Regorafenib Alteration of the BCL-xL/MCL-1 Ratio Provides a Therapeutic Opportunity for BH3-Mimetics in Hepatocellular Carcinoma Models

Background: The multikinase inhibitor regorafenib, approved as second-line treatment for hepatocellular carcinoma (HCC) after sorafenib failure, may induce mitochondrial damage. BH3-mimetics, inhibitors of specific BCL-2 proteins, are valuable drugs in cancer therapy to amplify mitochondrial-dependent cell death. Methods: In in vitro and in vivo HCC models, we tested regorafenib’s effect on the BCL-2 network and the efficacy of BH3-mimetics on HCC treatment. Results: In hepatoma cell lines and Hep3B liver spheroids, regorafenib cytotoxicity was potentiated by BCL-xL siRNA transfection or pharmacological inhibition (A-1331852), while BCL-2 antagonism had no effect. Mitochondrial outer membrane permeabilization, cytochrome c release, and caspase-3 activation mediated A-1331852/regorafenib-induced cell death. In a patient-derived xenograft (PDX) HCC model, BCL-xL inhibition stimulated regorafenib activity, drastically decreasing tumor growth. Moreover, regorafenib-resistant HepG2 cells displayed increased BCL-xL and reduced MCL-1 expression, while A-1331852 reinstated regorafenib efficacy in vitro and in a xenograft mouse model. Interestingly, BCL-xL levels, associated with poor prognosis in liver and colorectal cancer, and the BCL-xL/MCL-1 ratio were detected as being increased in HCC patients. Conclusion: Regorafenib primes tumor cells to BH3-mimetic-induced cell death, allowing BCL-xL inhibition with A-1331852 or other strategies based on BCL-xL degradation to enhance regorafenib efficacy, offering a novel approach for HCC treatment, particularly for tumors with an elevated BCL-xL/MCL-1 ratio.

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Curcumin a Multifaceted Compound with Hormetic Behaviour that Mediates an Intricate Crosstalk between Mitochondrial Biogenesis, Mitophagy, Mitophagic Death and Apoptosis

10.20944/preprints201701.0039.v1 ◽

2017 ◽

Cited By ~ 1

Author(s):

Nathan Earl Rainey ◽

Aoula Moustapha ◽

Raphaelle Parker ◽

Patrice Xavier Petit

Keyword(s):

Cell Death ◽

Mitochondrial Biogenesis ◽

Calcium Release ◽

Mitochondrial Outer Membrane ◽

Protective Mechanism ◽

High Dose ◽

M Cell ◽

Mitochondrial Outer Membrane Permeabilization

Curcumin, found in the rhizome of turmeric, has extensive therapeutic promises via its antioxidant, anti-inflammatory, and antiproliferative properties. Preclinical in vitro and in vivo data have shown curcumin to be an effective treatment for multiple cancers. These effects are drived by curcumin's ability to induce G2/M cell cycle arrest, induction of autophagy, activation of apoptotic pathways, disruption of molecular signaling, inhibition of invasion and metastasis, and by increasing the efficacy of existing chemotherapeutics. Here we focused on the hormetic behaviour of curcumin. Frequently, low doses of toxins and other stressors not only are harmless but also activate an adaptive stress whereas high dose activates acute responses like autophagy and cell death. This phenomenon is referred to as hormesis. Many molecules that cause cell death elicite an initial autophagic step that is a cytoprotective mechanism relying on elimination of dysfunctional structures intracellular, notably by mitophagy. This phenomenon is considered as a primarily protective mechanism against stressors. At higher doses, cells undergo mitochondrial outer membrane permeabilization due to calcium release from the endoplasmic reticulum and die. Herein, we address the complex crosstalk between the induced mitochondrial biogenesis, mitochondrial destabilization accompanied by mitophagy and cell death that can also be at play.

