Accumulation of oxidatively induced clustered DNA lesions in human tumor tissues

Nowsheen, Somaira; Wukovich, Rebecca L.; Aziz, Khaled; Kalogerinis, Peter T.; Richardson, Christopher; Panayiotidis, Mihalis Ι.; Bonner, William M.; Sedelnikova, Olga A.; Georgakilas, Alexandros G.

doi:10.1016/j.mrgentox.2008.09.010

Cited by 72 publications

(58 citation statements)

References 45 publications

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“…The implication of oxidative stress in genomic instability, cancer development, and cancer progression has been supported by experimental and clinical studies (24)(25)(26). Moreover, high levels of oxidative stress have been documented in cancer cells and human cancer tissues, including from PCA (12,(27)(28)(29)(30).…”

Section: Discussionmentioning

confidence: 95%

A Novel Experimental Heme Oxygenase-1–Targeted Therapy for Hormone-Refractory Prostate Cancer

Alaoui‐Jamali

Bismar

Gupta³

et al. 2009

Cancer Research

121

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Heme oxygenase-1 (HO-1), a member of the heat shock protein family, plays a key role as a sensor and regulator of oxidative stress. Herein, we identify HO-1 as a biomarker and potential therapeutic target for advanced prostate cancer (PCA). Immunohistochemical analysis of prostate tissue using a progression tissue microarray from patients with localized PCA and across several stages of disease progression revealed a significant elevation of HO-1 expression in cancer epithelial cells, but not in surrounding stromal cells, from hormonerefractory PCA (HRPCA) compared with hormone-responsive PCA and benign tissue. Silencing the ho-1 gene in HRPCA cells decreased the HO-1 activity, oxidative stress, and activation of the mitogen-activated protein kinase-extracellular signalregulated kinase/p38 kinase. This coincided with reduced cell proliferation, cell survival, and cell invasion in vitro, as well as inhibition of prostate tumor growth and lymph node and lung metastases in vivo. The effect of ho-1 silencing on these oncogenic features was mimicked by exposure of cells to a novel selective small-molecule HO-1 inhibitor referred to as OB-24. OB-24 selectively inhibited HO-1 activity in PCA cells, which correlated with a reduction of protein carbonylation and reactive oxygen species formation. Moreover, OB-24 significantly inhibited cell proliferation in vitro and tumor growth and lymph node/lung metastases in vivo. A potent synergistic activity was observed when OB-24 was combined with Taxol. Together, these results establish HO-1 as a potential therapeutic target for advanced PCA. [Cancer Res 2009;69(20):8017-24]

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Section: Discussionmentioning

confidence: 95%

A Novel Experimental Heme Oxygenase-1–Targeted Therapy for Hormone-Refractory Prostate Cancer

Alaoui‐Jamali

Bismar

Gupta³

et al. 2009

Cancer Research

121

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“…Second, Gln metabolism provides a source of reducing equivalents (NADPH) necessary to maintain GSH in its reduced state. 17 Studies have demonstrated that breast cancers show high levels of oxidative stress as verified by the detection of oxidative DNA adducts in breast cancer tissue 31 or a significant raise in oxidative stress markers in the plasma from breast cancer patients. 32 Moreover, the use of chemotherapy increases oxidative stress 33 FAC chemotherapy and radiotherapy promote further oxidative shift, which potentiate already existing chronic oxidative stress linked to breast cancer.…”

Section: Resultsmentioning

confidence: 99%

Oxidative stress parameters in women with breast cancer undergoing neoadjuvant chemotherapy and treated with nutraceutical doses of oral glutamine

Farias¹,

Furtado²,

Guimarães³

et al. 2011

Acta Cir. Bras.

