bims-glucam 2022-12-04 papers

bims-glucam

Biomed News

on Glutamine cancer metabolism

Issue of 2022‒12‒04
fourteen papers selected by
Sreeparna Banerjee
Middle East Technical University

Glutamine induces remodeling of tight junctions in Caco-2 colorectal cancer cell.
An active glutamine/α-ketoglutarate/HIF-1α axis prevents pregnancy loss by triggering decidual IGF1+GDF15+NK cell differentiation.
Glutamine promotes the proliferation of epithelial cells via mTOR/S6 pathway in oral lichen planus.
Metabolic determinants of tumour initiation.
Glutamine synthetase mRNA releases sRNA from its 3´UTR to regulate carbon/nitrogen metabolic balance in Enterobacteriaceae.
Isotope tracing reveals distinct substrate preference in murine melanoma subtypes with differing anti-tumor immunity.
Amino acid transporter SLC38A5 regulates developmental and pathological retinal angiogenesis.
CRISPR Cas9-mediated ablation of pyruvate carboxylase gene in colon cancer cell line HT-29 inhibits growth and migration, induces apoptosis and increases sensitivity to 5-fluorouracil and glutaminase inhibitor.
Inhibition of glutaminolysis restores mitochondrial function in senescent stem cells.
Two effective models based on comprehensive lipidomics and metabolomics can distinguish BC versus HCs, and TNBC versus Non-TNBC.
Targetting glutaminase to starve lymphoma cells.
PNO1 inhibits autophagy-mediated ferroptosis by GSH metabolic reprogramming in hepatocellular carcinoma.
Editorial: Metabolic reprogramming in breast cancer.
A multifunctional oxidative stress nanoamplifier with ROS amplification and GSH exhaustion for enhanced chemodynamic therapy.

Med Oncol. 2022 Dec 02. 40(1): 32

Glutamine induces remodeling of tight junctions in Caco-2 colorectal cancer cell.

Ching-Ying Huang, Ji-Kai Chen, Wei-Ting Kuo.

  Malignant cells often exhibit significant metabolic alterations, including the utilization of different nutrients to meet energetic and biosynthetic demands. Recent studies have shown that glutamine can support primary colorectal tumor growth and also serve as an alternate energy source during distant metastasis under glucose-limited conditions. However, the overall effects of glutamine on cancer cell physiology are not completely understood. In this study, we investigated how glutamine impacts epithelial integrity in colorectal cancer cells under glucose deprivation. Human colorectal cancer (Caco-2) cells were grown to confluency in transwells and cultured in glucose/pyruvate-free DMEM with various glutamine concentrations (0-50 mM). Cell viability was assessed, and monolayer integrity was examined in terms of transepithelial resistance (TER) and paracellular permeability. Tight junction (TJ) component proteins were examined by immunofluorescence staining and Western blotting. A dose-dependent decrease in TER was observed in Caco-2 cells, but paracellular permeability was not affected after 24 h incubation with glutamine. At the same time, the TJ proteins, zonula occludens (ZO)-1 and Claudin-1, showed lateral undulations and punctate staining patterns accompanied by enlargement of cellular and nuclear sizes. Furthermore, decreased protein levels of ZO-1, but not claudin-1, were found in detergent-insoluble cellular fractions. Notably, the decreased TER and alterations in TJ structure were not associated with cell viability changes. Moreover, the addition of glutamate, which is produced by the first step of glutamine catabolism, had no impact on TER. Our results suggested that the enteral glutamine may play an important role in the regulation of TJ dynamics in colorectal cancer cells.

Keywords:  Colorectal cancer; Glutamine; Tight junction; Transepithelial resistance; Zonula occludens (ZO)-1

DOI:  https://doi.org/10.1007/s12032-022-01896-5
Cell Mol Life Sci. 2022 Nov 30. 79(12): 611

An active glutamine/α-ketoglutarate/HIF-1α axis prevents pregnancy loss by triggering decidual IGF1+GDF15+NK cell differentiation.

Shao-Liang Yang, Hai-Xia Tan, Zhen-Zhen Lai, Hai-Yan Peng, Hui-Li Yang, Qiang Fu, Hai-Yan Wang, Da-Jin Li, Ming-Qing Li.