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Pyrrolizidine Alkaloids Induce Cell Death in Human HepaRG Cells in a Structure-Dependent Manner

International Journal of Molecular Sciences ◽

10.3390/ijms22010202 ◽

2020 ◽

Vol 22 (1) ◽

pp. 202

Author(s):

Josephin Glück ◽

Julia Waizenegger ◽

Albert Braeuning ◽

Stefanie Hessel-Pras

Keyword(s):

Cell Death ◽

Cell Viability ◽

Pyrrolizidine Alkaloids ◽

Defense Mechanism ◽

Hepatoma Cell ◽

Hepatoma Cell Line ◽

Dependent Manner ◽

Human Hepatoma Cell

Pyrrolizidine alkaloids (PAs) are a group of secondary metabolites produced in various plant species as a defense mechanism against herbivores. PAs consist of a necine base, which is esterified with one or two necine acids. Humans are exposed to PAs by consumption of contaminated food. PA intoxication in humans causes acute and chronic hepatotoxicity. It is considered that enzymatic PA toxification in hepatocytes is structure-dependent. In this study, we aimed to elucidate the induction of PA-induced cell death associated with apoptosis activation. Therefore, 22 structurally different PAs were analyzed concerning the disturbance of cell viability in the metabolically competent human hepatoma cell line HepaRG. The chosen PAs represent the main necine base structures and the different esterification types. Open-chained and cyclic heliotridine- and retronecine-type diesters induced strong cytotoxic effects, while treatment of HepaRG with monoesters did not affect cell viability. For more detailed investigation of apoptosis induction, comprising caspase activation and gene expression analysis, 14 PA representatives were selected. The proapoptotic effects were in line with the potency observed in cell viability studies. In vitro data point towards a strong structure–activity relationship whose effectiveness needs to be investigated in vivo and can then be the basis for a structure-associated risk assessment.

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Antioxidant supplements promote tumor formation and growth and confer drug resistance in hepatocellular carcinoma by reducing intracellular ROS and induction of TMBIM1

Cell & Bioscience ◽

10.1186/s13578-021-00731-0 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Vanilla Xin Zhang ◽

Karen Man-Fong Sze ◽

Lo-Kong Chan ◽

Daniel Wai-Hung Ho ◽

Yu-Man Tsui ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Hepatoma Cell ◽

Tumor Formation ◽

In Vitro Assays ◽

Migration And Invasion ◽

Intracellular Ros ◽

Antioxidant Supplements ◽

Sphere Formation

Abstract Background Controversy over the benefits of antioxidants supplements in cancers persists for long. Using hepatocellular carcinoma (HCC) as a model, we investigated the effects of exogenous antioxidants N-acetylcysteine (NAC) and glutathione (GSH) on tumor formation and growth. Methods Multiple mouse models, including diethylnitrosamine (DEN)-induced and Trp53KO/C-MycOE-induced HCC models, mouse hepatoma cell and human HCC cell xenograft models with subcutaneous or orthotopic injection were used. In vitro assays including ROS assay, colony formation, sphere formation, proliferation, migration and invasion, apoptosis, cell cycle assays were conducted. Western blot was performed for protein expression and RNA-sequencing to identify potential gene targets. Results In these multiple different mouse and cell line models, we observed that NAC and GSH promoted HCC tumor formation and growth, accompanied with significant reduction of intracellular reactive oxygen species (ROS) levels. Moreover, NAC and GSH promoted cancer stemness, and abrogated the tumor-suppressive effects of Sorafenib both in vitro and in vivo. Exogenous supplementation of NAC or GSH reduced the expression of NRF2 and GCLC, suggesting the NRF2/GCLC-related antioxidant production pathway might be desensitized. Using transcriptomic analysis to identify potential gene targets, we found that TMBIM1 was significantly upregulated upon NAC and GSH treatment. Both TCGA and in-house RNA-sequence databases showed that TMBIM1 was overexpressed in HCC tumors. Stable knockdown of TMBIM1 increased the intracellular ROS; it also abolished the promoting effects of the antioxidants in HCC cells. On the other hand, BSO and SSA, inhibitors targeting NAC and GSH metabolism respectively, partially abrogated the pro-oncogenic effects induced by NAC and GSH in vitro and in vivo. Conclusions Our data implicate that exogenous antioxidants NAC and GSH, by reducing the intracellular ROS levels and inducing TMBIM expression, promoted HCC formation and tumor growth, and counteracted the therapeutic effect of Sorafenib. Our study provides scientific insight regarding the use of exogenous antioxidant supplements in cancers.

