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  1. Article ; Online: Methylseleninic Acid Induces Lipid Peroxidation and Radiation Sensitivity in Head and Neck Cancer Cells

    John T. Lafin / Ehab H. Sarsour / Amanda L. Kalen / Brett A. Wagner / Garry R. Buettner / Prabhat C. Goswami

    International Journal of Molecular Sciences, Vol 20, Iss 1, p

    2019  Volume 225

    Abstract: Combination radiation and chemotherapy are commonly used to treat locoregionally advanced head and neck squamous cell carcinoma (HNSCC). Aggressive dosing of these therapies is significantly hampered by side effects due to normal tissue toxicity. ... ...

    Abstract Combination radiation and chemotherapy are commonly used to treat locoregionally advanced head and neck squamous cell carcinoma (HNSCC). Aggressive dosing of these therapies is significantly hampered by side effects due to normal tissue toxicity. Selenium represents an adjuvant that selectively sensitizes cancer cells to these treatments modalities, potentially by inducing lipid peroxidation (LPO). This study investigated whether one such selenium compound, methylseleninic acid (MSA), induces LPO and radiation sensitivity in HNSCC cells. Results from 4,4-difluoro-4-bora-3a,4a-diaza-S-indacene (BODIPY) C11 oxidation and ferric thiocyanate assays revealed that MSA induced LPO in cells rapidly and persistently. Propidium iodide (PI) exclusion assay found that MSA was more toxic to cancer cells than other related selenium compounds; this toxicity was abrogated by treatment with α-tocopherol, an LPO inhibitor. MSA exhibited no toxicity to normal fibroblasts at similar doses. MSA also sensitized HNSCC cells to radiation as determined by clonogenic assay. Intracellular glutathione in cancer cells was depleted following MSA treatment, and supplementation of the intracellular glutathione pool with N-acetylcysteine sensitized cells to MSA. The addition of MSA to a cell-free solution of glutathione resulted in an increase in oxygen consumption, which was abrogated by catalase, suggesting the formation of H2O2. Results from this study identify MSA as an inducer of LPO, and reveal its capability to sensitize HNSCC to radiation. MSA may represent a potent adjuvant to radiation therapy in HNSCC.
    Keywords head and neck cancer ; selenium ; methylseleninic acid ; radiation ; lipid peroxidation ; glutathione ; tocopherol ; Biology (General) ; QH301-705.5 ; Chemistry ; QD1-999
    Language English
    Publishing date 2019-01-01T00:00:00Z
    Publisher MDPI AG
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  2. Article ; Online: Hydrogen Peroxide Mediates Artemisinin-Derived C-16 Carba-Dimer-Induced Toxicity of Human Cancer Cells

    Amanda L. Kalen / Brett A. Wagner / Ehab H. Sarsour / Maneesh G. Kumar / Jessica L. Reedy / Garry R. Buettner / Nabin C. Barua / Prabhat C. Goswami

    Antioxidants, Vol 9, Iss 2, p

    2020  Volume 108

    Abstract: This study used a nitroaliphatic chemistry approach to synthesize a novel artemisinin-derived carba-dimer (AG-1) and determined its anti-proliferative effects in human normal and cancer cells. AG-1 treatments selectively inhibit proliferation of cancer ... ...

    Abstract This study used a nitroaliphatic chemistry approach to synthesize a novel artemisinin-derived carba-dimer (AG-1) and determined its anti-proliferative effects in human normal and cancer cells. AG-1 treatments selectively inhibit proliferation of cancer cells compared to normal human fibroblasts. Compared to artemisinin, AG-1 is more toxic to human breast, prostate, head−neck, pancreas and skin cancer cells; 50% inhibition (IC 50 ) 123 µM in AG-1 vs. 290 µM in artemisinin-treated breast cancer cells. AG-1 treatment decreased (~5 folds) cyclin D1 protein expression that correlated with an increase in the percentage of cells in the G 1 -phase, suggesting a G 1 delay. AG-1-induced toxicity was independent of the DNA damage at 72 h post-treatment, as measured by micronuclei frequency and γH2AX protein levels. Results from electron paramagnetic resonance spectroscopy showed Fe-catalyzed formation of AG-1 carbon-centered radicals in a cell-free system. Flow cytometry analysis of H 2 DCF-DA oxidation showed a significant increase in the steady-state levels of reactive oxygen species (ROS) in AG-1-treated cells. Pre-treatment with N -acetyl- l -cysteine and antioxidant enzymes (superoxide dismutase and catalase) significantly suppressed AG-1-induced toxicity, suggesting that superoxide and hydrogen peroxide contribute to AG-1-induced toxicity in human cancer cells. AG-1 represents a novel class of anti-cancer drug that is more potent than its parent compound, artemisinin.
    Keywords artemisinin ; carba-dimer ; aliphatic nitro chemistry ; oxidative stress ; cyclin d1 ; Therapeutics. Pharmacology ; RM1-950
    Language English
    Publishing date 2020-01-01T00:00:00Z
    Publisher MDPI AG
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  3. Article ; Online: 2-(4-Chlorophenyl)benzo-1,4-quinone induced ROS-signaling inhibits proliferation in human non-malignant prostate epithelial cells

