MDM2 Oncogene as a Novel Target for Human Cancer Therapy

Abstract

The MDM2 oncogene was first cloned as an amplified gene on a murine double-minute chromosome in the 3T3DM cell line, a spontaneously transformed derivative of BALB/c 3T3 cells. The MDM2 oncogene has now been shown to be amplified or overexpressed in many human cancers. It also has been suggested that MDM2 levels are associated with poor prognosis of several human cancers. The most exciting finding is the MDM2-p53 autoregulatory feedback loop that regulates the function of the p53 tumor suppressor gene. The MDM2 gene is a target for direct transcriptional activation by p53, and the MDM2 protein is a negative regulator of p53. The MDM2 oncoprotein binds to the p53 protein, inhibiting p53 functions as a transcription factor and inducing p53 degradation. The p53 tumor suppressor has an important role in cancer therapy, with p53-mediated cell growth arrest and/or apoptosis being major mechanisms of action for many clinically used cancer chemotherapeutic agents and radiation therapy. Therefore, the MDM2-p53 interaction may be a target for cancer therapy. In addition, the negative regulation of p53 by MDM2 may limit the magnitude of p53 activation by DNA damaging agents, thereby limiting their therapeutic effectiveness. If the MDM2 feed-back inhibition of p53 is interrupted, a significant increase in functional p53 levels will increase p53-mediated therapeutic effectiveness. Several approaches have now been tested using this strategy, including polypeptides targeted to MDM2-p53 binding domain and antisense oligonucleotides that specifically inhibit MDM2 expression. In addition to the interaction with p53, the MDM2 protein has been found to have interactions with other cellular proteins such as pRb and E2F-1. Although the exact function and significance of these interactions are not fully understood, the p53-independent functions of MDM2 may have a role in cancer etiology and progression, indicating that the MDM2 oncogene is a potential molecular target for cancer therapy.

The pyrido[b]indole MDM2 inhibitor SP-141 exerts potent therapeutic effects in breast cancer models

“…Both animal studies with transgenic mice and clinical observations have established that MDM2 is involved in cancer development and the response to treatment, both dependent and independent of p53 (refs 25,26). We and others have suggested that MDM2 could be used as a target for cancer therapy and prevention and have provided evidence supporting this notion [27][28][29][30] . Thus far, most MDM2 inhibitors have been designed to block the MDM2-p53 binding, such as nutlin-3 (ref.…”

MDM2 and CDK4 immunohistochemistry is a valuable tool in the differential diagnosis of low-grade osteosarcomas and other primary fibro-osseous lesions of the bone

“…7 However, the difference would be important with the discovery of targeted molecular therapy. 62 Despite standardized protocols, the formalin fixation of tissues and decalcification by acid-based products may result in the failure of FISH by hydrolysis of DNA and in the loss of sensitivity of immunohistochemical analysis. For example, of six cases of low-grade osteosarcoma with both biopsy and resection material available (data not shown), the IHC results were similar for both specimens in our series, except for one case.…”

Activation of p53 by MDM2 antagonists has differential apoptotic effects on Epstein–Barr virus (EBV)-positive and EBV-negative Burkitt's lymphoma cells

“…[6][7][8][9] Given the key role of p53 in determining cell fate, several strategies for disrupting the p53-MDM2 interaction have been explored. 10,11 Recently, potent, stable and selective smallmolecule antagonists of MDM2 have been synthesized. Among these molecules, nutlins are cis-imidazoline compounds that bind to MDM2, thereby preventing its molecular interaction with p53 and inducing activation of the p53 pathway.…”