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Therapeutic Targeting of the Bcl2 Family

Blood ◽

10.1182/blood.v122.21.sci-42.sci-42 ◽

2013 ◽

Vol 122 (21) ◽

pp. SCI-42-SCI-42

Author(s):

Anthony Letai ◽

Matthew S. Davids ◽

Triona Ni Chonghaile ◽

Jing Deng ◽

Luv Patel

Keyword(s):

Cell Death ◽

Cancer Cells ◽

Cancer Cell ◽

Lymphoblastic Leukemia ◽

Lymphocytic Leukemia ◽

Mitochondrial Outer Membrane ◽

Short Term ◽

Provocative Test ◽

Mitochondrial Outer Membrane Permeabilization

Abstract Many, perhaps most, cancer chemotherapy agents kill cancer cells via the mitochondrial pathway of apoptosis that is controlled by the Bcl-2 family of proteins. Bcl-2 family proteins regulate commitment to cell death by controlling mitochondrial outer membrane permeabilization (MOMP). To better understand how cancer cells commit to apoptosis, and what drugs might make them commit to apoptosis, we have studied perturbing mitochondria with BH3 peptides that are derived from pro-death Bcl-2 family proteins. Using this provocative test, which we call BH3 profiling, we are able to measure how close a cell is to the threshold of apoptosis, a property we call “priming”. Priming corresponds to sensitivity to chemotherapy. Moreover, BH3 profiling can be used to detect dependence on Bcl-2 and Bcl-xL for survival, which predicts cytotoxic response to small molecule antagonists such as ABT-199 and ABT-263. In acute lymphoblastic leukemia, we find that dependence on either Bcl-2 or Bcl-xL varies from case to case, with very important consequences for sensitivity to ABT-199 and ABT-263. In chronic lymphocytic leukemia, ABT-199 has already demonstrated significant clinical activity that corresponds to its on-target activity in mitochondria in vitro. We have been testing how this in vitro mitochondrial activity in BH3 profiling assays might be translated into a useful clinical predictive biomarker. Finally, we can measure how short term incubation with many kinds of drugs, including targeted pathway inhibitors, can increase cancer cell priming, including for primary lymphoid malignancy cells. This short term increase in priming predicts subsequent cancer cell death, including in clinical treatment. We call this method “Dynamic BH3 Profiling” and are exploring how it might best be utilized in the clinic. Disclosures: Letai: Dana-Farber Cancer Institute: Patents & Royalties; AbbVie: Consultancy.

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A study of the mechanism of lncRNA-CR594175 in regulating proliferation and invasion of hepatocellular carcinoma cells in vivo and in vitro

10.21203/rs.3.rs-15470/v3 ◽

2020 ◽

Author(s):

Quan Liu ◽

Xuxu Yu ◽

Minjie Yang ◽

Xiangke Li ◽

Xuejia Zhai ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

High Throughput Screening ◽

Hepatoma Cell ◽

Screening Method ◽

Negative Regulation ◽

Hepatoma Cell Line ◽

Incidence And Mortality ◽

Proliferation And Invasion

Abstract Abstract Background Hepatocellular carcinoma (HCC) is one of the cancers of highest incidence and mortality worldwide. The proliferation and invasion of tumor cells are the main reason for poor prognosis after HCC surgery. Long non-coding RNA (lncRNA) has been shown to play a key role in the progression of HCC. LncRNA-CR594175 is one of the highly expressed lncRNAs in HCC tumors and their metastatic tumors that we have obtained by the High-throughput screening method.Methods To elucidate the role of lncRNA-CR594175 in regulating the proliferation and invasion of human hepatoma cell line, HepG2, we operated through lncRNA-CR594175 silencing to inhibit the progression of HCC, either through in vitro or in vivo experiments.Results We found that lncRNA-CR594175 was lower in adjacent non-cancerous tissues than in primary HCC, and was lower in primary HCC than in its metastasis. Silencing of lncRNA-CR594175 inhibited the proliferation and invasion of HepG2 cells and growth of subcutaneous tumors. The results revealed that lncRNA-CR594175, as a RNA sponge, broke the negative regulation of hsa-miR-142-3p on Catenin, beta-1 (CTNNB1), and once lncRNA-CR594175 was silenced, the hsa-miR142-3p regained its negative regulation on CTNNB1 which can promote HCC progression by activating the wnt pathway. Conclusions Our present study demonstrated for the first time that lncRNA-CR594175 silencing suppressed proliferation and invasion of HCC cells in vivo and in vitro by restoring the negative regulation of hsa-miR-142-3p on CTNNB1, laying a solid theoretical base for using lncRNA-CR594175 as genetic target therapy for HCC and offering a reasonable explanation for inactivation of miRNA in different tumors or in the tumor at different stages.

