The role of p53 in cancer drug resistance and targeted chemotherapy

Abstract

Cancer has long been a grievous disease complicated by innumerable players aggravating its cure. Many clinical studies demonstrated the prognostic relevance of the tumor suppressor protein p53 for many human tumor types. Overexpression of mutated p53 with reduced or abolished function is often connected to resistance to standard medications, including cisplatin, alkylating agents (temozolomide), anthracyclines, (doxorubicin), antimetabolites (gemcitabine), antiestrogenes (tamoxifen) and EGFR-inhibitors (cetuximab). Such mutations in the TP53 gene are often accompanied by changes in the conformation of the p53 protein. Small molecules that restore the wild-type conformation of p53 and, consequently, rebuild its proper function have been identified. These promising agents include PRIMA-1, MIRA-1, and several derivatives of the thiosemicarbazone family. In addition to mutations in p53 itself, p53 activity may be also be impaired due to alterations in p53's regulating proteins such as MDM2. MDM2 functions as primary cellular p53 inhibitor and deregulation of the MDM2/p53-balance has serious consequences. MDM2 alterations often result in its overexpression and therefore promote inhibition of p53 activity. To deal with this problem, a judicious approach is to employ MDM2 inhibitors. Several promising MDM2 inhibitors have been described such as nutlins, benzodiazepinediones or spiro-oxindoles as well as novel compound classes such as xanthone derivatives and trisubstituted aminothiophenes. Furthermore, even naturally derived inhibitor compounds such as α-mangostin, gambogic acid and siladenoserinols have been discovered. In this review, we discuss in detail such small molecules that play a pertinent role in affecting the p53-MDM2 signaling axis and analyze their potential as cancer chemotherapeutics.

Keywords: cytotoxic chemotherapy; drug resistance; medicinal chemistry; prognostic factors; targeted chemotherapy.

Figure 1. Autoregulatory feedback loop between p53 and its negative regulator, MDM2

After activation due to stress signals, p53 upregulates MDM2 gene expression and increases MDM2 protein levels. As negative regulator, MDM2 protein then binds to p53 and induces its degradation [22].

Figure 2. Restoration of p53 conformation by reactivating substances

In cancer cells, the p53 protein is often inactivated by mutations. By binding misfolded and inactivated p53, reactivating compounds can restore its active form and tumor suppressor function [67].

Figure 3. Structure of pyroxanthone 1

Figure 4. Structure of the marine compound siladenoserinol A