  Deficiency of decidual NK (dNK) cell number and function has been widely regarded as an important cause of spontaneous abortion. However, the metabolic mechanism underlying the crosstalk between dNK cells and embryonic trophoblasts during early pregnancy remains largely unknown. Here, we observed that enriched glutamine and activated glutaminolysis in dNK cells contribute to trophoblast invasion and embryo growth by insulin-like growth factor-1 (IGF-1) and growth differentiation factor-15 (GDF-15) secretion. Mechanistically, these processes are dependent on the downregulation of EGLN1-HIF-1α mediated by α-ketoglutarate (α-KG). Blocking glutaminolysis with the GLS inhibitor BPTES or the glutamate dehydrogenase inhibitor EGCG leads to early embryo implantation failure, spontaneous abortion and/or fetal growth restriction in pregnant mice with impaired trophoblast invasion. Additionally, α-KG supplementation significantly alleviated pregnancy loss mediated by defective glutaminolysis in vivo, suggesting that inactivated glutamine/α-ketoglutarate metabolism in dNK cells impaired trophoblast invasion and induced pregnancy loss.

Keywords:  Decidual NK cells; GDF-15; Glutamine metabolism; IGF-1; Spontaneous abortion; α-Ketoglutarate

DOI:  https://doi.org/10.1007/s00018-022-04639-x
J Oral Pathol Med. 2022 Dec 02.

Glutamine promotes the proliferation of epithelial cells via mTOR/S6 pathway in oral lichen planus.

Jiaqi Hu, Zihang Ling, Wei Li, Zhangci Su, Jingyi Lu, Qi Zeng, Bin Cheng, Xiaoan Tao.

  BACKGROUND: Although abnormal cell proliferation and apoptosis are associated with the pathogenesis of OLP, the exactly mechanism of which is not yet known. It has been reported that glutamine (Gln) can promote cell proliferation and inhibit apoptosis of various tumor cells. This study aims to evaluate the effect of Gln metabolism on the balance of proliferation and apoptosis in epithelial cells of OLP.METHODS: 30 Human OLP specimens and 11 normal controls were stained by immunohistochemistry (IHC) to detect the levels of proliferation and Gln metabolism related proteins. Then, the critical role of Gln in cell proliferation and apoptosis was determined by Gln deprivation or treatment with glutaminase inhibitor (CB-839) to intervene Gln metabolism in human gingival epithelial cells (HGECs). Cell proliferation was detected using CCK8, p-mTOR and p-S6 proteins were detected using Western Blot, cell apoptosis and cell cycle were detected using flow cytometry, and cell stress was detected using immunofluorescence.
RESULTS: Compared with normal controls, OLP specimens showed higher levels of Ki-67 and Gln metabolism-related proteins, including Gln transporter (ASCT2), glutaminase (GLS), and pathway proteins (p-mTOR and p-S6). In vitro, Gln promoted cell proliferation and simultaneously upregulated the activity of mTOR/S6 pathway. Moreover, rapamycin, an mTOR pathway inhibitor, could effectively block the Gln-induced cell proliferation. MHY1485, an mTOR pathway agonist, could effectively reverse the decline of cell proliferation under Gln deprivation. In addition, inhibiting Gln metabolism caused the accumulation of intracellular ROS and induced cell apoptosis. However, N-acetylcysteine (NAC) reversed this state and then decreased cell apoptosis by eliminating intracellular ROS.
CONCLUSION: Gln metabolism is essential to maintain the balance of proliferation and apoptosis in oral epithelial cells, and inhibition of Gln metabolism may have a beneficial effect on OLP treatment.

Keywords:  S6; cell proliferation; glutamine; mTOR; oral lichen planus

DOI:  https://doi.org/10.1111/jop.13391
Nat Rev Endocrinol. 2022 Nov 29.

Metabolic determinants of tumour initiation.

Julia S Brunner, Lydia W S Finley.

Tumours exhibit notable metabolic alterations compared with their corresponding normal tissue counterparts. These metabolic alterations can support anabolic growth, enable survival in hostile environments and regulate gene expression programmes that promote malignant progression. Whether these metabolic changes are selected for during malignant transformation or can themselves be drivers of tumour initiation is unclear. However, intriguingly, many of the major bottlenecks for tumour initiation - control of cell fate, survival and proliferation - are all amenable to metabolic regulation. In this article, we review evidence demonstrating a critical role for metabolic pathways in processes that support the earliest stages of tumour development. We discuss how cell-intrinsic factors, such as the cell of origin or transforming oncogene, and cell-extrinsic factors, such as local nutrient availability, promote or restrain tumour initiation. Deeper insight into how metabolic pathways control tumour initiation will improve our ability to design metabolic interventions to limit tumour incidence.

