Combination of chemotherapy and oxidative stress to enhance cancer cell apoptosis

Li, Xinming; Hou, Yanan; Zhao, Jiang; Jin, Li; Wang, Song; Fang, Jianguo

doi:10.1039/c9sc05997k

Cited by 44 publications

(54 citation statements)

References 64 publications

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“… 107 1,2-Dithiolane probes, such as 34 , that turn on fluorescence (or release drugs) upon reductive opening as outlined in 35 , have been quite extensively explored by Fang and co-workers. 108 − 110 The puzzling relation of specific thioredoxin labeling with 34 and thiol-mediated uptake is being addressed by Thorn-Seshold and co-workers. 111 …”

Section: Privileged Scaffoldsmentioning

confidence: 99%

Thiol-Mediated Uptake

Laurent

Martinent

Lim

et al. 2021

JACS Au

105

208

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This Perspective focuses on thiol-mediated uptake, that is, the entry of substrates into cells enabled by oligochalcogenides or mimics, often disulfides, and inhibited by thiol-reactive agents. A short chronology from the initial observations in 1990 until today is followed by a summary of cell-penetrating poly(disulfide)s (CPDs) and cyclic oligochalcogenides (COCs) as privileged scaffolds in thiol-mediated uptake and inhibitors of thiol-mediated uptake as potential antivirals. In the spirit of a Perspective, the main part brings together topics that possibly could help to explain how thiol-mediated uptake really works. Extreme sulfur chemistry mostly related to COCs and their mimics, cyclic disulfides, thiosulfinates/-onates, diselenolanes, benzopolysulfanes, but also arsenics and Michael acceptors, is viewed in the context of acidity, ring tension, exchange cascades, adaptive networks, exchange affinity columns, molecular walkers, ring-opening polymerizations, and templated polymerizations. Micellar pores (or lipid ion channels) are considered, from cell-penetrating peptides and natural antibiotics to voltage sensors, and a concise gallery of membrane proteins, as possible targets of thiol-mediated uptake, is provided, including CLIC1, a thiol-reactive chloride channel; TMEM16F, a Ca-activated scramblase; EGFR, the epithelial growth factor receptor; and protein-disulfide isomerase, known from HIV entry or the transferrin receptor, a top hit in proteomics and recently identified in the cellular entry of SARS-CoV-2.

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Section: Privileged Scaffoldsmentioning

confidence: 99%

Thiol-Mediated Uptake

Laurent

Martinent

Lim

et al. 2021

JACS Au

105

208

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“…Chemotherapy-induced oxidative stress plays a controversial role in cancer and has raised some concerns regarding the effectiveness of combinatorial approaches ( Shacter et al, 2000 ; Liu and Wang, 2015 ; Li et al, 2020 ). A recent study suggested that oxidative stress could be another contributor to PDAC desmoplasia in the sense that it can induce p38-mediated monocyte-to-myofibroblast transdifferentiation (MMT), thereby leading to stromal activation, modulating immunosuppression, as well as promoting tumor progression ( Huang et al, 2020 ).…”

Section: The Effects Of Cancer Therapies On Cancer-associated Fibroblastsmentioning

confidence: 99%

The Cellular Origins of Cancer-Associated Fibroblasts and Their Opposing Contributions to Pancreatic Cancer Growth

Manoukian

Bijlsma

Laarhoven

2021

Front. Cell Dev. Biol.

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Pancreatic tumors are known to harbor an abundant and highly desmoplastic stroma. Among the various cell types that reside within tumor stroma, cancer-associated fibroblasts (CAFs) have gained a lot of attention in the cancer field due to their contributions to carcinogenesis and tumor architecture. These cells are not a homogeneous population, but have been shown to have different origins, phenotypes, and contributions. In pancreatic tumors, CAFs generally emerge through the activation and/or recruitment of various cell types, most notably resident fibroblasts, pancreatic stellate cells (PSCs), and tumor-infiltrating mesenchymal stem cells (MSCs). In recent years, single cell transcriptomic studies allowed the identification of distinct CAF populations in pancreatic tumors. Nonetheless, the exact sources and functions of those different CAF phenotypes remain to be fully understood. Considering the importance of stromal cells in pancreatic cancer, many novel approaches have aimed at targeting the stroma but current stroma-targeting therapies have yielded subpar results, which may be attributed to heterogeneity in the fibroblast population. Thus, fully understanding the roles of different subsets of CAFs within the stroma, and the cellular dynamics at play that contribute to heterogeneity in CAF subsets may be essential for the design of novel therapies and improving clinical outcomes. Fortunately, recent advances in technologies such as microfluidics and bio-printing have made it possible to establish more advanced ex vivo models that will likely prove useful. In this review, we will present the different roles of stromal cells in pancreatic cancer, focusing on CAF origin as a source of heterogeneity, and the role this may play in therapy failure. We will discuss preclinical models that could be of benefit to the field and that may contribute to further clinical development.

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“…Functionally, in addition to the key role of TrxR in redox regulation 20,21 , an ever-widening range of evidence has supported that TrxR highly enriched in many tumor types is essentially implicated with multiple steps of tumorigenesis and development [20][21][22][23] , and is a potential and promising target for the current anticancer drugs discovery [24][25][26][27] . As our continuing efforts in discovering therapeutic molecules derived from natural products that effectively interfere with cellular redox signaling [28][29][30][31][32][33][34][35][36][37][38][39] , we assessed herein the antitumor activity of ONP, C2 and C3, and systematically reported a new mechanism by which ONP targets intracellular TrxR inhibition to cause oxidative stress-mediated tumor cell apoptosis. Mechanistically, the b-carbocation of the lactone ring in ONP covalently bound to the redox-active Sec residue at the C-terminus of TrxR, thereby leading to a decrease in TrxR activity.…”

Section: Introductionmentioning

confidence: 99%

Onopordopicrin from the new genus Shangwua as a novel thioredoxin reductase inhibitor to induce oxidative stress-mediated tumor cell apoptosis

Zhang

Zheng

et al. 2021

Journal of Enzyme Inhibition and Medicinal Chemistry

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Isolation and identification of natural products from plants is an essential approach for discovering drug candidates. Herein we report the characterization of three sesquiterpene lactones from a new genus Shangwua, e.g. onopordopicrin (ONP), C2, and C3, and evaluation of their pharmacological functions in interfering cellular redox signaling. Compared to C2 and C3, ONP shows the most potency in killing cancer cells. Further experiments demonstrate that ONP robustly inhibits thioredoxin reductase (TrxR), which leads to perturbation of cellular redox homeostasis with the favor of oxidative stress. Knockdown of the TrxR sensitizes cells to the ONP treatment while overexpression of the enzyme reduces the potency of ONP, underpinning the correlation of TrxR inhibition to the cytotoxicity of ONP. The discovery of ONP expands the library of the natural TrxR inhibitors, and the disclosure of the action mechanism of ONP provides a foundation for the further development of ONP as an anticancer agent.

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Combination of chemotherapy and oxidative stress to enhance cancer cell apoptosis

Abstract: The 1,2-diselenolane unit is a general scaffold to construct glutathione-dependent prodrugs that show increased potency to cancer cells, and work via a combination of chemotherapy and oxidative stress.

Cited by 44 publications

References 64 publications

Thiol-Mediated Uptake

Thiol-Mediated Uptake

The Cellular Origins of Cancer-Associated Fibroblasts and Their Opposing Contributions to Pancreatic Cancer Growth

Onopordopicrin from the new genus Shangwua as a novel thioredoxin reductase inhibitor to induce oxidative stress-mediated tumor cell apoptosis

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