A novel inhibitor of MDM2 oncogene blocks metastasis of hepatocellular carcinoma and overcomes chemoresistance

Abstract

Overexpression of the MDM2 oncogene and mutations in the p53 tumor suppressor commonly occur in hepatocellular carcinoma (HCC) and are associated with increased mortality due to this disease. Inhibiting MDM2 has been demonstrated to be a valid approach for the treatment of HCC. However, most of the MDM2 inhibitors evaluated to date have been designed to block the MDM2 and p53 binding, and have limited efficacy against tumors with mutant or deficient p53. In the present study, we developed a novel MDM2 inhibitor (termed SP141) that has direct effects on MDM2 and exerts anti-HCC activity independent of the p53 status of the cancer cells. We demonstrate that SP141 inhibits cell growth and prevents cell migration and invasion, independent of p53. Mechanistically, SP141 directly binds the MDM2 protein and promotes MDM2 degradation. The inhibition of MDM2 by SP141 also increases the sensitivity of HCC cells to sorafenib. In addition, in orthotopic and patient-derived xenograft models, SP141 inhibits MDM2 expression and suppresses tumor growth and metastasis, without any host toxicity. Furthermore, the inhibition of MDM2 by SP141 is essential for its anti-HCC activities. These results provide support for the further development of SP141 as a lead candidate for the treatment of HCC.

Berbamine Inhibits Cell Proliferation, Migration, and Invasion and Induces Cell Apoptosis of A549 Cells Via Regulating C-Maf, PI3K/Akt and MDM2-P53 Pathways

“…Moreover, studies found that MDM2 may suppress the migration of cancer cells and could induce apoptosis [27,29,30]. Our results found that BBM inhibited the migration and invasion of A549 cells in vitro, and the number of nodules on lungs was signi cantly reduced in vivo, and the expression of MDM2 was downregulated both in vitro and in vivo.…”

Global transcriptomic study of circRNAs expression profile in sorafenib resistant hepatocellular carcinoma cells

“…In addition, Zhang et al found that p53 and MDM2 expression levels could be considered as useful indicators for predicting the prognosis of HCC [28]. Furthermore, MDM2 knockdown has also been demonstrated to inhibit cancer cell growth and invasion, induce apoptosis, and sensitize HCC cells to sorafenib [29]. Unfortunately, the specific targets of circRNAs regulation in sorafenib resistance HCC remain unknown and further in vitro and in vivo studies are needed to fully reveal the differentially expressed circRNAs and their underlying mechanisms, which may be useful for HCC therapy.…”

Targeted Brain Tumor Therapy by Inhibiting the MDM2 Oncogene: In Vitro and In Vivo Antitumor Activity and Mechanism of Action

“…Scratches were made at experimental time zero and then the cells were exposed to varying concentrations of SP-141. The wells were photographed at different time points and the migration was quantified [ 30 , 31 , 32 ]. Transwell invasion assays were performed by exposing tumor cells to SP-141 for 24 h, and the cells that migrated into the lower chambers were stained with crystal violet [ 30 , 31 , 32 ].…”

“…Following NaBH 4 reduction, cells were blocked, treated with corresponding antibodies in the presence of 0.2% Triton X-100, then incubated with FITC-conjugated secondary antibodies. The washed cells were analyzed by flow cytometry [ 30 , 31 , 32 , 34 ].…”

“…SP-141 is a first-in-class MDM2 inhibitor with unique mechanisms of action different from the existing reported p53-dependent MDM2 inhibitors that have been evaluated in preclinical and clinical investigations. Specifically, SP-141 directly binds to the MDM2 protein, inhibits MDM2 expression, and induces its autoubiquitination and proteasomal degradation [ 29 , 30 , 31 , 32 ]. Because SP-141 can cross the blood–brain barrier fairly well [ 29 ] and can inhibit MDM2 in the presence or absence of wild-type p53 [ 29 , 31 , 32 ], the current study investigated the effects of SP-141 in brain tumor cell cultures and orthotopic xenograft models of medulloblastoma and glioblastoma.…”