Optimizing the design and in vitro evaluation of bioreactive glucose oxidase-microspheres for enhanced cytotoxicity against multidrug resistant breast cancer cells

Cheng, Ji; Li, Qun; Shuhendler, Adam J.; Rauth, Andrew M.; Wu, Xiao Yu

doi:10.1016/j.colsurfb.2015.04.002

Cited by 14 publications

(11 citation statements)

References 47 publications

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“…Actually, there have been many efforts to increase the levels of ROS specifically in cancer cells, which is known as "oxidation therapy". 6−8 One strategy for the oxidation therapy is to directly deliver ROS-promoting agents, such as piperlongumine (1, Figure 1), 9 arsenic trioxide (As 2 O 3 ), 10 or glucose oxidase 11 to tumor tissues.…”

Section: ■ Introductionmentioning

confidence: 99%

Novel Ligustrazine-Based Analogs of Piperlongumine Potently Suppress Proliferation and Metastasis of Colorectal Cancer Cells in Vitro and in Vivo

et al. 2018

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Piperlongumine 1 increases reactive oxygen species (ROS) levels and preferably induces cancer cell apoptosis by triggering different pathways. However, the poor solubility of 1 limits its intensive investigation and clinical application. Ligustrazine possesses a water-soluble pyrazine skeleton and can inhibit proliferation and metastasis of cancer cells. We synthesized compound 3 by replacement of the trimethoxyphenyl of 1 with ligustrazine moiety and further introduced 2-Cl, -Br, and -I to 3 for synthesis of 4-6, respectively. Compound 4 possessed 14-fold greater aqueous solubility than 1 and increased ROS levels in colorectal cancer HCT-116 cells. Additionally, 4 preferably inhibited proliferation, migration, invasion, and heteroadhesion of HCT-116 cells. Treatment with 4 suppressed tumor growth and lung metastasis in vivo and prolonged the survival of tumor-bearing mice. Furthermore, 4 mitigated TGF-β1-induced epithelial-mesenchymal transition and Wnt/β-catenin activation by inhibiting the Akt and GSK-3β phosphorylation in HCT-116 cells. Collectively, 4 displayed significant antiproliferation and antimetastasis activities, superior to 1.

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Section: ■ Introductionmentioning

confidence: 99%

Novel Ligustrazine-Based Analogs of Piperlongumine Potently Suppress Proliferation and Metastasis of Colorectal Cancer Cells in Vitro and in Vivo

et al. 2018

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“…Although it was frequently argued that DSF toxicity was mostly dependent on a stable DSF complex with Cu, others recently showed that upon addition of the Cu (II) ions to the media, the cells are exposed to a rapid redox decomposition of DSF with a catastrophic release of H 2 O 2 , implying generation of the latter as crucial in DSF toxicity [ 50 ]. The translational potential of enhancing DSF toxicity by gradual H 2 O 2 delivery to tumor cells [ 38 , 39 ] by small micron-sized glucose oxidase –microspheres as a source of exogenous ROS [ 51 ], but avoiding toxicity from Cu overload is supported by data showing that melanoma cells have increased SOD which generates more H 2 O 2 but lower catalase activities, compared to normal human melanocytes [ 52 ]. This study emphasizing the relevance of exogenous H 2 O 2 generation by exogenous dismutase activity like that provided by extracellular SOD3 [ 13 ] is compatible with other results showing that loss of SOD3 expression promotes an invasive phenotype in human pancreatic adenocarcinoma [ 53 ].…”

Section: Discussionmentioning

confidence: 99%

Disulfiram anti-cancer efficacy without copper overload is enhanced by extracellular H2O2 generation: antagonism by tetrathiomolybdate

2015

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Highlightsexogenous SOD increases apoptosis by sub-toxic disulfiram without copper overloadH2O2 generation from glucose oxidase also potentiates disulfiram toxicityN-acetylcysteine suppresses antitumor potentiation of DSF by H2O2 generationsub-toxic tetrathiomolybdate inhibits potentiation of DSF by SODBackgroundCu/Zn superoxide dismutases (SODs) like the extracellular SOD3 and cytoplasmic SOD1 regulate cell proliferation by generating hydrogen peroxide (H2O2). This pro-oxidant inactivates essential cysteine residues in protein tyrosine phosphatases (PTP) helping receptor tyrosine kinase activation by growth factor signaling, and further promoting downstream MEK/ERK linked cell proliferation. Disulfiram (DSF), currently in clinical cancer trials is activated by copper chelation, being potentially capable of diminishing the copper dependent activation of MEK1/2 and SOD1/SOD3 and promoting reactive oxygen species (ROS) toxicity. However, copper (Cu) overload may occur when co-administered with DSF, resulting in toxicity and mutagenicity against normal tissue, through generation of the hydroxyl radical (•OH) by the Fenton reaction.PurposeTo investigate: a) whether sub-toxic DSF efficacy can be increased without Cu overload against human melanoma cells with unequal BRAF(V600E) mutant status and Her2-overexpressing SKBR3 breast cancer cells, by increasing H2O2from exogenous SOD; b) to compare the anti-tumor efficacy of DSF with that of another clinically used copper chelator, tetrathiomolybdate (TTM)Resultsa) without copper supplementation, exogenous SOD potentiated sub-toxic DSF toxicity antagonized by sub-toxic TTM or by the anti-oxidant N-acetylcysteine; b) exogenous glucose oxidase, another H2O2 generator resembled exogenous SOD in potentiating sub-toxic DSF.Conclusionspotentiation of sub-lethal DSF toxicity by extracellular H2O2 against the human tumor cell lines investigated, only requires basal Cu and increased ROS production, being unrelated to non-specific or TTM copper chelator sequestration.SignificanceThese findings emphasize the relevance of extracellular H2O2 as a novel mechanism to improve disulfiram anticancer effects minimizing copper toxicity.

