Abstract
Lung cancer is a serious public health problem. Although there has been significant progress in chemotherapy, non-small cell lung cancer is still resistant to current treatments, primarily because of the slow rate of cell development. It is thus important to find new molecules directed against targets other than proliferation agents. Considering the high proportion of mutant proteins in tumor cells, and the high rate of mutation of the TP53 gene in all cancers, and in NSCLC in particular, this gene is a perfect target. Certain new molecules have been shown to restore the activity of mutated p53 protein, for example PRIMA-1, which reactivates the His273 mutant p53. In a previous study, we presented triazine A190, a molecule with a cytostatic activity that blocks cells in the G1 phase and induces apoptosis. Here, we show that A190 not only restores mutant p53 activity, but also induces an overexpression of the NEDD9 gene, leading to apoptotic death. These findings might offer hope for the development of new targeted therapies, specific to tumor cells, which spare healthy cells.
Highlights
Regular progress is being made in chemotherapy, including for non-small cell lung cancer (NSCLC), which shows significant improvement when treated with cis-platin in association with older, conventional, molecules
We reported tumor regression on nude mice xenografted with NSCLC-N6-L16
We provide strong evidence that, in the presence of A190, the His[273] p53 mutated protein recovers its capacity to bind DNA and enables the overexpression of NEDD9, which leads to apoptosis
Summary
Regular progress is being made in chemotherapy, including for non-small cell lung cancer (NSCLC), which shows significant improvement when treated with cis-platin in association with older, conventional, molecules. Developed by a Swedish laboratory, it has a significant cytostatic effect on cell lines with a mutated TP53, but is not toxic in wild type TP53 gene cell lines, as it has the capacity to restore the wild type spatial conformation of the central domain of mutated p53 proteins, or to create a new p53-DNA interaction. These proteins increase their binding DNA capacity and in particular their effectiveness as a transcription factor. A derivate of PRIMA-1, APR-246, is currently in phase I of clinical trials[13]
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