MDM2 overexpression

PELI1 is overexpressed in PC, which increased ubiquitination of RPS3 proteins and activates the PI3K/Akt/GSK3β signaling pathway, as well as reduces the protective effect of RPS3 on p53 and promotes the degradation of the p53 protein, which facilitates the progression of PC and leads to a poor prognosis for patients. Therefore, PELI1 is a potential target for the treatment of PC.

TP53/MDM2 over expression is a frequent and significant genetic event in CRCs associated with an aggressive biological behavior, as a result of increased dedifferentiation grade and advanced stage/elevated tumor volume, respectively. MDM2 oncogene overactivation combined with mutated and overexpressed TP53 is observed in sub-groups of patients leading to specific gene/protein signatures - targets for personalized chemotherapeutic approaches.

Overexpression of MDM2 in ameloblastomas is not associated with MDM2 amplification, but most probably with MAPK activation and WTp53 expression. Further verification of those findings could form the basis for the use of MDM2 expression as a marker of MAPK activation in ameloblastomas and the trial of dual BRAF/MDM2 inhibition in the management of MDM2-overexpressing/BRAFV600E-positive/WTp53 ameloblastomas.

Also, the combined treatment of 9 with 5-FU caused the activation of nucleolar stress and a synergic apoptotic effect. Hence, the co-delivery of MDM2/4 heterodimer disruptors with 5-FU through nanoparticles might be a promising strategy to overcome drug resistance in CRC.

The natural product fusicoccin A forms a ternary complex with a 14-3-3σ dimer and an MDM2 di-phosphorylated peptide resulting in stablisation of the 14-3-3σ/MDM2 PPI. This work serves as a proof-of-concept of the drugability of the 14-3-3/MDM2 PPI and paves the way toward the development of more selective and efficacious small molecule stabilisers.

Given their underlying shared cytogenetic abnormality, molecular testing has no utility in this distinction. Herein is a comprehensive historical overview of ALT/WDL, with updates on its distinction from other similar lipomatous tumors and DL, including practical evidence-based criteria for the appropriate cost-effective use of MDM2 testing.

CCDC106 overexpression downregulates the cellular level of p53 and Mdm2/MdmX, and decreased p53 reversibly downregulates the cellular level of CCDC106. Our work provides a molecular mechanism by which CCDC106 regulates the cellular levels of p53 and Mdm2/MdmX.

Consequently, RG7112 effectively cooperated with CEP-1347 to reduce MDM4 expression, activate the p53 pathway, and inhibit cell growth. The present results suggest the combination of CEP-1347-induced MDM2 overexpression with the selective inhibition of MDM2's interaction with p53, while preserving its ability to inhibit MDM4 expression, as a novel and rational strategy to effectively reactivate p53 in wild-type p53 cancer cells.

All TP53 and its regulating genes may be predictive for prognosis. The results of the present study need to be validated through future screening, in vivo, and in vitro studies.

Importantly, we observe striking cell-to-cell variability in MDM2 copy number and expression in tumors and models. Whereas liposarcoma cells are generally sensitive to MDM2 inhibitors and their combination with pro-apoptotic drugs, MDM2-high cells tolerate them and may underlie the poor clinical efficacy of these agents.

In this study, we suggest that miR-215-5p can target and promote MDM2 expression, promote the proliferation and invasion of LPS cells SW-872, and inhibit apoptosis.Targeting miR-215-5p may be a novel therapeutic strategy for the treatment of LPS.

MDM2 binds directly to p53 and represses its transcriptional activity, promoting p53 degradation. In colon adenocarcinoma, MDM2 oncogene overexpression directly influences p53 oncoprotein expression levels.

Combination of both drugs allowed to reduce the toxicity associated with Siremadlin while increasing the individual drug effect in tumor growth inhibition.ConclusionOverall, our study demonstrates the synergistic effect of the combination between Siremadlin and Olaparib in the inhibition of p53WT RMS tumor growth in vitro and in vivo. Our findings support the potential to study the combination of both drugs in clinical trials and warrants further investigation in other tumors with similar molecular features.

Molecular-guided precision medicine holds a bright future in bringing more active treatments for advanced sarcoma patients.

Acid decalcification still has an adverse impact on RNA. Some MDM2-nonamplified tumors may show positivity for MDM2 RNA-ISH, which needs to be analyzed comprehensively in combination with clinicopathological features.

The enhancing role of MDM2 in tumorigenesis and resistance to chemotherapeutic drugs was also confirmed in vivo. Our findings highlight that MDM2 modifies the transcription factor ING3 by ubiquitination-proteasome pathway degradation, thus reducing ING3 protein stability, which finally promotes CRC cell growth and chemoresistance.

