Pharmacological concentrations of ascorbate radiosensitize glioblastoma multiforme primary cells by increasing oxidative DNA damage and inhibiting G2/M arrest

Herst, Patries M.; Broadley, Kate W.R.; Harper, Jacquie L.; McConnell, Melanie J.

doi:10.1016/j.freeradbiomed.2012.01.021

Cited by 78 publications

(81 citation statements)

References 48 publications

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“…Annexin V-fluorescein isothiocyanate staining was used for a cell apoptosis assay as previously described (31). Propidium iodide (PI) staining was performed to analyze cell cycle progression as previously described (32). Briefly, 1x10 6 colon cancer cells were washed three times in cold phosphate-buffered saline (PBS) and fixed in 4% paraformaldehyde for 30 min.…”

Section: Methodsmentioning

confidence: 99%

Interference of Skp2 effectively inhibits the development and metastasis of colon carcinoma

Chen¹,

Mo²,

Yu³

et al. 2014

Molecular Medicine Reports

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Abstract. Colon cancer is a common type of malignancy in the digestive system. The aim of the present study was to investigate the role of S-phase kinase-associated protein 2 (Skp2) in colon carcinoma and to identify whether depletion of Skp2 by Skp2-RNA interference (RNAi) attenuates the proliferation and migration of colon carcinoma. Three pairs of small interfering (si)RNA were designed based on the Skp2 gene sequence and the most effective one was used to silence the Skp2 gene in SW620 cells. Subsequent to the interference, quantitative polymerase chain reaction and western blot analysis were used for detecting the expression of Skp-2 mRNA and protein, respectively. The data demonstrated that the Skp2-siRNA effectively inhibited proliferation (P<0.01), increased the levels of apoptosis and induced G 0 /G 1 phase arrest of the SW620 cells (P<0.01). Transfection of the Skp2 siRNA into SW620 cells effectively reduced Skp2 protein levels, while p27 protein levels increased. In the in vivo experiments, a lentiviral vector of the Skp2-RNAi transfected into SW620 cells markedly inhibited Skp2 expression, as detected by immunohistochemical analysis of nude mice. Additionally, tumorigenicity experiments showed that inhibition of Skp2 significantly increased the survival rate of nude mice. Thus, the in vitro and in vivo results demonstrated that interference of Skp2 expression significantly inhibited the proliferation and induced the apoptosis of SW620 cells. This suggests that Skp2 protein has an important role in the progression of colon cancer. Therefore, Skp2 may enable the early diagnosis of colon cancer and provide new insights into molecular targets for cancer therapy.

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Section: Methodsmentioning

confidence: 99%

Interference of Skp2 effectively inhibits the development and metastasis of colon carcinoma

Chen¹,

Mo²,

Yu³

et al. 2014

Molecular Medicine Reports

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“…Sensitivity of both primary and immortalized glioblastoma multiforme cells to radiation was enhanced by exposure to pharmacologic ascorbate (33). One Gray (Gy) radiation in combination with 0.5 mM ascorbate decreased viability of primary cells by 15%-20% and viability of the mouse astrocytoma cell line, GL261, by 25% compared with treatment with 1 Gy radiation alone.…”

Section: Synergy With Radiotherapymentioning

confidence: 99%

Parenteral Ascorbate As a Cancer Therapeutic: A Reassessment Based on Pharmacokinetics

Parrow

Leshin

Levine

2013

Antioxidants & Redox Signaling

110

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Significance: Ewan Cameron reported that ascorbate, given orally and intravenously at doses of up to 10 g/day, was effective in the treatment of cancer. Double-blind placebo-controlled clinical trials showed no survival advantage when the same doses of ascorbate were given orally, leading the medical and scientific communities to dismiss the use of ascorbate as a potential cancer treatment. However, the route of administration results in major differences in ascorbate bioavailability. Tissue and plasma concentrations are tightly controlled in response to oral administration, but this can be bypassed by intravenous administration. These data provide a plausible scientific rationale for the absence of a response to orally administered ascorbate in the Mayo clinic trials and indicate the need to reassess ascorbate as a cancer therapeutic. Recent Advances: High dose ascorbate is selectively cytotoxic to cancer cell lines through the generation of extracellular hydrogen peroxide (H 2 O 2 ). Murine xenograft models confirm a growth inhibitory effect of pharmacological concentrations. The safety of intravenous ascorbate has been verified in encouraging pilot clinical studies. Critical Issues: Neither the selective toxicity of pharmacologic ascorbate against cancer cells nor the mechanism of H 2 O 2 -mediated cytotoxicity is fully understood. Despite promising preclinical data, the question of clinical efficacy remains. Future Directions: A full delineation of mechanism is of interest because it may indicate susceptible cancer types. Effects of pharmacologic ascorbate used in combination with standard treatments need to be defined. Most importantly, the clinical efficacy of ascorbate needs to be reassessed using proper dosing, route of administration, and controls.

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“…The overexpression of catalase protected cancer cell from excessive peroxide production as a result of combined menadione/ascorbate anticancer treatment (Glorieux, et al, 2011). Also, the ability of ascorbate to radiosensitize primary human glioblastoma cells and mouse astrocytes and astrocytoma, was investigated and it was concluded that pharmacological concentrations of ascorbate radiosensitize glioblastoma primary cells more than astrocytes and this can be of clinical significance in therapeutic approach (Herst, et al, 2012). Besides, the activation of ferroptosis was shown to be resulted in the nonapoptotic destruction of some cancer cells and inhibiting this process by ferrostatin-1 seems to protect from neurodegeneration (Dixon, et al, 2012).…”

Section: The Potential Therapy In Brain Tumors Regarding Antioxidantsmentioning

confidence: 99%

“…The potential therapeutic effect of resveratrol being a dietary phytochemical antioxidant, is investigated in glioma type brain tumors (Gangliano et al, 2010) and glioblastoma multiforme cells exhibited variable responses to resveratrol depending on the brain associated sulfonation activity of the cells and resveratrol seemed to have value in glioblastoma treatment (Sun, et al, 2012). Also the combination of resveratrol with alkylating agent temozolomide was shown to improve the efficacy of chemotherapy for brain tumors (Herst, et al, 2012). EGCG also exhibited the same effect with temozolomide like as resveratrol in another study, in brain tumor therapy (Chen, et al, 2011).…”

Section: Therapy Via Natural Antioxidantsmentioning

confidence: 99%

The Stance of Antioxidants in Brain Tumors

Atukeren¹,

Yiğitoğlu²

2013

Clinical Management and Evolving Novel Therapeutic Strategies for Patients With Brain Tumors

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Pharmacological concentrations of ascorbate radiosensitize glioblastoma multiforme primary cells by increasing oxidative DNA damage and inhibiting G2/M arrest

Cited by 78 publications

References 48 publications

Interference of Skp2 effectively inhibits the development and metastasis of colon carcinoma

Interference of Skp2 effectively inhibits the development and metastasis of colon carcinoma

Parenteral Ascorbate As a Cancer Therapeutic: A Reassessment Based on Pharmacokinetics

The Stance of Antioxidants in Brain Tumors

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