NQO1 targeting prodrug triggers innate sensing to overcome checkpoint blockade resistance

Li, Xiaoguang; Liu, Zhida; Zhang, Anli; Han, Chuanhui; Shen, Aijun; Jiang, Lingxiang; Boothman, David A.; Qiao, Jian; Wang, Yan; Huang, Xiumei; Fu, Yang Xin

doi:10.1038/s41467-019-11238-1

Cited by 66 publications

(63 citation statements)

References 53 publications

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“…Although immunotherapeutic approaches have been approved in several tumors, the anti-tumor efficacy appears to be modest in clinical therapy ( 42 ). This tumor resistance might be partly related to the highly immunosuppressive TME ( 43 ).…”

Section: Discussionmentioning

confidence: 99%

RETRACTED: The Design, Characterizations, and Tumor Angiogenesis Inhibition of a Multi-Epitope Peptibody With bFGF/VEGFA

et al. 2020

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Tumor angiogenesis is dependent on growth factors, and inhibition of their pathways is one of the promising strategies in cancer therapy. However, resistance to single pathway has been a great concern in clinical trials so that it necessitates multiple targetable factors for developing tumor angiogenesis inhibitors. Moreover, the strategy of Fc fusion protein is an attractive platform for novel peptide agents, which gains increasing importance with FDA approval because of better immunogenicity and stability. Here, we applied the Fc fusion protein concept to bFGF/VEGFA pathways and designed a multi-epitope Peptibody with immunogenic peptides derived from human bFGF and VEGFA sequences. Immunization with Peptibody could elicit high-titer anti-bFGF and anti-VEGFA antibodies, activate T cells, and induce Th1/Th2-type cytokines. In in vitro experiments, the isolated anti-Peptibody antibody inhibited the proliferation and migration of A549 cells and human umbilical vein endothelial cells (HUVECs) by decreasing the MAPK/Akt/mTOR signal pathways. In the murine tumor model, pre-immunization with Peptibody suppressed the tumor growth and neovascularization of lung cancer by decreasing the production of bFGF/VEGFA/PDGF, the MAPK/Akt/mTOR signal pathways, and the activation of suppressive cells in tumor sites. Further, the biological characterizations of the recombinant Peptibody were investigated systematically, including protein primary structure, secondary structure, stability, and toxicity. Collectively, the results highlighted the strategy of bFGF/VEGFA pathways and Fc fusion protein in suppressing tumor progression and angiogenesis, which emphasized the potential of multiple targetable factors for producing enduring clinical responses in tumor patients.

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Section: Discussionmentioning

confidence: 99%

RETRACTED: The Design, Characterizations, and Tumor Angiogenesis Inhibition of a Multi-Epitope Peptibody With bFGF/VEGFA

et al. 2020

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“…Furthermore, NQO1 also maintains the reduced form of CoQ 9 and CoQ 10 inside the unilamellar or multilamellar vesicles, thereby protecting the plasma membrane from lipid peroxidation and free radicals. Knockout of NQO1 is associated with high susceptibility to immune disorders [ 87 , 88 ]. Moreover, the double knockout of both NQO1 and NQO2 strongly enhances the infiltration of neutrophils and macrophages in bronchial-associated lymphoid tissue, leading to an increase in pro-inflammatory cytokines in lung macrophages [ 89 ].…”

Section: Nrf2 and Nf-ĸb Interplay In The Regulation Of Cellular Rementioning

confidence: 99%

An Overview of Nrf2 Signaling Pathway and Its Role in Inflammation

Saha¹,

Buttari²,

et al. 2020

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Inflammation is a key driver in many pathological conditions such as allergy, cancer, Alzheimer’s disease, and many others, and the current state of available drugs prompted researchers to explore new therapeutic targets. In this context, accumulating evidence indicates that the transcription factor Nrf2 plays a pivotal role controlling the expression of antioxidant genes that ultimately exert anti-inflammatory functions. Nrf2 and its principal negative regulator, the E3 ligase adaptor Kelch-like ECH- associated protein 1 (Keap1), play a central role in the maintenance of intracellular redox homeostasis and regulation of inflammation. Interestingly, Nrf2 is proved to contribute to the regulation of the heme oxygenase-1 (HO-1) axis, which is a potent anti-inflammatory target. Recent studies showed a connection between the Nrf2/antioxidant response element (ARE) system and the expression of inflammatory mediators, NF-κB pathway and macrophage metabolism. This suggests a new strategy for designing chemical agents as modulators of Nrf2 dependent pathways to target the immune response. Therefore, the present review will examine the relationship between Nrf2 signaling and the inflammation as well as possible approaches for the therapeutic modulation of this pathway.

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“…What is the molecular mechanism of isoplumbagin-induced NQO1 action on suppression of cancer cell growth and invasion? β-lapachone, which is currently under multiple phase I/II clinical trials, is known to be bioactivated by NQO1 in NQO1 high tumors, leading to generation of reactive oxygen species [17][18][19]. Elevated oxidative stress is correlated with tumor initiation, metastasis, and therapeutic resistance.…”

Section: Isoplumbagin Does Not Increase Oxidative Stress or Dna Fragmmentioning

confidence: 99%

Discovery of Isoplumbagin as a Novel NQO1 Substrate and Anti-Cancer Quinone

Tsao

Chang

Wang

et al. 2020

IJMS

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Isoplumbagin (5-hydroxy-3-methyl-1,4-naphthoquinone), a naturally occurring quinone from Lawsonia inermis and Plumbago europaea, has been reported to have anti-inflammatory and antimicrobial activity. Inflammation has long been implicated in cancer progression. In this study, we examined the anticancer effect of chemically synthesized isoplumbagin. Our results revealed that isoplumbagin treatment suppressed cell viability and invasion of highly invasive oral squamous cell carcinoma (OSCC) OC3-IV2 cells, glioblastoma U87 cells, non-small cell lung carcinoma H1299 cells, prostate cancer PC3 cells, and cervical cancer HeLa cells by using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and Boyden chamber assays. In vivo studies demonstrate the inhibitory effect of 2 mg/kg isoplumbagin on the growth of orthotopic xenograft tumors derived from OSCC cells. Mechanistically, isoplumbagin exerts its cytotoxic effect through acting as a substrate of reduced nicotinamide adenine dinucleotide phosphate [NAD(P)H] dehydrogenase quinone 1 (NQO1) to generate hydroquinone, which reverses mitochondrial fission phenotype, reduces mitochondrial complex IV activity, and thus compromises mitochondrial function. Collectively, this work reveals an anticancer activity of isoplumbagin mainly through modulating mitochondrial dynamics and function.

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NQO1 targeting prodrug triggers innate sensing to overcome checkpoint blockade resistance

Cited by 66 publications

References 53 publications

RETRACTED: The Design, Characterizations, and Tumor Angiogenesis Inhibition of a Multi-Epitope Peptibody With bFGF/VEGFA

RETRACTED: The Design, Characterizations, and Tumor Angiogenesis Inhibition of a Multi-Epitope Peptibody With bFGF/VEGFA

An Overview of Nrf2 Signaling Pathway and Its Role in Inflammation

Discovery of Isoplumbagin as a Novel NQO1 Substrate and Anti-Cancer Quinone

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