DOI: https://doi.org/10.1038/s41574-022-00773-5
Elife. 2022 Nov 28. pii: e82411. [Epub ahead of print]11

Glutamine synthetase mRNA releases sRNA from its 3´UTR to regulate carbon/nitrogen metabolic balance in Enterobacteriaceae.

Masatoshi Miyakoshi, Teppei Morita, Asaki Kobayashi, Anna Berger, Hiroki Takahashi, Yasuhiro Gotoh, Tetsuya Hayashi, Kan Tanaka.

  Glutamine synthetase (GS) is the key enzyme of nitrogen assimilation induced under nitrogen limiting conditions. The carbon skeleton of glutamate and glutamine, 2-oxoglutarate, is supplied from the TCA cycle, but how this metabolic flow is controlled in response to nitrogen availability remains unknown. We show that the expression of the E1o component of 2-oxoglutarate dehydrogenase, SucA, is repressed under nitrogen limitation in Salmonella enterica and E coli. The repression is exerted at the post-transcriptional level by an Hfq-dependent sRNA GlnZ generated from the 3´UTR of the GS-encoding glnA mRNA. Enterobacterial GlnZ variants contain a conserved seed sequence and primarily regulate sucA through base-pairing far upstream of the translation initiation region. During growth on glutamine as the nitrogen source, the glnA 3´UTR deletion mutants expressed SucA at higher levels than the S. enterica and E. coli wild-type strains, respectively. In E. coli, the transcriptional regulator Nac also participates in the repression of sucA. Lastly, this study clarifies that the release of GlnZ from the glnA mRNA by RNase E is essential for the post-transcriptional regulation of sucA. Thus the mRNA coordinates the two independent functions to balance the supply and demand of the fundamental metabolites.

Keywords:  E. coli; S. enterica serovar typhi; infectious disease; microbiology

DOI:  https://doi.org/10.7554/eLife.82411
Cancer Metab. 2022 Dec 01. 10(1): 21

Isotope tracing reveals distinct substrate preference in murine melanoma subtypes with differing anti-tumor immunity.

Xinyi Zhang, Alexandra A Halberstam, Wanling Zhu, Brooks P Leitner, Durga Thakral, Marcus W Bosenberg, Rachel J Perry.

  BACKGROUND: Research about tumor "metabolic flexibility"-the ability of cells to toggle between preferred nutrients depending on the metabolic context-has largely focused on obesity-associated cancers. However, increasing evidence for a key role for nutrient competition in the tumor microenvironment, as well as for substrate regulation of immune function, suggests that substrate metabolism deserves reconsideration in immunogenic tumors that are not strongly associated with obesity.METHODS: We compare two murine models: immunologically cold YUMM1.7 and immunologically-hot YUMMER1.7. We utilize stable isotope and radioisotope tracer-based metabolic flux studies as well as gas and liquid chromatography-based metabolomics analyses to comprehensively probe substrate preference in YUMM1.7 and YUMMER1.7 cells, with a subset of studies on the impact of available metabolites across a panel of five additional melanoma cell lines. We analyze bulk RNA-seq data and identify increased expression of amino acid and glucose metabolism genes in YUMMER1.7. Finally, we analyze melanoma patient RNA-seq data to identify potential prognostic predictors rooted in metabolism.
RESULTS: We demonstrate using stable isotope tracer-based metabolic flux studies as well as gas and liquid chromatography-based metabolomics that immunologically-hot melanoma utilizes more glutamine than immunologically-cold melanoma in vivo and in vitro. Analyses of human melanoma RNA-seq data demonstrate that glutamine transporter and other anaplerotic gene expression positively correlates with lymphocyte infiltration and function.
CONCLUSIONS: Here, we highlight the importance of understanding metabolism in non-obesity-associated cancers, such as melanoma. This work advances the understanding of the correlation between metabolism and immunogenicity in the tumor microenvironment and provides evidence supporting metabolic gene expression as potential prognostic factors of melanoma progression and may inform investigations of adjunctive metabolic therapy in melanoma.
TRIAL REGISTRATION: Deidentified data from The Cancer Genome Atlas were analyzed.

