Temozolomide induces senescence but not apoptosis in human melanoma cells View Full Text


Ontology type: schema:ScholarlyArticle      Open Access: True


Article Info

DATE

2007-10-30

AUTHORS

N M Mhaidat, X D Zhang, J Allen, K A Avery-Kiejda, R J Scott, P Hersey

ABSTRACT

Temozolomide (TMZ), a DNA alkylating agent used in the treatment of melanoma, is believed to mediate its effect by addition of a methyl group to the O6 position of guanine in DNA. Resistance to the agent may be in part due to the activity of O6-methylguanine-DNA methyl transferase (MGMT). In the present study, we show that sensitivity of melanoma cells to TMZ was dependent on their p53 status and levels of MGMT. Analysis of the mechanisms underlying reduced viability showed no evidence for induction of apoptosis even though marked levels of apoptosis was seen in TK6 lymphoma cells. Sensitivity of melanoma cells was associated with p53-dependent G2/M cell cycle arrest and induction of senescence. To verify the role of p53, the assays were repeated in presence of pifithrin-α, an inhibitor of p53. This resulted in increased viability of melanoma cells with wild-type p53 and reversed G2/M cell cycle arrest. Paradoxically, apoptosis was increased in melanoma but decreased as expected in TK6 lymphoma cells. These results are consistent with the view that TMZ is relatively ineffective against melanoma due to defective apoptotic signalling resulting from activation of p53. The nature of the defects in apoptotic signalling remains to be explored. More... »

PAGES

1225-1233

Identifiers

URI

http://scigraph.springernature.com/pub.10.1038/sj.bjc.6604017

DOI

http://dx.doi.org/10.1038/sj.bjc.6604017

DIMENSIONS

https://app.dimensions.ai/details/publication/pub.1020206627

PUBMED

https://www.ncbi.nlm.nih.gov/pubmed/17968428


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