Superactivation of p53 Using Drug Combinations and New Insights into p53 Functions and Anticancer Therapy

The p53 tumour suppressor protein exerts its influence on cells by regulating the expression of more than one thousand genes. To study p53 functions, cells are treated with various p53 activators, mostly established or experimental anticancer drugs. Some of these substances strongly collaborate in the activation of p53, which is manifested by a pronounced increase in the number of p53 molecules phosphorylated at both the amino and carboxyl terminus, a sign of p53 activation. Another manifestation of this collaboration is an increase in the number of upregulated genes. A good example of apparent synergy is the treatment of cells with actinomycin D and nutlin-3a, although other drug combinations show similar effects. The molecular mechanism underlying this collaboration is not precisely known. This superactivation of p53 has potential therapeutic applications. For example, it strongly sensitises cancer cells to apoptosis induced by FASLG, a ligand of the FAS death receptor. Moreover, superactivated p53 enables the identification of new p53 target genes, which helps us to better understand poorly studied p53 functions, such as the regulation of innate immunity, modification of cell microenvironments, removal of apoptotic bodies, tissue repair, and hormone production. However, innovative drug combinations targeting the p53 pathway have yet to be successfully translated into clinical practice.