Adaptive Responses to Low-Dose/Low-Dose-Rate γ Rays in Normal Human Fibroblasts: The Role of Growth Architecture and Oxidative Metabolism

Toledo, Sonia M. de; Asaad, Nesrin; Prakash, Venkatachalam; Li, Ling; Howell, Roger W.; Spitz, Douglas R.; Azzam, Edouard I.

doi:10.1667/rr0640.1

Cited by 107 publications

(74 citation statements)

References 58 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Micronucleus frequency was significantly (Po0.01) increased in cells exposed to 0.1 Gy delivered acutely ( Figure 3). As expected, protracting delivery of this small dose over 48 h resulted in sparing of induced DNA damage (de Toledo et al, 2006). In contrast, in cells exposed to 4 Gy, the micronucleus frequency was 50-fold greater than background (Figure 3).…”

Section: Exposure Of Mefs To Dpi Results In Reversible Decrease In CLsupporting

confidence: 68%

Regulation of normal cell cycle progression by flavin-containing oxidases

Prakash¹,

Toledo²,

Pandey³

et al. 2007

Oncogene

View full text Add to dashboard Cite

Mechanisms underlying the role of reactive oxygen species (ROS) generated by flavin-containing oxidases in regulating cell cycle progression were examined in human and rodent fibroblasts. Incubation of confluent cell cultures with nontoxic/nonclastogenic concentrations of the flavoprotein inhibitor, diphenyleneiodonium (DPI), reduced nicotinamide adenine dinucleotide phosphate (NAD(P)H) oxidase activity and basal ROS levels, but increased proteolysis of cyclin D1, p21 Waf1 and phospho-p38 MAPK . When these cells were allowed to proliferate by subculture in DPI-free medium, an extensive G 1 delay was observed with concomitant activation of p53/p21 Waf1 signaling and reduced phosphorylation of mitogen-activated kinases. Compensation for decreased oxidant generation by simultaneous exposure to DPI and nontoxic doses of the ROS generators, c-radiation or t-butyl-hydroperoxide, attenuated the G 1 delay. Whereas the DPI-induced G 1 checkpoint was completely dependent on PHOX91, ATM and WAF1, it was only partially dependent on P53. Interestingly, G 1 to S progression was not affected when another flavin-containing enzyme, nitric oxide synthase, was inhibited nor was it associated with changes in mitochondrial membrane potential. Proliferating cells treated with DPI also experienced a significant but attenuated delay in G 2 . We propose that ATM performs a critical function in mediating normal cellular proliferation that is regulated by nonphagocytic NAD(P)H oxidase enzymes activity, which may serve as a novel target for arresting cancer cells in G 1 .

show abstract

Section: Exposure Of Mefs To Dpi Results In Reversible Decrease In CLsupporting

confidence: 68%

Regulation of normal cell cycle progression by flavin-containing oxidases

Prakash¹,

Toledo²,

Pandey³

et al. 2007

Oncogene

View full text Add to dashboard Cite

show abstract

“…Some studies have found that low doses of ionizing radiation induce DNA damage in tumor or normal cells (25). We next focused on H2AX, which is phosphorylated in DNA-damaged cells (26,27).…”

Section: Low Doses Of Ionizing Radiation Do Not Induce Dna Damage In mentioning

confidence: 99%

Low doses of ionizing radiation suppress doxorubicin-induced senescence-like phenotypes by activation of ERK1/2 and suppression of p38 kinase in MCF7 human breast cancer cells