Keywords:  Amino acid; Glucose; Melanoma; Tumor metabolism; Tumor microenvironment

DOI:  https://doi.org/10.1186/s40170-022-00296-7
Elife. 2022 Dec 01. pii: e73105. [Epub ahead of print]11

Amino acid transporter SLC38A5 regulates developmental and pathological retinal angiogenesis.

Zhongxiao Wang, Felix Yemanyi, Alexandra K Blomfield, Kiran Bora, Shuo Huang, Chi-Hsiu Liu, William R Britton, Steve S Cho, Yohei Tomita, Zhongjie Fu, Jian-Xing Ma, Wen-Hong Li, Jing Chen.

  Amino acid (AA) metabolism in vascular endothelium is important for sprouting angiogenesis. SLC38A5 (solute carrier family 38 member 5), an AA transporter, shuttles neutral AAs across cell membrane, including glutamine, which may serve as metabolic fuel for proliferating endothelial cells (ECs) to promote angiogenesis. Here, we found that Slc38a5 is highly enriched in normal retinal vascular endothelium, and more specifically, in pathological sprouting neovessels. Slc38a5 is suppressed in retinal blood vessels from Lrp5-/- and Ndpy/- mice, both genetic models of defective retinal vascular development with Wnt signaling mutations. Additionally, Slc38a5 transcription is regulated by Wnt/β-catenin signaling. Genetic deficiency of Slc38a5 in mice substantially delays retinal vascular development and suppresses pathological neovascularization in oxygen-induced retinopathy modeling ischemic proliferative retinopathies. Inhibition of SLC38A5 in human retinal vascular ECs impairs EC proliferation and angiogenic function, suppresses glutamine uptake, and dampens vascular endothelial growth factor receptor 2. Together these findings suggest that SLC38A5 is a new metabolic regulator of retinal angiogenesis by controlling AA nutrient uptake and homeostasis in ECs.

Keywords:  SLC38A5; amino acids; angiogenesis; developmental biology; endothelial cells; mouse; neovascularization; retinopathy

DOI:  https://doi.org/10.7554/eLife.73105
Front Oncol. 2022 ;12 966089

CRISPR Cas9-mediated ablation of pyruvate carboxylase gene in colon cancer cell line HT-29 inhibits growth and migration, induces apoptosis and increases sensitivity to 5-fluorouracil and glutaminase inhibitor.

Jarunya Ngamkham, Siraprapa Siritutsoontorn, Saowaluk Saisomboon, Kulthida Vaeteewoottacharn, Sarawut Jitrapakdee.

  Pyruvate carboxylase (PC) is an important anaplerotic enzyme that replenishes the tricarboxylic acid cycle (TCA) intermediates. It prevents the collapse of the TCA cycle upon its intermediates are removed during high anabolic demand. We have recently shown that overexpression of PC protein was associated with staging, metastasis and poor survival of colorectal cancer patients. Herein, we generated the PC knockout (PC KO) colon cancer cell lines, HT-29, by CRISPR-Cas9 technique, as a model to understand the role of this enzyme in colorectal cancer. The PC KO HT-29 cell lines had no detectable PC protein and did not show abnormal cellular or nuclear structures. However, PC KO HT-29 cells showed a 50-60% reduction in their growth rate and a 60-70% reduction in migration. The deficient growth phenotype of PC KO HT-29 cells was associated with apoptotic induction with no apparent cell cycle disruption following five days of growth. Down-regulation of key lipogenic enzymes, including acetyl-CoA carboxylase-1 and fatty acid synthase, was also associated with growth inhibition, suggesting that the de novo lipogenesis is impaired. Furthermore, PC KO HT-29 cells were 50% and 60% more sensitive to 5-fluorouracil and glutaminase inhibitor, CB-839, at their IC50 concentrations, respectively, following 48 h exposure. The increased cytotoxicity of CB-839 to PC KO HT-29 cells was associated with increased poly (ADP-ribose) polymerase cleavage. However, this was not observed with PC KO cells exposed to 5-fluorouracil, suggesting that PC KO HT-29 cells were prone to CB-839-induced apoptosis. Collectively, these findings indicate that ablation of PC expression in HT-29 cells disrupts the metabolic homeostasis of cells and inhibits proliferation and migration, accompanied by apoptotic induction. This study highlights the crucial role of PC in supporting the survival of HT-29 cells during exposure to chemotherapeutic drugs.