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PURPOSE: To evaluate the effects of oral administration of GLN on the oxidative stress in women with breast cancer undergoing neoadjuvant FAC chemotherapy (5 fluouracil 500 mg/m²+Doxorubicin 50 mg/m²+Cyclophosphamide 500 mg/m² body surface area). METHODS: Twenty women (mean age: 51.7 years) with breast ductal carcinomas classified as T3 or T4 were included in the study, regardless of pre or post menopause status. Sachets containing glutamine 15g ("A") or milk protein 15g ("B") were prepared by a registered pharmacist. Allocation of patients was made by software program. Patients who received sachets labeled "A" were included in G1 group. The remaining patients, treated with the preparation labeled "B", were included in group G2. Sachets contents were blended in 150 ml of drinking water, and were given daily to each patient during the entire course of neoadjuvant chemotherapy. Peripheral blood samples were collected in the first day of each of the three cycles of chemotherapy before drug infusion. Tumor and normal breast samples were collected at the end of Patey´s surgical procedure. Samples were analysed for GSH and TBARS contents. RESULTS: TBARS and GSH values were not different in breast healthy and tumor tissues nor blood when comparing control (G-2) and glutamine-treated (G-1) patients. Also, no significant differences were found in TBARS and GSH levels comparing different timepoints within the same group. CONCLUSION: Oral GLN (15g/kg/day) offers no protection against systemic or local oxidative stress in women with breast Ca undergoing neoadjuvant chemotherapy (FAC).

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“…In addition, they showed evidence of bystander or so-called distal effects [12] . In a later study, Nowsheen et al [5] showed that, in the majority of human tumor cases examined, there were higher levels of OCDLs in tumors compared with normal tissues. These data suggest for the first time the importance of endogenous non-DSB clusters in human cancer and their potential use as cancer biomarkers.…”

Section: Detection Of Ocdls In Vivo: Potential Clinical Applicationsmentioning

confidence: 92%

“…Georgakilas and his team through collaborations with various elite research groups (ECU, NCI) have taken advantage of the properties of human repair enzymes OGG1 (oxidized purines), EndoIII (oxidized pyrimidines) and APE1 (abasic sites) in order to detect a variety of bistranded OCDLs in human and mouse tissues, using adaptations of DNA gel electrophoresis [4][5][6][7][8] . The concepts in DNA cluster quantification are simple, but their execution is technically and analytically demanding.…”

Section: Detection Of Ocdls In Vivo: Potential Clinical Applicationsmentioning

confidence: 99%

Detection of clustered DNA lesions: Biological and clinical applications

Georgakilas

2011

WJBC

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Humans are daily exposed to background radiation and various sources of oxidative stress. My research has focused in the last 12 years on the effects of ionizing radiation on DNA, which is considered as the key target of radiation in the cell. Ionizing radiation and endogenous cellular oxidative stress can also induce closely spaced oxidatively induced DNA lesions called "clusters" of DNA damage or locally multiply damage sites, as first introduced by John Ward. I am now interested in the repair mechanisms of clustered DNA damage, which is considered as the most difficult for the cell to repair. A main part of my research is devoted to evaluating the role of clustered DNA damage in the promotion of carcinogenesis in vitro and in vivo . Currently in my laboratory, there are two main ongoing projects. (1) Study of the role of BRCA1 and DNA-dependent protein kinase catalytic subunit repair proteins in the processing of clustered DNA damage in human cancer cells. For this project, we use several tumor cell lines, such as breast cancer cell lines MCF-7 and HCC1937 (BRCA1 deficient) and human glioblastoma cells MO59J/K; and (2) Possible use of DNA damage clusters as novel cancer biomarkers for prognostic and therapeutic applications related to modulation of oxidative stress. In this project human tumor and mice tissues are being used.

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Accumulation of oxidatively induced clustered DNA lesions in human tumor tissues

Cited by 72 publications

References 45 publications

A Novel Experimental Heme Oxygenase-1–Targeted Therapy for Hormone-Refractory Prostate Cancer

A Novel Experimental Heme Oxygenase-1–Targeted Therapy for Hormone-Refractory Prostate Cancer

Oxidative stress parameters in women with breast cancer undergoing neoadjuvant chemotherapy and treated with nutraceutical doses of oral glutamine

Detection of clustered DNA lesions: Biological and clinical applications

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