    Leena Chaudhuri / Ehab H. Sarsour / Prabhat C. Goswami

    Environment International, Vol 36, Iss 8, Pp 924-

    2010  Volume 930

    Abstract: Polychlorinated biphenyls (PCBs) and their metabolites are environmental chemical contaminants which can produce reactive oxygen species (ROS) by auto-oxidation of di-hydroxy PCBs as well as the reduction of quinones and redox-cycling. We investigate the ...

    Abstract Polychlorinated biphenyls (PCBs) and their metabolites are environmental chemical contaminants which can produce reactive oxygen species (ROS) by auto-oxidation of di-hydroxy PCBs as well as the reduction of quinones and redox-cycling. We investigate the hypothesis that 2-(4-chlorophenyl)benzo-1,4-quinone (4-Cl-BQ), a metabolite of 4-chlorobiphenyl (PCB3), induced ROS-signaling inhibits cellular proliferation. Monolayer cultures of exponentially growing asynchronous human non-malignant prostate epithelial cells (RWPE-1) were incubated with 0–6 μM of 4-Cl-BQ and harvested at the end of 72 h of incubation to assess antioxidant enzyme expression, cellular ROS levels, cell growth, and cell cycle phase distributions. 4-Cl-BQ decreased manganese superoxide dismutase (MnSOD) activity, protein, and mRNA levels. 4-Cl-BQ treatment increased dihydroethidium (DHE) fluorescence, which was suppressed in cells pretreated with polyethylene glycol conjugated superoxide dismutase (PEG-SOD). The increase in ROS levels was associated with a decrease in cell growth, and an increase in the percentage of S-phase cells. These effects were suppressed in cells pretreated with PEG-SOD. 4-Cl-BQ treatment did not change the protein levels of phosphorylated H2AX at the end of 72 h of incubation, suggesting that the inhibition in cell growth and accumulation of cells in S-phase at the end of the treatments were probably not due to 4-Cl-BQ induced DNA double strand break. These results demonstrate that MnSOD activity and ROS-signaling perturb proliferation in 4-Cl-BQ treated in vitro cultures of human prostate cells. Keywords: Polychlorinated biphenyls, PCB3, Reactive oxygen species, MnSOD, Superoxide, Prostate epithelial cells
    Keywords Environmental sciences ; GE1-350
    Subject code 500
    Language English
    Publishing date 2010-11-01T00:00:00Z
    Publisher Elsevier
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  4. Article ; Online: AP-2γ Induces p21 Expression, Arrests Cell Cycle, Inhibits the Tumor Growth of Human Carcinoma Cells

    Hualei Li / Prabhat C. Goswami / Frederick E. Domann

    Neoplasia : An International Journal for Oncology Research, Vol 8, Iss 7, Pp 568-

    2006  Volume 577

    Abstract: Activating enhancer-binding protein 2γ (AP-2γ) is a member of the developmentally regulated AP-2 transcription factor family that regulates the expression of many downstream genes. Whereas the effects of AP-2α overexpression on cell growth are fairly ... ...