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Protein Kinase B Inactivation Is Associated with Magnolol-Enhanced Therapeutic Efficacy of Sorafenib in Hepatocellular Carcinoma In Vitro and In Vivo

Cancers ◽

10.3390/cancers12010087 ◽

2019 ◽

Vol 12 (1) ◽

pp. 87 ◽

Cited By ~ 3

Author(s):

Jiann-Hwa Chen ◽

I-Tsang Chiang ◽

Fei-Ting Hsu

Keyword(s):

Hepatocellular Carcinoma ◽

Protein Kinase ◽

Protein Kinase B ◽

Bioactive Compound ◽

Critical Issue ◽

Akt Inhibitor ◽

Multikinase Inhibitor ◽

Therapeutic Benefits

Although sorafenib, an oral multikinase inhibitor, was approved as a treatment drug of advance hepatocellular carcinoma (HCC), treatment efficacy still requires improvement. Searching for the adjuvant reagent for enhancing sorafenib efficacy remains as a critical issue. Sorafenib has been proved to suppress extracellular signal-regulated kinases (ERK) in HCC; however, protein kinase B (AKT) was not affected by it. Targeting AKT in combination with sorafenib could be an important breakthrough point of HCC treatment. Many herbal compounds and composite formulas have been shown to enhance anti-HCC activity of sorafenib. Magnolol is a bioactive compound extracted from the bark of the Magnolia officinalis and has been shown to induce apoptosis and inhibit cell invasion in HCC in vitro. However, whether magnolol sensitizes HCC to sorafenib is ambiguous. In this study, we indicated that magnolol significantly enhanced sorafenib-diminished tumor cell growth, expression of anti-apoptotic proteins, and migration/invasion ability compared to sorafenib alone. Magnolol significantly boosted sorafenib-induced extrinsic/intrinsic dependent apoptosis pathways in HCC. Notably sorafenib could not reduce protein level of AKT (Ser473), but expression of AKT (Ser473) was significantly decreased by magnolol or magnolol combined with sorafenib. LY294002 as specific AKT inhibitor was used to confirm that AKT inactivation may promote anticancer effect of sorafenib. Taken together, AKT inhibition is associated with magnolol-enhanced the therapeutic effect of sorafenib in HCC. We suggested magnolol as the potential adjuvant which may enhance therapeutic benefits of sorafenib in patients with HCC.

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Abstract 1950: Role of Superoxide, Nitric Oxide and Peroxynitrite in Doxorubicin-induced Cell Death in vitro and in vivo

Circulation ◽

10.1161/circ.116.suppl_16.ii_420-a ◽

2007 ◽

Vol 116 (suppl_16) ◽

Author(s):

Partha Mukhopadhyay ◽

Mohanraj Rajesh ◽

Sandor Bátkai ◽

György Haskó ◽

Csaba Szabo ◽

...

Keyword(s):

