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A NADPH oxidase-dependent redox signaling pathway mediates the selective radiosensitization effect of parthenolide in prostate cancer cells.

ABSTRACT: Cancer cells are usually under higher oxidative stress compared with normal cells. We hypothesize that introducing additional reactive oxygen species (ROS) insults or suppressing antioxidant capacity may selectively enhance cancer cell killing by oxidative stress-generating agents through stress overload or stress sensitization, whereas normal cells may be able to maintain redox homeostasis under exogenous ROS by adaptive response. Here, we show that parthenolide, a sesquiterpene lactone, selectively exhibits a radiosensitization effect on prostate cancer PC3 cells but not on normal prostate epithelial PrEC cells. Parthenolide causes oxidative stress in PC3 cells but not in PrEC cells, as determined by the oxidation of the ROS-sensitive probe H(2)DCFDA and intracellular reduced thiol and disulfide levels. In PC3 but not PrEC cells, parthenolide activates NADPH oxidase, leading to a decrease in the level of reduced thioredoxin, activation of phosphoinositide 3-kinase/Akt, and consequent FOXO3a phosphorylation, which results in the downregulation of FOXO3a targets antioxidant enzyme manganese superoxide dismutase and catalase. Importantly, when combined with radiation, parthenolide further increases ROS levels in PC3 cells whereas it decreases radiation-induced oxidative stress in PrEC cells, possibly by increasing reduced glutathione levels. Together, the results show that parthenolide selectively activates NADPH oxidase and mediates intense oxidative stress in prostate cancer cells by both increasing ROS generation and decreasing antioxidant defense capacity. The results support the concept of exploiting the intrinsic differences in the redox status of cancer cells and normal cells as targets for selective cancer killing.

SUBMITTER: Sun Y

PROVIDER: S-EPMC2848907 | biostudies-literature | 2010 Apr

REPOSITORIES: biostudies-literature

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A NADPH oxidase-dependent redox signaling pathway mediates the selective radiosensitization effect of parthenolide in prostate cancer cells.

Sun Yulan Y St Clair Daret K DK Xu Yong Y Crooks Peter A PA St Clair William H WH

Cancer research 20100316 7

Cancer cells are usually under higher oxidative stress compared with normal cells. We hypothesize that introducing additional reactive oxygen species (ROS) insults or suppressing antioxidant capacity may selectively enhance cancer cell killing by oxidative stress-generating agents through stress overload or stress sensitization, whereas normal cells may be able to maintain redox homeostasis under exogenous ROS by adaptive response. Here, we show that parthenolide, a sesquiterpene lactone, select ...[more]

PMID: 20233868

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Project description:Neutrophils migrating from the blood (pH 7.35-7.45) into the surrounding tissues encounter changes in extracellular pH (pHe) conditions. Upon activation of NADPH oxidase 2 (Nox), neutrophils generate large amounts of H+ ions reducing the intracellular pH (pHi). Nevertheless, how extracellular pH regulates neutrophil extracellular trap (NET) formation (NETosis) is not clearly established. We hypothesized that increasing pH increases Nox-mediated production of reactive oxygen species (ROS) and neutrophil protease activity, stimulating NETosis. Here, we found that raising pHe (ranging from 6.6 to 7.8; every 0.2 units) increased pHi of both activated and resting neutrophils within 10-20?min (Seminaphtharhodafluor dual fluorescence measurements). Since Nox activity generates H+ ions, pHi is lower in neutrophils that are activated compared to resting. We also found that higher pH stimulated Nox-dependent ROS production (R123 generation; flow cytometry, plate reader assay, and imaging) during spontaneous and phorbol myristate acetate-induced NETosis (Sytox Green assays, immunoconfocal microscopy, and quantifying NETs). In neutrophils that are activated and not resting, higher pH stimulated histone H4 cleavage (Western blots) and NETosis. Raising pH increased Escherichia coli lipopolysaccharide-, Pseudomonas aeruginosa (Gram-negative)-, and Staphylococcus aureus (Gram-positive)-induced NETosis. Thus, higher pHe promoted Nox-dependent ROS production, protease activity, and NETosis; lower pH has the opposite effect. These studies provided mechanistic steps of pHe-mediated regulation of Nox-dependent NETosis. Raising pH either by sodium bicarbonate or Tris base (clinically known as Tris hydroxymethyl aminomethane, tromethamine, or THAM) increases NETosis. Each Tris molecule can bind 3H+ ions, whereas each bicarbonate HCO3- ion binds 1H+ ion. Therefore, the amount of Tris solution required to cause the same increase in pH level is less than that of equimolar bicarbonate solution. For that reason, regulating NETosis by pH with specific buffers such as THAM could be more effective than bicarbonate in managing NET-related diseases.

Dataset Information

A NADPH oxidase-dependent redox signaling pathway mediates the selective radiosensitization effect of parthenolide in prostate cancer cells.

Publications

A NADPH oxidase-dependent redox signaling pathway mediates the selective radiosensitization effect of parthenolide in prostate cancer cells.

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