| P53 mediates tumor suppression by activating the transcription of multiple genes specifically involved in cell cycle regulation, apoptosis, and genomic stability. Its activation responds to various stress signals. Mutant p53 proteins fail to bind DNA and transactivate p53 target genes that mediate cell cycle arrest or apoptosis. Mutation of the p53 tumor suppressor gene is the most frequently reported genetic defect in human lung cancer, with mutations observed in greater than 50% of non-small cell lung cancer. The frequent mutation of p53 and loss of p53 function in tumors make mutant p53 a prime target for pharmacological therapeutic interventions in cancer. The novel small molecule PRIMA-1 (p53-dependent reactivation and induction of massive apoptosis) has been shown to induce apoptosis in human tumor cell lines containing mutant p53 by restoration of the tumor suppressor function of p53. This is believed to be mediated by a change in the conformation of mutated p53 protein, restoring DNA binding and activation of p53 target genes. We investigated this compound in several human lung cancer cell lines A549 (wild type p53), H23 (mutant p53, 246I), H211 (mutant p53, 248Q), and H1155 (mutant p53, 273H). We found that PRIMA-1 selectively induced apoptosis in lung cancer cells containing mutant p53 (H23, H211 and H1155), but was less toxic to the cells containing wild type p53 (A549). In addition, we found that PRIMA-1 up-regulates micro RNA 34s to promote apoptosis in the lung cancer cells containing mutant p53.
We have previously developed a line of transgenic mice in which a frequent mutant p53(273H) is expressed in a lung specific manner through the control of the surfactant C (SPC) promoter. These mice develop a single lung tumor with histological characteristics of human adenocarcinomas. Here we propose to treat these lung tumor bearing mice with PRIMA-1 either as a single agent or in combination with cisplatin. We hypothesize that: 1. the small molecule PRIMA-1 can be used to restore the p53 function to mutant p53 leading to regression of lung cancers in the SPC-p53/273H transgenic mice. 2. PRIMA-1 can induce apoptosis in the non small cell lung cancers containing mutant p53(273H). 3. Prima-1 can up-regulate tumor suppressor micro RNA 34 family to induce apoptosis. 4. Combination of PRIMA-1 with cisplatin will increase the response of lung tumors to anticancer therapy.
The aim of this study is to uncover the potential role of PRIMA-1 in inducing apoptosis in spontaneous non small cell lung cancers. We are especially interested in the relationship between PRIMA-1 and micro RNAs in the apoptotic pathway in spontaneous non small cell lung cancers. Knowledge obtained from this study may help guide therapeutic strategies to develop effective strategies for p53-related pharmacological therapeutic intervention in patients with lung cancers.
|
