MDM2 Inhibitors as Potential Anti-Cancer Agents for Treating Osteosarcoma

MDM2 Inhibitors as Potential Anti-Cancer Agents for Treating Osteosarcoma

Osteosarcoma (OS) is the most common type of bone cancer that affects thousands of young adults every year and requires immediate attention. One major regulatory pathway that is activated in cancer cells is the inhibitory interaction between Murine Double Minute 2 (MDM2)-p53 tumor suppressor gene. Hence, blocking the MDM2-p53 interaction has long been considered to offer a broad range of cancer therapeutic strategy. In this study, we determined the differential mechanism of apoptosis induced by the two small-molecule inhibitors of MDM2, RG-7388, and Nutlin-3, in SJSA-1 Osteosarcoma cells. Interestingly, RG-7388 was able to enhance the phosphorylation of anti-apoptotic protein Mcl-1 at Ser-159 that significantly enhanced the degradation of this protein. Degradation of Mcl- 1 relieved the pro-apoptotic protein, Bak and thus initiated the process of apoptosis. On the other hand, Nutlin-3 caused the release of Bax from the Bcl-2/Bax complex, which led to the inactivation of Bcl-2, and subsequently loss of mitochondrial membrane potential. The above mentioned intrinsic pathway events seems to cause the release of cyt-C and Apaf-1, and thereby triggering apoptosis. The results of our study demonstrate that MDM2 inhibitors could become valuable drugs to treat osteosarcoma. (This project was supported by the Royal dames of Cancer Research, Ft. Lauderdale, FL).