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Editorials
Figure 1. The p53-MDM2 feedback loop and the effect of RG7388 on this loop in normal and tumor cells. (Top) The p53-MDM2 feedback loop plays a central role in keeping p53 at a low level in non-stressed cells, thus protecting them from undesirable induction of apoptosis. MDM2 is a ubiquitin ligase that facilities the nuclear export of p53 and targets p53 for proteosomal degradation. Under non-stressed conditions, p53 is continuously targeted by MDM2 for degradation. (Bottom) A sec- ond-generation MDM2 inhibitor, RG7388, affects normal and tumor cells differently. RG7388 leads to p53 transcriptional activation in both normal and tumor cells. However, while treatment of chronic lymphocytic leukemia (CLL) cells induces p53 transcriptional activation and subsequent upregulation of mostly pro-apoptotic genes (left), in mature blood cells and hematopoietic (CD34+) progenitors treatment leads to MDM2 upregulation, thus preventing the induction of unwanted apop- tosis coupled with p53 reactivation (right).
and evolution underlies treatment resistance, clinical pro- gression, and disease transformation, particularly in CLL with DDR defects, and efforts are still ongoing to under- stand and counteract this process.
The p53 pathway as a therapeutic target
The TP53 tumor suppressor is a transcription factor that responds to various forms of cellular stress imposed by DNA damage, hypoxia, telomere erosion, nucleotide depletion or oncogene activation. In response to genotox- ic stress, p53 accumulates in the nucleus and becomes activated through numerous post-translational modifica- tions leading to different outcomes depending on the level of stress and cellular context. Under moderate levels of DNA damage, p53 facilitates growth arrest enabling DNA repair, whereas excessive DNA damage causes p53 to initiate programmed cell death - apoptosis.13 This abil- ity of p53 to induce apoptosis in cells under genotoxic stress serves as the underlying mechanism of killing by many chemotherapeutic drugs.
A p53-MDM2 feedback loop plays a central role in keeping p53 at a low level in non-stressed cells, thus pro-
tecting them from undesirable induction of apoptosis (Figure 1). MDM2 (mouse double minute 2 homolog) is a ubiquitin ligase that facilitates the nuclear export of p53 and targets p53 for proteosomal degradation. Under non- stressed conditions, p53 is continuously targeted by MDM2 for degradation. Consequently, inhibition of the p53-MDM2 interaction is an attractive strategy to acti- vate p53-dependent apoptosis in a non-genotoxic man- ner, thus facilitating selectivity and efficiency of tumor cell elimination.14-17
Indeed, the first-generation non-peptide small molecule MDM2 inhibitors, known as Nutlins, have been shown to activate the p53 pathway in cancer cells harboring wildtype p53 both in vitro and in vivo. Nutlins inhibit the p53-binding pocket on MDM2, resulting in the accumula- tion of p53 and restoration of both its transcriptional activity and ability to induce apoptosis. Nutlins have shown preclinical activity in malignancies with elevated MDM2 or MDM4 expression such as sarcomas, neurob- lastomas and some leukemias, including CLL.18-23 Despite these promising initial results, the limited potency and bioavailability of these compounds restrict their clinical
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