Cell Death ◽

Caspase 3 ◽

Superoxide Generation ◽

Cytochrome C Release ◽

Mitochondrial Superoxide ◽

Induced Apoptosis ◽

Peroxynitrite Scavengers

Although doxorubicin (DOX) is one of the most potent antitumor agents available, its clinical use is limited because of the risk of severe cardiotoxicity often leading to irreversible congestive heart failure. Apoptotic cell death is a key component in DOX-induced cardiotoxicity, but its trigger(s) and mechanisms are poorly understood. Here, we explore the role of peroxynitrite (a reactive oxidant produced from the diffusion-controlled reaction between nitric oxide and superoxide anion) in DOX-induced cell death. Using a well-established in vivo mouse model of DOX-induced acute heart failure, we demonstrate marked increases in myocardial apoptosis (caspase-3 and 9 gene expression, caspase 3 activity, cytochrome-c release, and TUNEL), iNOS but not eNOS and nNOS expression, 3-nitrotyrosine formation and a decrease in myocardial contractility following DOX treatment. Pre-treatment of mice with peroxynitrite scavengers markedly attenuated DOX-induced myocardial cell death and dysfunction without affecting iNOS expression. DOX induced increased superoxide generation and nitrotyrosine formation in the mitochondria, dissipation of mitochondrial membrane potential, apoptosis (cytochrome-C release, annexin V staining, caspase activation, nuclear fragmentation), and disruption of actin cytoskeleton structure in cardiac-derived H9c2 cells. Selective iNOS inhibitors attenuated DOX-induced apoptosis, without affecting increased mitochondrial superoxide generation, whereas NO donors increased DOX-induced cell death in vitro . The peroxynitrite scavengers FeTMPyP and MnTMPyP markedly reduced both DOX- or peroxynitrite-induced nitrotyrosine formation and cell death in vitro , without affecting DOX-induced increased mitochondrial superoxide formation. Thus, peroxynitrite is a major trigger of DOX-induced apoptosis, and its effective neutralization can be of significant therapeutic benefit.

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Non-genotoxic hepatocarcinogenesis in vitro: the FaO hepatoma line responds to peroxisome proliferators and retains the ability to undergo apoptosis

Journal of Cell Science ◽

10.1242/jcs.104.2.307 ◽

1993 ◽

Vol 104 (2) ◽

pp. 307-315 ◽

Cited By ~ 1

Author(s):

A.C. Bayly ◽

N.J. French ◽

C. Dive ◽

R.A. Roberts

Keyword(s):

Cell Death ◽

Cell Line ◽

Cell Lines ◽

Hepatoma Cell ◽

Hepatoma Cell Line ◽

Peroxisome Proliferator ◽

Peroxisome Proliferators ◽

Hepatoma Cell Lines

A range of hepatoma cell lines (RH1, HTC, FaO, 7800C1 and MH1C1), has been studied with the aim of establishing an in vitro model to investigate the molecular mechanisms of hepatocarcinogenicity induced by the peroxisome proliferator class of non-genotoxic carcinogens. In view of speculation that peroxisome proliferators suppress hepatocyte apoptosis in vivo, we have placed particular emphasis on evaluating whether hepatoma cell lines retain the ability to undergo apoptotic cell death. Expression of the liver-specific differentiation marker albumin and the peroxisome proliferator-activated receptor (PPAR) was highest in the Reuber hepatoma cell line, FaO. This cell line also demonstrated the most marked response to the peroxisome proliferator nafenopin with a 2.2-fold induction of the microsomal enzyme cytochrome p450IVA1. This response was found to display intercellular heterogeneity by immunocytochemistry. Thus, the FaO cell line maintained characteristics of hepatocytes, both in vivo and in vitro, in terms of expression of constitutive and inducible markers. However, none of the cell lines tested mirrored the hyperplastic response of hepatocytes to nafenopin, since no increase in cell growth kinetics was observed on addition of nafenopin to the growth medium. The mode of cell death in confluent FaO cultures was characterised as apoptosis, by fluorescence microscopy and agarose gel electrophoresis of extracted DNA. Cells detaching from confluent FaO cultures exhibited chromatin condensation and DNA fragmentation patterns characteristic of cels undergoing apoptotic death.Interestingly, no apoptosis was seen in monolayer cells, suggesting that apoptosis in vitro is associated with cell shrinkage and detachment similar to that documented for the liver in vivo.(ABSTRACT TRUNCATED AT 250 WORDS)

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CASK Silence Enhances Chemosensitivity of Hepatocellular Carcinoma Through activating Apoptosis, Inducing JNK/c-Jun-Mediated Autophagic Cell Death and Decreasing ABCG2

10.21203/rs.3.rs-152447/v1 ◽

2021 ◽

Author(s):

BiSha Ding ◽

Chang Bao ◽

Luqi Jin ◽

Liang Xu ◽

Zhijun Dai ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Drug Resistance ◽

