Senescence-like changes induced by hydroxyurea in human diploid fibroblasts

Yeo, Eui‐Ju; Hwang, Young-Soo; Kang, Chang‐Mo; Kim, I H; Kim, D I; Parka, J S; Choy, Hyon E.; Park, W Y; Park, S C

doi:10.1016/s0531-5565(00)00108-x

Cited by 70 publications

(50 citation statements)

References 71 publications

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“…Moderate doses of doxorubicin induced a senescent phenotype in 11 out of 14 tumor cell lines, independent of p53 status [38]. A similar effect has been observed in cell lines derived from human tumors treated with cisplatin [39], hydroxyurea [40], and bromodeoxyuridine [41], which are all DNA-damaging agents. The propensity of tumor cells to undergo senescence in response to damage induced by commonly used chemicals was compared in cell lines from various origins [23].…”

Section: Discussionmentioning

confidence: 72%

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Cellular Senescence Controlled by p53 is a Barrier to Environmental Carcinogenesis

Carnero¹

2015

J Carcinog Mutagen

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Cancer development in humans and animals may be caused by environmental factors. It has been estimated that approximately 80% of human tumors are generated by exposure to environmental carcinogens. The carcinogens may initiate or induce progression of tumors in several ways. Cellular senescence is a natural barrier used by cells to respond to stress. The molecular analysis of immortal clones shows alterations, either structural or epigenetic, in the genes involved in cellular senescence. It is thought that these alterations are caused directly by mutating or methylating the genes involved in cellular senescence. Therefore, understanding cellular senescence and how it can be modified by environmental carcinogens may be essential to control the increase in cancer prevalence. In the present work, we explored the role of cellular senescence barrier in the carcinogenic potential of some known carcinogens. We found that most carcinogens tested induce a primary senescent response in diploid mouse embryonic fibroblasts (MEFs) and the clones arising with proliferative capacity contain mutated p53 protein. This primary response of senescence induction is abolished in the presence of the p53 inhibitor, pifithrin-a. Under these conditions, the tumorigenic potential of carcinogens is greatly increased. Upon elimination of pifithrin-a from the media, cellular senescence is restored. Therefore, the first cellular response to a carcinogen is a cell cycle arrest program that may result in a permanent arrest with features of cellular senescence. If there is a concomitant alteration of genes involved in cellular senescence, which promotes cellular immortalization, a further carcinogenic insult may increase the chances of tumorigenesis and a malignant clone may develop.

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Section: Discussionmentioning

confidence: 72%

“…A moderate response was observed with ionizing radiation, cytarabine, and etoposide. The induction of senescence by the drugs was dose dependent and correlated with the growth arrest observed in culture [8,[40][41][42]. Drug-induced senescent phenotypes have been confirmed in vivo ( [22,43,44] and references therein).…”

Section: Discussionmentioning

confidence: 99%

Cellular Senescence Controlled by p53 is a Barrier to Environmental Carcinogenesis

Carnero¹

2015

J Carcinog Mutagen

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“…Because cellular senescence is evidenced by permanent cell cycle arrest as well as elevated SA‐β‐gal expression (Yeo et al ., 2000b), cellular SA‐β‐gal activity was monitored by X‐gal staining. Treatment of young HDFs with 1 mM PPKO induced morphological enlargement and increased SA‐β‐gal staining in a time‐dependent manner (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Cellular senescence has also been characterized by increases in the levels of some senescence‐associated proteins, such as P‐ERK1/2 (Lim et al ., 2000), caveolin‐1 (Park et al ., 2000), and cell cycle regulators like p53, p16 ink4a , and p21 waf1 (Yeo et al ., 2000b). Therefore, to confirm PPKO‐induced cellular senescence, we examined levels of these proteins by Western blot analysis after treating HDFs with 1 mM PPKO for 3–7 days.…”

Section: Resultsmentioning

confidence: 99%

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Phenyl 2‐pyridyl ketoxime induces cellular senescence‐like alterations via nitric oxide production in human diploid fibroblasts

et al. 2015

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SummaryPhenyl‐2‐pyridyl ketoxime (PPKO) was found to be one of the small molecules enriched in the extracellular matrix of near‐senescent human diploid fibroblasts (HDFs). Treatment of young HDFs with PPKO reduced the viability of young HDFs in a dose‐ and time‐dependent manner and resulted in senescence‐associated β‐galactosidase (SA‐β‐gal) staining and G2/M cell cycle arrest. In addition, the levels of some senescence‐associated proteins, such as phosphorylated ERK1/2, caveolin‐1, p53, p16ink4a, and p21waf1, were elevated in PPKO‐treated cells. To monitor the effect of PPKO on cell stress responses, reactive oxygen species (ROS) production was examined by flow cytometry. After PPKO treatment, ROS levels transiently increased at 30 min but then returned to baseline at 60 min. The levels of some antioxidant enzymes, such as catalase, peroxiredoxin II and glutathione peroxidase I, were transiently induced by PPKO treatment. SOD II levels increased gradually, whereas the SOD I and III levels were biphasic during the experimental periods after PPKO treatment. Cellular senescence induced by PPKO was suppressed by chemical antioxidants, such as N‐acetylcysteine, 2,2,6,6‐tetramethylpiperidinyloxy, and L‐buthionine‐(S,R)‐sulfoximine. Furthermore, PPKO increased nitric oxide (NO) production via inducible NO synthase (iNOS) in HDFs. In the presence of NOS inhibitors, such as L‐NG‐nitroarginine methyl ester and L‐NG‐monomethylarginine, PPKO‐induced transient NO production and SA‐β‐gal staining were abrogated. Taken together, these results suggest that PPKO induces cellular senescence in association with transient ROS and NO production and the subsequent induction of senescence‐associated proteins.

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Stem cell dynamics during growth, feeding, and starvation in the basal flatworm Macrostomum sp. (Platyhelminthes)

Nimeth

Mahlknecht

Mezzanato

et al. 2004

Developmental Dynamics

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Senescence-like changes induced by hydroxyurea in human diploid fibroblasts

Cited by 70 publications

References 71 publications

Cellular Senescence Controlled by p53 is a Barrier to Environmental Carcinogenesis

Cellular Senescence Controlled by p53 is a Barrier to Environmental Carcinogenesis

Phenyl 2‐pyridyl ketoxime induces cellular senescence‐like alterations via nitric oxide production in human diploid fibroblasts

Stem cell dynamics during growth, feeding, and starvation in the basal flatworm Macrostomum sp. (Platyhelminthes)

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