Clinical Significance of the p53 Pathway and Associated Gene Therapy in Non-Small Cell Lung Cancers

Abstract

Many molecules, including several regulators and various target genes, are involved in the biological functions of p53, thus making the p53 pathway rather complicated. However, recent clinical studies have demonstrated that most human cancers have an abnormality in some of the molecules associated with the p53 pathway. Most non-small cell lung cancers (NSCLCs) have either mutations of p53, a reduced p14 alternate reading frame expression, a reduced herpesvirus-associated ubiquitin-specific protease expression or a reduced p33 inhibitor of growth gene1b expression. As a result, the balance of expression of p53 target genes, such as p21, Bax and PUMA, regulates the biological behavior and determines the fate of tumor cells. To date, many studies on cancer gene therapy using these molecules associated with the p53 pathway have been performed to develop new strategies for treating NSCLC patients. Thus, the establishment of a comprehensive and simple evaluation protocol for the p53 pathway is required for clinical use.

WTp53 induction does not override MTp53 chemoresistance and radioresistance due to gain-of-function in lung cancer cells

“…When taken together, these results suggest that a therapeutic maneuver that solely reintroduces WTp53 expression (e.g., adenoviral WTp53 therapies) on a MTp53 background may not necessarily overcome MTp53-mediated resistance. This could explain suboptimal responses in some patients using adenoviral WTp53 therapy in clinical trials (31,33). Clinical trials are awaited for compounds, such as PRIMA-1 (34), which can revert MTp53 back into a WTp53 conformation (as monotherapy or an adjunct to radiotherapy and chemotherapy) to determine their relative efficacy as p53-targeting agents.…”

“…For example, in most non-small cell lung cancers, p53 can be disrupted through mutation or decreased expression leading to a poor prognosis (31). As a result, the balance of expression of p53 target genes, such as p21 WAF1 , Bax, and PUMA, may alter the biological behavior and sensitivity of tumor cells to cancer therapy (32).…”

“…These therapies have been suggested as novel monotherapies or as relative sensitizers when used in combination with chemotherapy and radiotherapy in several cancers (31,33,34). Whether this maneuver is successful may depend on whether WTp53 function can override independent MTp53 effects [e.g., gain-of-function (GOF)] with respect to the cellular sensitivity to DNAdamaging agents (35).…”

Rosiglitazone inhibits α4 nicotinic acetylcholine receptor expression in human lung carcinoma cells through peroxisome proliferator-activated receptor γ-independent signals

“…Thiazolidinediones including rosiglitazone have been shown to increase the expression of p53 in several tumor cells (38, 39). As a tumor suppressor gene, p53 is lost or functionally inactivated in the majority of human tumors including lung (40). p53 mutations are also frequent in tobacco-related cancers, and overexpression of p53 inhibits NSCLC growth and induces apoptosis both in vitro and in vivo (20, 41).…”

Synergistic cytotoxic effects of recombinant human adenovirus p53 and radiation at various time points in A549 lung adenocarcinoma cells

“…To date, dysfunction of tumor suppressor genes has been confirmed as the most significant genetic damage in human cancers. Mutations or deletions of p53 occur in 50-70% of non-small cell lung cancers (NSCLCs) and are associated with poor prognosis of lung cancer patients (3,4).…”