    Abstract Activating enhancer-binding protein 2γ (AP-2γ) is a member of the developmentally regulated AP-2 transcription factor family that regulates the expression of many downstream genes. Whereas the effects of AP-2α overexpression on cell growth are fairly well established, the cellular effects of AP-2γ overexpression are less well studied. Our new findings show that AP-2γ significantly upregulates p21 mRNA and proteins, inhibits cell growth, decreases clonogenic survival. Cell cycle analysis revealed that forced AP-2γ expression induced G1-phase arrest, decreased DNA synthesis, decreased the fraction of cells in S phase. AP-2γ expression also led to cyclin D1 repression, decreased Rb phosphorylation, decreased E2F activity in breast carcinoma cells. AP-2γ binding to the p21 promoter was observed in vivo, the absence of growth inhibition in response to AP-2γ expression in p21 (-/-) cells demonstrated that p21 caused, at least in part, AP-2-induced cell cycle arrest. Finally, the tumor growth of human breast carcinoma cells in vivo was inhibited by the expression of AP-2γ relative to empty vector-infected cells, suggesting that AP-2γ acts as a tumor suppressor. In summary, expression of either AP-2γ or AP-2α inhibited breast carcinoma cell growth; thus, these genes may be therapeutic targets for breast cancer.
    Keywords AP-2 ; p21 ; cell cycle ; carcinoma ; tumor suppressor ; Medicine ; R ; Internal medicine ; RC31-1245 ; Neoplasms. Tumors. Oncology. Including cancer and carcinogens ; RC254-282
    Publishing date 2006-07-01T00:00:00Z
    Publisher Elsevier
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  5. Article ; Online: Triphenylphosphonium derivatives disrupt metabolism and inhibit melanoma growth in vivo when delivered via a thermosensitive hydrogel.

    Kyle C Kloepping / Alora S Kraus / Devin K Hedlund / Colette M Gnade / Brett A Wagner / Michael L McCormick / Melissa A Fath / Dongrim Seol / Tae-Hong Lim / Garry R Buettner / Prabhat C Goswami / F Christopher Pigge / Douglas R Spitz / Michael K Schultz

    PLoS ONE, Vol 15, Iss 12, p e

    2020  Volume 0244540

    Abstract: Despite dramatic improvements in outcomes arising from the introduction of targeted therapies and immunotherapies, metastatic melanoma is a highly resistant form of cancer with 5 year survival rates of <35%. Drug resistance is frequently reported to be ... ...

    Abstract Despite dramatic improvements in outcomes arising from the introduction of targeted therapies and immunotherapies, metastatic melanoma is a highly resistant form of cancer with 5 year survival rates of <35%. Drug resistance is frequently reported to be associated with changes in oxidative metabolism that lead to malignancy that is non-responsive to current treatments. The current report demonstrates that triphenylphosphonium(TPP)-based lipophilic cations can be utilized to induce cytotoxicity in pre-clinical models of malignant melanoma by disrupting mitochondrial metabolism. In vitro experiments demonstrated that TPP-derivatives modified with aliphatic side chains accumulated in melanoma cell mitochondria; disrupted mitochondrial metabolism; led to increases in steady-state levels of reactive oxygen species; decreased total glutathione; increased the fraction of glutathione disulfide; and caused cell killing by a thiol-dependent process that could be rescued by N-acetylcysteine. Furthermore, TPP-derivative-induced melanoma toxicity was enhanced by glutathione depletion (using buthionine sulfoximine) as well as inhibition of thioredoxin reductase (using auranofin). In addition, there was a structure-activity relationship between the aliphatic side-chain length of TPP-derivatives (5-16 carbons), where longer carbon chains increased melanoma cell metabolic disruption and cell killing. In vivo bio-distribution experiments showed that intratumoral administration of a C14-TPP-derivative (12-carbon aliphatic chain), using a slow-release thermosensitive hydrogel as a delivery vehicle, localized the drug at the melanoma tumor site. There, it was observed to persist and decrease the growth rate of melanoma tumors. These results demonstrate that TPP-derivatives selectively induce thiol-dependent metabolic oxidative stress and cell killing in malignant melanoma and support the hypothesis that a hydrogel-based TPP-derivative delivery system could represent a therapeutic drug-delivery strategy for melanoma.
    Keywords Medicine ; R ; Science ; Q
    Subject code 570
    Language English
    Publishing date 2020-01-01T00:00:00Z
    Publisher Public Library of Science (PLoS)
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  6. Article ; Online: AP-2α Inhibits c-MYC Induced Oxidative Stress and Apoptosis in HaCaT Human Keratinocytes

    Frederick E. Domann / Aloysius J. Klingelhutz / Prabhat C. Goswami / Ehab H. Sarsour / Wenqing Sun / Michael J. Hitchler / Lei Yu

    Journal of Oncology, Vol

    2009  Volume 2009

    Keywords Neoplasms. Tumors. Oncology. Including cancer and carcinogens ; RC254-282 ; Internal medicine ; RC31-1245 ; Medicine ; R ; DOAJ:Oncology ; DOAJ:Medicine (General) ; DOAJ:Health Sciences
    Language English
    Publishing date 2009-01-01T00:00:00Z
    Publisher Hindawi Publishing Corporation
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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