Shin

Woo²,

Lee³

et al. 2010

Int J Oncol

View full text Add to dashboard Cite

Abstract. Low-dose radiation has a variety of effects on cellular activities, including the cell division cycle, apoptosis, proliferation and senescence. However, the effects of low doses of radiation remain controversial. In this study, we examined the effects of low-dose radiation on cellular senescence. We treated MCF7 cells with 0.01 μg/ml doxorubicin to induce replicative senescence, 2 h after exposure to low doses of ionizing radiation of 0.05, 0.1, or 0.2 Gy. The status of p53, senescence-associated ß-galactosidase activity, p38 kinase levels, H2AX levels and ERK/MAPK levels were examined. Low doses of ionizing radiation inhibit doxorubicininduced senescence in human breast cancer MCF7 cells. The phosphorylations of both p38 MAP kinase and p53 induced by doxorubicin were suppressed by low doses of ionizing radiation. The senescence was inhibited without genomic damage, because the level of Á-H2AX protein was not changed. Moreover, low doses of ionizing radiation inhibited senescence through the activation of ERK1/2. The results thus suggest that low doses of radiation suppress doxorubicin-induced replicative senescence through the inhibition of p38-dependent phosphorylation of p53 and by activation of ERK1/2, without genomic damage. Overall, our results suggest that low doses of ionizing radiation may have a protective role against replicative senescence induced by doxorubicin.

show abstract

“…The SDHC mutants also showed cell physiological characteristics associated with cancer cells, including aneuploidy, increases in glucose consumption, and sensitivity to glucose deprivation-induced cytotoxicity (1). Importantly, expression of wildtype (WT) human SDHC in the SDHC mutant background caused prooxidant production, glucose consumption, sensitivity to glucose deprivation-induced cytotoxicity, and aneuploidy to revert to the WT phenotype (1). These data clearly showed that SDHC mutations cause increased O 2 -, H 2 O 2 production, metabolic oxidative stress, and genomic instability and that mutation of genes coding for mitochondrial electron transport chain proteins can contribute to phenotypic changes associated with cancer.…”

mentioning

confidence: 98%

“…, H 2 O 2 , increases in % glutathione disulfide (indicative of oxidative stress), as well as increases in superoxide dismutase activity, relative to parental and vector controls (1). The SDHC mutants also showed cell physiological characteristics associated with cancer cells, including aneuploidy, increases in glucose consumption, and sensitivity to glucose deprivation-induced cytotoxicity (1).…”

mentioning

confidence: 99%

mentioning

confidence: 99%

See 1 more Smart Citation

Mitochondrial-Derived Oxidants and Cellular Responses to Low Dose/Low LET Ionizing Radiation

Spitz¹

2009

View full text Add to dashboard Cite

Oxidants and Cellular Responses to Low Dose/Low LET Ionizing Radiation"; Spitz, Douglas R. (Principal Investigator), 05/15/05 -12/31/09 A. Progress Report: The objective during the last period of support (5/15/05-12/31/09) was to determine the involvement of mitochondrial genetic defects in metabolic oxidative stress and the biological effects of low dose/low LET radiation. Aim 1 was to determine if cells with mutations in succinate dehydrogenase (SDH) subunits C and D (SDHC and SDHD in mitochondrial complex II) demonstrated increases in steady-state levels of reactive oxygen species (ROS; O 2 -and H 2 O 2 ) as well as demonstrating increased sensitivity to low dose/low LET radiation (10 cGy) in vitro. Aim #2 was to determine if specific mitochondrially-derived ROS contributed to increased sensitivity to low dose/low LET radiation in cells containing mutations in SDH subunits in vitro. Aim #3 was to determine if a causal relationship existed between persistent increases in mitochondrial ROS production, alterations in electron transport chain proteins, and genomic instability in the progeny of irradiated cells.Progress in Aim #1 and #2 included the isolation and characterization of SDHC and SDHD mutants in Chinese hamster fibroblasts that were found to demonstrate increased steady-state levels of O 2 -, H 2 O 2 as well as genomic instability (1, 2). The cells expressing SDHC mutations showed 3-fold increases steady-state levels of O 2 -

show abstract

Adaptive Responses to Low-Dose/Low-Dose-Rate γ Rays in Normal Human Fibroblasts: The Role of Growth Architecture and Oxidative Metabolism

Cited by 107 publications

References 58 publications

Regulation of normal cell cycle progression by flavin-containing oxidases

Regulation of normal cell cycle progression by flavin-containing oxidases

Low doses of ionizing radiation suppress doxorubicin-induced senescence-like phenotypes by activation of ERK1/2 and suppression of p38 kinase in MCF7 human breast cancer cells

Mitochondrial-Derived Oxidants and Cellular Responses to Low Dose/Low LET Ionizing Radiation

Contact Info

Product

Resources

About