Specific activation of the p53 pathway by low dose actinomycin D: A new route to p53 based cyclotherapy

Specific activation of the p53 pathway by low dose actinomycin D: A new route to p53 based cyclotherapy
Title:
Specific activation of the p53 pathway by low dose actinomycin D: A new route to p53 based cyclotherapy
Other Titles:
Cell Cycle
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Publication Date:
01 September 2009
Citation:
Specific activation of the p53 pathway by low dose actinomycin D: A new route to p53 based cyclotherapy Meng Ling Choong, Henry Yang, May Ann Lee, David P. Lane Cell Cycle Vol. 8, Iss. 17, 2009
Abstract:
The activation of p53 has been proposed as a novel anti-cancer treatment in two distinct contexts. In the first activation of p53 in tumor cells can promote apoptosis and senescence and enhance the anti-tumor activity of cytotoxic chemotherapeutic drugs. In the second application activation of p53 in normal tissues can cause a reversible cell cycle arrest that can be used to protect normal cells from the action of anti-mitotics. In this cyclotherapy role p53 mutant tumor cells are not arrested and remain sensitive to anti-mitotics. The advent of specific p53 activating molecules such as nutlin-3 has encouraged both approaches. We have sought for a clinically approved drug that can mimic nutlin-3. We show here that low doses of actinomycin D mimic nutlin-3 in the highly specific activation of p53 dependant transcription, in the induction of a reversible protective growth arrest in normal cells and in the enhancement of the activity of chemotherapeutic drug induced killing of p53 positive human tumor cells. While high doses of actinomycin D reveal its more non-specific activities, low doses of the drug will allow exploration of the value of p53 activation in preclinical and clinical models before nutlin-3 like drugs are approved.
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ISSN:
1538-4101
1551-4005
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