The Undervalued Avenue to Reinstate Tumor Suppressor Functionality of the p53 Protein Family for Improved Cancer Therapy-Drug Repurposing

Abstract

p53 and p73 are critical tumor suppressors that are often inactivated in human cancers through various mechanisms. Owing to their high structural homology, the proteins have many joined functions and recognize the same set of genes involved in apoptosis and cell cycle regulation. p53 is known as the ‘guardian of the genome’ and together with p73 forms a barrier against cancer development and progression. The TP53 is mutated in more than 50% of all human cancers and the germline mutations in TP53 predispose to the early onset of multiple tumors in Li–Fraumeni syndrome (LFS), the inherited cancer predisposition. In cancers where TP53 gene is intact, p53 is degraded. Despite the ongoing efforts, the treatment of cancers remains challenging. This is due to late diagnoses, the toxicity of the current standard of care and marginal benefit of newly approved therapies. Presently, the endeavors focus on reactivating p53 exclusively, neglecting the potential of the restoration of p73 protein for cancer eradication. Taken that several small molecules reactivating p53 failed in clinical trials, there is a need to develop new treatments targeting p53 proteins in cancer. This review outlines the most advanced strategies to reactivate p53 and p73 and describes drug repurposing approaches for the efficient reinstatement of the p53 proteins for cancer therapy.

The Function of the Mutant p53-R175H in Cancer

“…However, another p73 isoform, ∆Np73, which lacks the Nterminus, has oncogenic functions by interacting with and inhibiting the function of TAp73 and p53 [30]. The stagnant of p53-targeted drug development might be caused by the ignorance of the importance of p73 in cancer eradication [31]. Mutant p53 can also exert its gain of function by inhibiting p73 [28].…”

“…Mutant p53 can also exert its gain of function by inhibiting p73 [28]. Several promising drugs that can repurpose p73, such as ALA-protoporphyrin IX and verteporfin, are under development [31]. In addition, in breast MDA-MB-231 cells, TGFβ and oncogenic RAS promote the interaction between mutant p53 and SMAD2 by triggering the phosphorylation of the mutant p53 N-terminus through CK1ε/δ kinases.…”

Development of Tailor-Made Dendrimer Ternary Complexes for Drug/Gene Co-Delivery in Cancer

“…It promotes the expression or silencing of a specific gene to achieve a therapeutic effect [ 2 , 3 ]. Gene therapy based on the reestablishment of p53 tumor suppressor protein has been one of the most researched approaches, as TP53 gene is mutated in, about, 50% of all human cancers [ 4 , 5 ]. p53 plays a relevant role in cell apoptosis and in the regulation of cell cycle, being critical for normal cell function [ 6 ].…”

The Role of p53 Family in Cancer

“…These two isoforms are the transcriptionally active (TA) isoforms, acting as tumor suppressors and the N-terminus truncated isoforms (dN), dominant-negative towards TA isoforms; acting as oncogenes. In cancer, the degree of methylation of P1 and P2 dictates the ratio between the TA and dN isoforms and has been reported to significantly alter the response to chemotherapy in several cancer types [3]. In addition, all p53 family proteins undergo alternative splicing at the C-terminus, as exemplified by p53 and p73 (Figure 1A).…”

“…Akin to p53, p73 activity is controlled by protein concentration and p73 protein undergoes similar posttranslational modifications as p53 [5]. The full-length p73 isoform (designated as TAp73α) recognizes the same range of p53 genes involved in apoptosis, cell cycle, or senescence, is an important tumor suppressor which compensates for p53 loss in tumor regression and can be reactivated pharmacologically using repurposed drugs, as I have discussed in [3]. P53 is the best-characterized protein among the p53 protein family and is known to possess both transcription-dependent and transcription-independent functions.…”