Title: Influence of p53 reactivation by RETRA and its novel analogue on the anti-tumour effect of doxorubicin in tumour cells bearing mutated p53.
Authors: Alexandra A. Dalina1, Alexandra I. Rostovtseva3, Alexey B. Kornev2, Peter M. Chumakov1,4
Affiliations: 1 - Engelhardt Institute of Molecular Biology of the Russian Academy of Sciences, Moscow, Russia; 2 - Institute of Problems of Chemical Physics of the Russian Academy of Sciences, Chernogolovka, Russia; 3 - Faculty of Fundamental Medicine of Lomonosov Moscow State University, Moscow, Russia; 4 - Novosibirsk State University, Novosibirsk, Russia.
Abstract: P53 family comprises three transcription factors: p53, p63, and p73. p53 is a tumour suppressor protein which participates in many cellular processes and mediates cell response to a wide range of stress stimuli. Its importance for cell quality control is supported by the fact that p53 is mutated in about 50% of human malignant tumours. Mutation of one allele inactivates functional p53 and its siblings p73 and p63 by a dominant-negative mechanism forming oligomers that fail to transcriptionally activate target genes which promote cytotoxic and cytostatic effects. The small molecule RETRA which was identified in our laboratory reactivates p53 family function in cells with mutant p53 following by p73-dependent tumour cell growth inhibition. We designed modifications of RETRA and tested the most efficient analogue (estimated by activation of p53-dependent reporter) for ability to inhibit growth of tumour cells alone and in combination with a routinely-used chemotherapeutic drug doxorubicin since activation of p53-dependent reporter is pronounced at concentrations non-toxic for cells with wild-type p53. This approach may provide a specific elimination of tumour cells with mutant p53 allowing to reduce adverse effects and general toxicity of chemotherapy due to decreased doses of drugs. We are also searching for other combinations of small molecules that may enhance anti-tumour effect of chemotherapeutic drugs in cells bearing both mutant and wild-type p53.