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“…Quantitative analysis of the fluorescence ratio (green/red) also revealed a nearly threefold higher base‐line lipid peroxidation in untreated EMT6/AR1 cells compared to parent drug‐sensitive EMT6/WT cells (Figure d), indicating excessive ROS generation in MDR cancer cells that could be a target for lipid‐oxidation therapy. [10a] To identify the subcellular site of lipid peroxidation, mitochondria of cancer cells were stained with Mitotracker Deep Red. In MMC‐DHA‐PLN treated cells, strong green fluorescence of lipid peroxidation was visualized to co‐localize with far‐red fluorescence of mitochondria (Figure e, Figure S5, Supporting Information).…”

Section: Resultsmentioning

confidence: 59%

“…[2b,6,9] This phenomenon has been demonstrated by recent biophysical studies of extracted plasma membrane from MDR cancer cells, in which P‐gp overexpressing cytoplasmic membrane shows high amounts of cholesterol and sphingolipids. [2b,9a,b,10] These lipids tend to form lipid rafts that co‐exist with the transporter proteins, complementing the transporters and supporting their efflux function. [2b,9b] Such lipid rafts in MDR cell membrane are insoluble in commonly used membrane detergents; thus application of the detergents does not improve cellular nanoparticle uptake.…”

Section: Introductionmentioning

confidence: 99%

Coordinating Biointeraction and Bioreaction of a Nanocarrier Material and an Anticancer Drug to Overcome Membrane Rigidity and Target Mitochondria in Multidrug‐Resistant Cancer Cells

Zhang

et al. 2017

Adv Funct Materials

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Multidrug resistance (MDR) is a main cause of chemotherapy failure in cancer treatment. It is associated with complex cellular and molecular mechanisms including overexpression of drug efflux transporters, increased membrane rigidity, and impaired apoptosis. Numerous efforts have been made to overcome efflux transporter-mediated MDR using nanotechnology-based approaches. However, these approaches fail to surmount plasma membrane rigidity that attenuates drug penetration and nanoparticle endocytosis. Here, a "one-two punch" nanoparticle approach is proposed to coordinate intracellular biointeraction and bioreaction of a nanocarrier material docosahexaenoic acid (DHA) and an anticancer prodrug mitomycin C (MMC) to enhance mitochondrion-targeted toxicity. Incorporation of DHA in solid polymer-lipid nanoparticles first reduces the membrane rigidity in live cancer cells thereby increasing nanoparticle cellular uptake and MMC accumulation. Subsequent intracellular MMC bioreduction produces free radicals that in turn react with adjacent DHA inducing significantly elevated mitochondrial lipid peroxidation, leading to irreversible damage to mitochondria. Preferential tumor accumulation of the nanoparticles and the synergistic anticancer cytotoxicity remarkably inhibit tumor growth and prolonged host survival without any systemic toxicity in an orthotopic MDR breast tumor model. This work suggests that combinatorial use of biophysical and biochemical properties of nanocarrier materials with bioreactive prodrugs is a powerful approach to overcoming multifactorial MDR in cancer.

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Optimizing the design and in vitro evaluation of bioreactive glucose oxidase-microspheres for enhanced cytotoxicity against multidrug resistant breast cancer cells

Cited by 14 publications

References 47 publications

Novel Ligustrazine-Based Analogs of Piperlongumine Potently Suppress Proliferation and Metastasis of Colorectal Cancer Cells in Vitro and in Vivo

Novel Ligustrazine-Based Analogs of Piperlongumine Potently Suppress Proliferation and Metastasis of Colorectal Cancer Cells in Vitro and in Vivo

Disulfiram anti-cancer efficacy without copper overload is enhanced by extracellular H2O2 generation: antagonism by tetrathiomolybdate

Coordinating Biointeraction and Bioreaction of a Nanocarrier Material and an Anticancer Drug to Overcome Membrane Rigidity and Target Mitochondria in Multidrug‐Resistant Cancer Cells

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