Targeting p53 for Novel Anticancer Therapy

Abstract

Carcinogenesis is a multistage process, involving oncogene activation and tumor suppressor gene inactivation as well as complex interactions between tumor and host tissues, leading ultimately to an aggressive metastatic phenotype. Among many genetic lesions, mutational inactivation of p53 tumor suppressor, the "guardian of the genome," is the most frequent event found in 50% of human cancers. p53 plays a critical role in tumor suppression mainly by inducing growth arrest, apoptosis, and senescence, as well as by blocking angiogenesis. In addition, p53 generally confers the cancer cell sensitivity to chemoradiation. Thus, p53 becomes the most appealing target for mechanism-driven anticancer drug discovery. This review will focus on the approaches currently undertaken to target p53 and its regulators with an overall goal either to activate p53 in cancer cells for killing or to inactivate p53 temporarily in normal cells for chemoradiation protection. The compounds that activate wild type (wt) p53 would have an application for the treatment of wt p53-containing human cancer. Likewise, the compounds that change p53 conformation from mutant to wt p53 (p53 reactivation) or that kill the cancer cells with mutant p53 using a synthetic lethal mechanism can be used to selectively treat human cancer harboring a mutant p53. The inhibitors of wt p53 can be used on a temporary basis to reduce the normal cell toxicity derived from p53 activation. Thus, successful development of these three classes of p53 modulators, to be used alone or in combination with chemoradiation, will revolutionize current anticancer therapies and benefit cancer patients.

Figure 1

Current approaches for p53 targeting: p53, the “guardian of the genome,” consists of 393 amino acids with four distinct functional domains. The transactivation domain (TD) and proline-rich domain (PD) is located at the N-terminus, the DNA binding andmutation hot spots domain at the central of themolecule, whereas the oligomerization domain (OD) and regulatory domain (RD) at the C-terminus. On activation, p53 plays a pivotal role in tumor suppression by inducing growth arrest, apoptosis, and senescence, as well as by blocking angiogenesis. Wild-type p53 also confers the sensitivity of cancer cells to chemoradiation. Thus, p53 becomes an appealing therapeutic target for anticancer drug discovery. As illustrated in the figure, three classes of p53 targeting compounds have been identified and characterized. The first class are the compounds that activate or restore wild-type p53 function and can be used in human cancers harboring a wt p53. The second class of compounds reactivates and rescues the mutant p53 with an application in human cancers carrying a p53 mutation. The third class is capable of inhibiting wt p53 and can be used during chemoradiation to block p53 activation in normal cells, thus reducing cytotoxicity.

Figure 2

Synthetic lethality for p53 mutation: Synthetic lethality refers to the situation in which the cancer-associated mutation itself is nonlethal but renders cancer cells susceptible to the second hit, which results in lethal phenotype. Because p53 is most frequently mutated in more than half of human cancer cells, it is feasible in theory to use this strategy to identify drug candidates that preferentially kill cancer cells with a p53 mutation. The p53 synthetic lethal drugs, if identified and developed, should have a minimal toxicity to normal cells and can be used for cancer chemoprevention and treatment of mutant p53-containing cancers.

Table 1

Structure of Small-Molecule p53 Activators, Reactivators, and Inhibitors.