Specific activation of the p53 pathway by low dose actinomycin D: a new route to p53 based cyclotherapy.
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.
Choong
Meng Ling
ML
Experimental Therapeutics Centre, Singapore.
Yang
Henry
H
Lee
May Ann
MA
Lane
David P
DP
D000903:Antibiotics, Antineoplastic / Q000494:pharmacology*; D017209:Apoptosis; D002453:Cell Cycle; D045744:Cell Line, Tumor; D003609:Dactinomycin / Q000494:pharmacology*; D020869:Gene Expression Profiling; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D010766:Phosphorylation; D010879:Piperazines / Q000494:pharmacology; D013997:Time Factors; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*
D000903:Antibiotics, Antineoplastic; D007093:Imidazoles; D010879:Piperazines; D016159:Tumor Suppressor Protein p53; D003609:Dactinomycin; C482205:nutlin 3