Keywords:  5-FU; cancer metabolism; colorectal cancer; glutaminase; pyruvate carboxylase

DOI:  https://doi.org/10.3389/fonc.2022.966089
Cell Rep. 2022 Nov 29. pii: S2211-1247(22)01622-9. [Epub ahead of print]41(9): 111744

Inhibition of glutaminolysis restores mitochondrial function in senescent stem cells.

Debanik Choudhury, Na Rong, Izuagie Ikhapoh, Nika Rajabian, Georgios Tseropoulos, Yulun Wu, Pihu Mehrotra, Ramkumar Thiyagarajan, Aref Shahini, Kenneth L Seldeen, Bruce R Troen, Pedro Lei, Stelios T Andreadis.

  Mitochondrial dysfunction, a hallmark of aging, has been associated with the onset of aging phenotypes and age-related diseases. Here, we report that impaired mitochondrial function is associated with increased glutamine catabolism in senescent human mesenchymal stem cells (MSCs) and myofibroblasts derived from patients suffering from Hutchinson-Gilford progeria syndrome. Increased glutaminase (GLS1) activity accompanied by loss of urea transporter SLC14A1 induces urea accumulation, mitochondrial dysfunction, and DNA damage. Conversely, blocking GLS1 activity restores mitochondrial function and leads to amelioration of aging hallmarks. Interestingly, GLS1 expression is regulated through the JNK pathway, as demonstrated by chemical and genetic inhibition. In agreement with our in vitro findings, tissues isolated from aged or progeria mice display increased urea accumulation and GLS1 activity, concomitant with declined mitochondrial function. Inhibition of glutaminolysis in progeria mice improves mitochondrial respiratory chain activity, suggesting that targeting glutaminolysis may be a promising strategy for restoring age-associated loss of mitochondrial function.

Keywords:  CP: Cell biology; GLS1; Hutchinson-Gilford progeria syndrome; JNK; SLC14A1; aging; glutamine; mitochondria; senescence; urea

DOI:  https://doi.org/10.1016/j.celrep.2022.111744
Proteomics Clin Appl. 2022 Nov 28. e2200042

Two effective models based on comprehensive lipidomics and metabolomics can distinguish BC versus HCs, and TNBC versus Non-TNBC.

Yu Jin, Shuoqing Fan, Wenna Jiang, Jingya Zhang, Lexin Yang, Jiawei Xiao, Haohua An, Li Ren.

  BACKEGROUND: Lipidomics and metabolomics are closely related to tumor phenotypes, and serum lipoprotein subclasses and small-molecule metabolites are considered as promising biomarkers for breast cancer (BC) diagnosis. This study aimed to explore potential biomarker models based on lipidomic and metabolomic analysis that could distinguish BC from healthy controls (HCs) and triple-negative BC (TNBC) from non-TNBC.METHODS: Blood samples were collected from 114 patients with BC and 75 healthy controls (HCs). A total of 112 types of lipoprotein subclasses and 30 types of small-molecule metabolites in the serum were detected by 1 H-NMR. All lipoprotein subclasses and small-molecule metabolites were subjected to a three-step screening process in the order of significance (P < 0.05), univariate regression (P < 0.1), and lasso regression (non-zero coefficient). Discriminant models of BC versus HCs and TNBC versus non-TNBC were established using binary logistic regression.
RESULTS: We developed a valid discriminant model based on three-biomarker panel (formic acid, TPA2, and L6TG) that could distinguish patients with BC from HCs. The area under the receiver operating characteristic curve (AUC) was 0.999 (95% confidence interval [CI]: 0.995-1.000) and 0.990 (95% CI: 0.959-1.000) in the training and validation sets, respectively. Based on the panel (D-dimer, CA15-3, CEA, L5CH, glutamine, and ornithine), a discriminant model was established to differentiate between TNBC and non-TNBC, with AUC of 0.892 (95% CI: 0.778-0.967) and 0.905 (95% CI: 0.754-0.987) in the training and validation sets, respectively.
CONCLUSION: This study revealed lipidomic and metabolomic differences between BC versus HCs and TNBC versus non-TNBC. Two validated discriminatory models established against lipidomic and metabolomic differences can accurately distinguish BC from HCs and TNBC from non-TNBC.
IMPACT: Two validated discriminatory models can be used for early BC screening and help BC patients avoid time-consuming, expensive, and dangerous BC screening. This article is protected by copyright. All rights reserved.

Keywords:  1H-NMR; Breast cancer (BC); Lipidomics; Metabolomics; Triple-negative breast cancer (TNBC)

DOI:  https://doi.org/10.1002/prca.202200042
Haematologica. 2022 Dec 01.

