Flavopiridol enhances human tumor cell radiosensitivity and prolongs expression of γH2AX foci

Camphausen, Kevin; Brady, Kristin J.; Burgan, William; Cerra, Michael; Russell, J S; Bull, Elizabeth E.A.; Tofilon, Philip J.

doi:10.1158/1535-7163.409.3.4

Cited by 32 publications

(4 citation statements)

References 25 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The proportion of mitotic cells in a control culture was 2.5% (Figure 4B), in agreement with previous reports on PC-3 cells and consonant with the notion that mitosis contributes 30−60 min of the 24 h cell cycle. 27,28 After 48 h treatment with 1, mitotic spindles were observed in 0.4% of the cells, corresponding to an 80% decrease in frequency (Figure 4B). No evident distortion of the mitotic spindles could be observed in the presence of 1 (Figure 4A).…”

mentioning

confidence: 99%

Canthin-6-one Displays Antiproliferative Activity and Causes Accumulation of Cancer Cells in the G2/M Phase

et al. 2014

View full text Add to dashboard Cite

Canthinones are natural substances with a wide range of biological activities, including antipyretic, antiparasitic, and antimicrobial. Antiproliferative and/or cytotoxic effects of canthinones on cancer cells have also been described, although their mechanism of action remains ill defined. To gain better insight into this mechanism, the antiproliferative effect of a commercially available canthin-6-one (1) was examined dose-dependently on six cancer cell lines (human prostate, PC-3; human colon, HT-29; human lymphocyte, Jurkat; human cervix, HeLa; rat glioma, C6; and mouse embryonic fibroblasts, NIH-3T3). Cytotoxic effects of 1 were investigated on the same cancer cell lines by procaspase-3 cleavage and on normal human skin fibroblasts. Strong antiproliferative effects of the compound were observed in all cell lines, whereas cytotoxic effects were very dependent on cell type. A better definition of the mechanism of action of 1 was obtained on PC-3 cells, by showing that it decreases BrdU incorporation into DNA by 60% to 80% and mitotic spindle formation by 70% and that it causes a 2-fold accumulation of cells in the G2/M phase of the cell cycle. Together, the data suggest that the primary effect of canthin-6-one (1) is antiproliferative, possibly by interfering with the G2/M transition. Proapoptotic effects might result from this disturbance of the cell cycle.

show abstract

mentioning

confidence: 99%

Canthin-6-one Displays Antiproliferative Activity and Causes Accumulation of Cancer Cells in the G2/M Phase

et al. 2014

View full text Add to dashboard Cite

show abstract

“…Immunofluorescence analyses of pATM Ser-1981 and phospho-H2A.X on Ser-139 (γH2A.X) were performed as previously described. , All photos were taken using the same parameters and processed by deconvolution. The focus-positive cells are defined as those containing at least five foci …”

Section: Methodsmentioning

confidence: 99%

“…The focus-positive cells are defined as those containing at least five foci. 36 Flow Cytometric Analysis. Cells were treated with 2 μM MSeA for 24 h, followed by a 1À7 day recovery.…”

Section: Immunofluorescence Immunofluorescence Analyses Of Patmmentioning

confidence: 99%

Role for p53 in Selenium-Induced Senescence

Wang

et al. 2011

J. Agric. Food Chem.

View full text Add to dashboard Cite

The tumor suppressor p53 and the ataxia-telangiectasia mutated (ATM) kinase play important roles in the senescence response to oncogene activation and DNA damage. It was previously shown that selenium-containing compounds can activate an ATM-dependent senescence response in MRC-5 normal fibroblasts. Here, the shRNA knockdown approach and other DNA damage assays are employed to test the hypothesis that p53 plays a role in selenium-induced senescence. In MRC-5 cells treated with methylseleninic acid (MSeA, 0-10 μM), depletion of p53 hampers senescence-associated expression of β-galactosidase, disrupts the otherwise S and G2/M cell cycle arrest, desensitizes such cells to MSeA treatment, and increases genome instability. Pretreatment with KU55933, an ATM kinase inhibitor, or NU7026, an inhibitor of DNA-dependent protein kinase, desensitizes MSeA cytotoxicity in scrambled but not p53 shRNA MRC-5 cells. These results suggest that p53 is critical for senescence induction in the response of MRC-5 noncancerous cells to selenium compounds.

show abstract

“…All the photos were taken using the same magnification scale (630X), followed by deconvolution according to the manufacturer's instruction. The pATM S1981 and γH2AX focus-positive cells are defined as those containing at least five foci (Camphausen et al 2004).…”

Section: Immunofluorescencementioning

confidence: 99%

Selenium compounds activate early barriers of tumorigenesis

Kang

Schoene³

et al. 2010

The FASEB Journal

View full text Add to dashboard Cite

Selenium chemoprevention by apoptosis has been well studied, but it is not clear whether selenium can activate early barriers of tumorigenesis, namely senescence and DNA damage response. To test this hypothesis, we treated normal and cancerous cells with a gradient concentration of sodium selenite, methylseleninic acid and methylselenocysteine for 48 h, followed by a recovery of 1-7 days. Here we show that selenium compounds at doses of ≤LD 50 can induce cellular senescence, as evidenced by the expression of senescence-associated β-galactosidase and 5-bromo-2deoxyuridine incorporation, in normal but not cancerous cells. In response to clastogens, the ataxia telangiectasia mutated (ATM) protein is rapidly activated, which in turn initiates a cascade of DNA damage response. We found that the ATM pathway is activated by the selenium compounds, and the kinase activity is required for the selenium induced senescence response. Pretreatment of the MRC-5 noncancerous cells with the antioxidant N-acetylcysteine or 2,2,6,6tetramethylpiperidine-1-oxyl suppresses the selenium induced ATM activation and senescence. Taken together, the results suggest a novel role of selenium in the activation of early tumorigenesis barriers specific in non-cancerous cells, whereby selenium induces an ATM-dependent senescence response that depends on reactive oxygen species.The tumor suppressor p53 is a substrate of the ATM kinase and plays an important role in senescence. To determine mechanism by which selenium induces the ATMdependent senescence, we employed shRNA knockdown approach and other DNA damage assays to determine the role of p53 in the senescence response. Results from senescence-associated expression of β-galactosidase assay indicate that p53 shRNA MRC-5 cells did not show senescent phenotype with a series of concentrations of methylseleninic acid (0-10 μM) after 7-day recovery. However, loss of p53 renders MRC-5 cells more resistant to MSeA treatment and increased its genomic instability.We also observe that MSeA can cause increased irreversible G2/M arrest in scramble MRC-5 cells but treated p53 shRNA MRC-5 can recover back to non-treated status after 7-day recovery. Taken together, p53 is involved in the ATM-dependent senescence in the response of MRC-5 normal cells to selenium compounds. SELENIUM COMPOUNDS ACTIVATE EARLY BARRIERS OF TUMORIGENESIS

show abstract

Flavopiridol enhances human tumor cell radiosensitivity and prolongs expression of γH2AX foci

Cited by 32 publications

References 25 publications

Canthin-6-one Displays Antiproliferative Activity and Causes Accumulation of Cancer Cells in the G2/M Phase

Canthin-6-one Displays Antiproliferative Activity and Causes Accumulation of Cancer Cells in the G2/M Phase

Role for p53 in Selenium-Induced Senescence

Selenium compounds activate early barriers of tumorigenesis

Contact Info

Product

Resources

About