Cell Death ◽

Molecular Mechanisms ◽

Autophagic Cell Death ◽

Cell Counting ◽

Advanced Hepatocellular Carcinoma ◽

Sorafenib Treatment

Abstract Background: Advanced hepatocellular carcinoma (HCC) patients usually fail to be treated because of drug resistance, including sorafenib. Methods: The expression and prognostic role of calcium/calmodulin-dependent serine protein kinase (CASK) in HCC were assessed by combination of bioinformatic analysis and experimental validation. The effects of CASK in regulating proliferation, apoptosis and drug resistance of HCC cells in vitro and in vivo were investigated using gain- or loss-of-function strategies by performing lots of specific methods including Cell Counting kit-8 (CCK8), colony formation assay, flow cytometry, transmission electron microscopy, immunofluorescent confocal laser microscopy and tumor xenograft experiments, immunohistochemistry staining. Moreover, the underlying molecular mechanisms responsible for CASK’s functions in HCC were also explored. Results: Currently, we discovered that CASK was positively associated with sorafenib resistance of HCC in vitro and in vivo, and was significantly related with poor prognosis in HCC. Moreover, inhibition of CASK can increase the effect of sorafenib partially by promoting apoptosis and autophagy, while CASK overexpression presented the opposite results. Besides, all the pan-caspase inhibitor Z-VAD-FMK, autophagy inhibitor 3-Methyladenine (3-MA) and small interfering RNA (siRNA) of LC3B reversed CASK knockout-induced effects with sorafenib treatment, suggesting that both apoptosis and autophagy were involved in CASK-mediated above functions and autophagy played a pro-death role in this research. Intriguingly, similar results were observed in vivo. In molecular level, CASK knockout activated the c-Jun N-terminal kinase (JNK) pathway, and treatment with JNK inhibitor SP600125 or transiently transfected with si-JNK significantly attenuated CASK knockout-mediated autophagic cell death. Besides, knockout of CASK dramatically inhibited the expression of ATP binding cassette subfamily G member 2 (ABCG2) and reversed of multidrug-resistance (MDR) of HCC. Conclusions: Collectively, all these results together indicated that CASK might be a promising biomarker for HCC patients and a potential therapeutic target for relieving drug resistance of HCC.

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Self-amplification of oxidative stress with tumour microenvironment-activatable iron-doped nanoplatform for targeting hepatocellular carcinoma synergistic cascade therapy and diagnosis

Journal of Nanobiotechnology ◽

10.1186/s12951-021-01102-0 ◽

2021 ◽

Vol 19 (1) ◽

Author(s):

Qiao-Mei Zhou ◽

Yuan-Fei Lu ◽

Jia-Ping Zhou ◽

Xiao-Yan Yang ◽

Xiao-Jie Wang ◽

...

Keyword(s):

Magnetic Resonance Imaging ◽

Hepatocellular Carcinoma ◽

Hydrogen Peroxide ◽

Cell Death ◽

Magnetic Resonance ◽

Tumour Microenvironment ◽

Chemotherapeutic Agents ◽

Resonance Imaging

Abstract Background Hepatocellular carcinoma is insensitive to many chemotherapeutic agents. Ferroptosis is a form of programmed cell death with a Fenton reaction mechanism. It converts endogenous hydrogen peroxide into highly toxic hydroxyl radicals, which inhibit hepatocellular carcinoma progression. Methods The morphology, elemental composition, and tumour microenvironment responses of various organic/inorganic nanoplatforms were characterised by different analytical methods. Their in vivo and in vitro tumour-targeting efficacy and imaging capability were analysed by magnetic resonance imaging. Confocal microscopy, flow cytometry, and western blotting were used to investigate the therapeutic efficacy and mechanisms of complementary ferroptosis/apoptosis mediated by the nanoplatforms. Results The nanoplatform consisted of a silica shell doped with iron and disulphide bonds and an etched core loaded with doxorubicin that generates hydrogen peroxide in situ and enhances ferroptosis. It relied upon transferrin for targeted drug delivery and could be activated by the tumour microenvironment. Glutathione-responsive biodegradability could operate synergistically with the therapeutic interaction between doxorubicin and iron and induce tumour cell death through complementary ferroptosis and apoptosis. The nanoplatform also has a superparamagnetic framework that could serve to guide and monitor treatment under T2-weighted magnetic resonance imaging. Conclusion This rationally designed nanoplatform is expected to integrate cancer diagnosis, treatment, and monitoring and provide a novel clinical antitumour therapeutic strategy. Graphical Abstract

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