MI-773, a breaker of the MDM2/p53 axis, exhibits anticancer effects in neuroblastoma via downregulation of INSM1

by Selleckchem | Jun 19 2023

Neuroblastoma (NB) is a common pediatric malignancy associated with poor outcomes. Recent studies have shown that murine double minute2 homolog (MDM2) protein inhibitors are promising anticancer agents. MI-773 is a novel and specific antagonist of MDM2, however, the molecular mechanism of its anti-NB activity remains unclear. NB cell viability was measured by Cell Counting Kit-8 assay following MI-773 treatment. Cell cycle progression was analyzed using PI staining and apoptosis was assessed using Annexin V/PI staining. The molecular mechanisms by which MI-773 exerted its effects were investigated using a microarray. The results showed that disturbance of the MDM2/p53 axis by MI-773 resulted in potent suppression of proliferation, induction of apoptosis and cell cycle arrest in NB cells. In addition, microarray analysis showed that MI-773 led to significant downregulation of genes involved in the G2/M phase checkpoint and upregulation of hallmark gene associated with the p53 pathway. Meanwhile, knockdown of insulinoma-associated 1 decreased proliferation and increased apoptosis of NB cells. In conclusion, the present study demonstrated that MI-773 exhibited high selectivity and blockade affinity for the interaction between MDM2 and TP53 and may serve as a novel strategy for the treatment of NB.

Comments:

The passage discusses a study conducted to investigate the anti-neuroblastoma activity of MI-773, a specific antagonist of the murine double minute2 homolog (MDM2) protein. Neuroblastoma (NB) is a common pediatric cancer with poor outcomes, and researchers have found MDM2 inhibitors to be promising in the treatment of this malignancy.

The study utilized various techniques to explore the molecular mechanisms underlying MI-773's anti-NB effects. Cell viability of NB cells was assessed using the Cell Counting Kit-8 assay after treatment with MI-773. The researchers also analyzed cell cycle progression through PI staining and evaluated apoptosis using Annexin V/PI staining. Additionally, they employed microarray analysis to investigate the molecular changes induced by MI-773.

The results of the study revealed that MI-773 disrupted the MDM2/p53 axis, leading to potent suppression of NB cell proliferation, induction of apoptosis, and cell cycle arrest. Microarray analysis demonstrated that MI-773 downregulated genes involved in the G2/M phase checkpoint, which regulates cell cycle progression, and upregulated genes associated with the p53 pathway, a crucial pathway involved in cell cycle control and apoptosis. These findings suggest that MI-773's effects on NB cells are mediated through its interference with the MDM2/p53 interaction.

Furthermore, the study found that knocking down insulinoma-associated 1, a gene implicated in NB, decreased cell proliferation and increased apoptosis in NB cells. This suggests that targeting multiple pathways, including the MDM2/p53 axis and insulinoma-associated 1, could provide a more effective therapeutic strategy for NB treatment.

In summary, the study demonstrates that MI-773 has high selectivity and affinity for blocking the interaction between MDM2 and TP53 (p53), resulting in suppression of NB cell proliferation, induction of apoptosis, and cell cycle arrest. These findings suggest that MI-773 could be a promising novel therapeutic approach for the treatment of neuroblastoma.