration strategy, and then doxorubicin is loaded followed by surface decoration with hyaluronan. The obtained DOX@ Fe/CuTH exhibits tumor microenvironment-triggered catalytic therapeutic property, wherein it can amplify cellular oxidative stress by simultaneously boosting H 2 O 2 production and depleting glutathione. Moreover, it can cause mitochondrial dysfunction and downregulate the expressions of copper transporter ATP7A and iron transporter FPN 1, thereby leading to metabolic disorders and high retentions of copper/iron in cytoplasm for •OH generation. The overloaded Cu 2+ can cause lipoylated protein dihydrolipoamide S-acetyltransferase aggregation and lead to cellular cuproptosis. Collectively, both augmented oxidative stress and overloaded copper/iron induce potent ferroptosis, which synergizes with cuproptosis and DOX-mediated apoptosis to efficiently suppress tumor growth. This bimetallic hollow nanoplatform provides a new therapeutic modality paradigm to boost cuproptosis-related therapies.

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Section: Introductionmentioning

confidence: 99%

A Hollow Amorphous Bimetal Organic Framework for Synergistic Cuproptosis/Ferroptosis/Apoptosis Anticancer Therapy via Disrupting Intracellular Redox Homeostasis and Copper/Iron Metabolisms

Qian

Hou

et al. 2022

Adv Funct Materials

140

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“…In contrast, knockdown of MTHFD2 expression reduced xenograft tumor growth ( Green et al, 2019 ). This may be associated with modulation of the NADPH to NADP ratio in cancer cells, depleting GSH, and triggering cancer cell apoptosis ( Yang et al, 2022 ). MTHFD2 is also a metabolic checkpoint linking purine metabolism to autoimmune responses ( Sugiura et al, 2022 ).…”

Section: Discussionmentioning

confidence: 99%

A Cluster of Metabolic-Related Genes Serve as Potential Prognostic Biomarkers for Renal Cell Carcinoma

et al. 2022

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Renal cell carcinoma (RCC) is the most common type of renal cancer, characterized by the dysregulation of metabolic pathways. RCC is the second highest cause of death among patients with urologic cancers and those with cancer cell metastases have a 5-years survival rate of only 10–15%. Thus, reliable prognostic biomarkers are essential tools to predict RCC patient outcomes. This study identified differentially expressed genes (DEGs) in the gene expression omnibus (GEO) database that are associated with pre-and post-metastases in clear cell renal cell carcinoma (ccRCC) patients and intersected these with metabolism-related genes in the Kyoto encyclopedia of genes and genomes (KEGG) database to identify metabolism-related DEGs (DEMGs). GOplot and ggplot packages for gene ontology (GO) and KEGG pathway enrichment analysis of DEMGs with log (foldchange) (logFC) were used to identify metabolic pathways associated with DEMG. Upregulated risk genes and downregulated protective genes among the DEMGs and seven independent metabolic genes, RRM2, MTHFD2, AGXT2, ALDH6A1, GLDC, HOGA1, and ETNK2, were found using univariate and multivariate Cox regression analysis, intersection, and Lasso-Cox regression analysis to establish a metabolic risk score signature (MRSS). Kaplan-Meier survival curve of Overall Survival (OS) showed that the low-risk group had a significantly better prognosis than the high-risk group in both the training cohort (p < 0.001; HR = 2.73, 95% CI = 1.97–3.79) and the validation cohort (p = 0.001; HR = 2.84, 95% CI = 1.50–5.38). The nomogram combined with multiple clinical information and MRSS was more effective at predicting patient outcomes than a single independent prognostic factor. The impact of metabolism on ccRCC was also assessed, and seven metabolism-related genes were established and validated as biomarkers to predict patient outcomes effectively.

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“…In addition, to further improve the therapeutic profile, ROS generation combined with GSH depletion can effectively disturb redox homeostasis to augment oxidative stress, thus resulting in tumor cell apoptosis [ 123 ]. ROS are generated by the partial reduction of O 2 which is necessary for maintaining the normal function of aerobic organisms using energy provided from four electron reduction reaction [ 124 – 129 ]. As shown in Table 2 , most efforts have been to develop ROS-responsive building blocks, which can be combined with chemotherapeutics to achieve excellent antitumor activity with few side effects.…”

Section: Stimuli-responsive Targeting Strategiesmentioning

confidence: 99%

Enhancing the therapeutic efficacy of nanoparticles for cancer treatment using versatile targeted strategies

et al. 2022

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Poor targeting of therapeutics leading to severe adverse effects on normal tissues is considered one of the obstacles in cancer therapy. To help overcome this, nanoscale drug delivery systems have provided an alternative avenue for improving the therapeutic potential of various agents and bioactive molecules through the enhanced permeability and retention (EPR) effect. Nanosystems with cancer-targeted ligands can achieve effective delivery to the tumor cells utilizing cell surface-specific receptors, the tumor vasculature and antigens with high accuracy and affinity. Additionally, stimuli-responsive nanoplatforms have also been considered as a promising and effective targeting strategy against tumors, as these nanoplatforms maintain their stealth feature under normal conditions, but upon homing in on cancerous lesions or their microenvironment, are responsive and release their cargoes. In this review, we comprehensively summarize the field of active targeting drug delivery systems and a number of stimuli-responsive release studies in the context of emerging nanoplatform development, and also discuss how this knowledge can contribute to further improvements in clinical practice.

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ROS-responsive fluorinated polyethyleneimine vector to co-deliver shMTHFD2 and shGPX4 plasmids induces ferroptosis and apoptosis for cancer therapy

Cited by 59 publications

References 29 publications

A Hollow Amorphous Bimetal Organic Framework for Synergistic Cuproptosis/Ferroptosis/Apoptosis Anticancer Therapy via Disrupting Intracellular Redox Homeostasis and Copper/Iron Metabolisms

A Hollow Amorphous Bimetal Organic Framework for Synergistic Cuproptosis/Ferroptosis/Apoptosis Anticancer Therapy via Disrupting Intracellular Redox Homeostasis and Copper/Iron Metabolisms

A Cluster of Metabolic-Related Genes Serve as Potential Prognostic Biomarkers for Renal Cell Carcinoma

Enhancing the therapeutic efficacy of nanoparticles for cancer treatment using versatile targeted strategies

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