Targetting glutaminase to starve lymphoma cells.

Charles Dumontet.

Not available.

DOI: https://doi.org/10.3324/haematol.2022.282348
Cell Death Dis. 2022 Nov 29. 13(11): 1010

PNO1 inhibits autophagy-mediated ferroptosis by GSH metabolic reprogramming in hepatocellular carcinoma.

Xiaomeng Hu, Yuchao He, Zhiqiang Han, Wei Liu, Dongming Liu, Xihao Zhang, Lu Chen, Lisha Qi, Liwei Chen, Yi Luo, Qiang Li, Peng Chen, Qiang Wu, Xiaolin Zhu, Hua Guo.

Effective strategies for hepatocellular carcinoma, which is the second leading cause of death worldwide, remain limited. A growing body of emerging evidence suggests that ferroptosis activation is a novel promising approach for the treatment of this malignancy. Nevertheless, the potential therapeutic targets and molecular mechanisms of ferroptosis remain elusive. In this study, we found that PNO1 is a bona fide inhibitor of ferroptosis and that autophagy induced by PNO1 promotes cystine/glutamate antiporter SLC7A11 while increasing the synthesis and accumulation of intracellular glutamate. This increase is followed by an equally proportional addition in cystine uptake, which consequently enhances system Xc- activity that leads to the inhibition of ferroptosis. In the maintenance of redox homeostasis, system Xc- activated via PNO1-autophagy metabolism is responsible for maintaining cysteine for glutathione (GSH) synthesis, and the final GSH metabolic reprogramming protects HCC cells from ferroptosis. The combination of PNO1 inhibition with drugs causing ferroptosis induction, particularly sorafenib, the first-line drug associated with ferroptosis in liver cancer shows therapeutic promise in vitro and in vivo. Together, our findings indicated that PNO1 protects HCC cells from ferroptotic death through autophagy-mediated GSH metabolic remodeling, and we identified a candidate therapeutic target that may potentiate the effect of ferroptosis-based antitumor therapy.

DOI: https://doi.org/10.1038/s41419-022-05448-7
Front Oncol. 2022 ;12 1081171

Editorial: Metabolic reprogramming in breast cancer.

Cristian Scatena, Antonio Giuseppe Naccarato, Bela Ozsvari, Domenica Scumaci.



Keywords:  breast cancer; breast cancer treatment; metabolic reprogramming; metabolic therapy; resistance mechanisms

DOI:  https://doi.org/10.3389/fonc.2022.1081171
Front Pharmacol. 2022 ;13 1044083

A multifunctional oxidative stress nanoamplifier with ROS amplification and GSH exhaustion for enhanced chemodynamic therapy.

Wenzhao Zhong, Feng Guo, Fangman Chen, Man-Kay Law, Jun Lu, Dan Shao, Hua Yu, Ging Chan, Meiwan Chen.

  Chemodynamic therapy (CDT) eradicates tumors by intratumoral catalytic chemical reaction and subsequently disrupts redox homeostasis, which shows tumor specific reactive oxygen species (ROS)-mediated therapy. However, insufficient ROS generation and high levels of glutathione (GSH) in cancer cells have limited the therapeutic efficacy of CDT. Herein, we constructed a multifunctional oxidative stress nanoamplifier with ROS amplification and GSH exhaustion for enhanced CDT. Such a sandwich-like nanoamplifier comprised layer-by-layer artesunate (AS) and calcium carbonate coatings on the surface of manganese dioxide (MnO2) nanoparticles. The nanoamplifier was disassembled under an acidic environment once accumulated into tumor sites, and subsequently released AS to replenish the intratumoral peroxide pool for ROS amplification. Besides being an AS carrier, MnO2 exhausted GSH to yield Mn2+ ions that catalyzed the overexpression of H2O2 in the tumor, further intensifying the oxidative stress and facilitating cancer cell death. Taken together, our findings not only provide a paradigm for fabricating intratumoral catalytic nanomaterials, but also present a new ROS enhancement strategy to improve anti-tumor efficacy. Our multifunctional oxidative stress nanoamplifier might broaden the future of CDT.

Keywords:  GSH exhaustion; ROS amplification; artesunate; chemodynamic therapy; intratumoral catalytic nanomaterials

DOI:  https://doi.org/10.3389/fphar.2022.1044083