The mortality of apoptotic cells was examined by double staining with Annexin V-FITC and 7-Amino-Actinomycin D (7-AAD). The combination of AZA and FLU has a synergistic anti-leukemia effect on cell proliferation arrest and apoptosis in Ph+ALL cells. Our data provide experimental evidence for a new potential combination of AZA with FLU in the therapy of Ph+ALL and highlight the likelihood of further in vivo pre-clinical study for the potential clinical trial ofthe novel combination in ALL patients. Azacitidine, Apoptosis, Ph+ ALL, Cell cycle

In summary, we demonstrated that high MDMX expression, in a p53-independent manner, was associated with higher HMA resistance and significantly worse survival in MDS patients. Moreover, drug treatment tests suggested the potential of combinatorial therapy of MDMX inhibitor along with HMA. Further experiments and prospectivestudies are warranted to support these observations.

P16 was expressed in all cases, losing intensity in local recurrence and xenografts. Two new alterations, a BRAF mutation and a KRAS amplification, were detected by NGS in different tumors, opening up new therapeutic options for these patients.

Importantly, MX69-114b had minimal or no inhibitory effect on normal human hematopoiesis in vitro and was very well tolerated in vivo in animal models. Based on the strong inhibitory and apoptotic activity against MDM2-overexpressing ALL, along with minimal or no toxicity to normal cells/tissues, MX69-114b is a candidate for further development as a novel MDM2-targeted therapeutic drug for refractory ALL.

MDM2 overexpression reverses the promotion of UBE2J1 knockdown on cell apoptosis in EC. Overall, UBE2J1 knockdown induces cell apoptosis in EC by inactivating the PI3K/AKT signaling and suppressing the MDM2/p53 signaling.

Inhibition of MDM2 and/or HIF-1α with specific inhibitors induced RB cell death and decreased the stem cell properties of primary RB cells. Taken together, our study has shown that MDM2 promotes RB survival through regulating the expression of pVHL and HIF-1α, and targeting MDM2 and/or HIF-1α represents a potential effective approach for RB treatment.

These results suggest the critical role of NAT10-mediated ac4C modification in GC oncogenesis and reveal a previously unrecognized signaling cascade involving the Hp-NAT10-MDM2-p53 axis during GC development.

Multiple agents have been developed, including Nutlins such as RG7112 and small molecular inhibitors including SAR405838 and HDM201. Mechanisms of resistance are being elucidated, and novel inhibitors and combination therapies are currently under investigation. This review provides an overview of these strategies for targeting MDM2 in DDLPS.

These included clinical ALL drugs dexamethasone and daunorubicin, proteasome inhibitor carfilzomib, BCL2/BCLxL inhibitor navitoclax, and histone deacetylase inhibitors romidepsin and pracinostat...Combination of idasanutlin with navitoclax exhibited both the greatest and most consistent synergistic interaction (δ = 24.7±8.7, n=11) of the candidate combinations (n=10) across an extensive landscape of dose combinations; additionally alluding to synergy indiscriminate of ALL subtype...Together, we provide strong evidence that concurrent targeting of MDM2-p53 binding and BCL2/BCLxL leads to potent and synergistic enhancement of apoptotic cell death in a range of high-risk ALL subtypes. The proposed combination of two clinical-stage compounds could have considerable positive clinical impact for the treatment of adult ALL.

Navtemadlin induces potent, threshold-dependent apoptosis in cell culture models of TP53WT myeloid malignancies at clinically relevant concentrations. Navtemadlin-induced p53 activity initiates apoptosis by activating the caspase cascade via cytochrome c release. Navtemadlin was shown to induce the expression of pro-apoptotic BCL-2 family proteins, key mediators in driving cell death.

In MDS both mutational and non-mutational p53 dysfunction are associated with poor survival and resistance to conventional treatments. These subjects have a distinct immunosuppressive profile that could be the primary driver of the dismal prognosis found in these patients.

Three compounds inhibited MDM2/4-p53 PPIs with IC values in the nM range, while one compound inhibited more selectively the MDM2-p53 PPI over the MDM4-p53 PPI. Collectively, these results show: i) 3b may serve as a valuable lead for obtaining selective MDM2-p53 PPI inhibitors and more efficient anti-osteosarcoma agents; ii) 2a, 2q and 3f may serve as valuable leads for obtaining dual MDM2/4 inhibitors and more effective p53 activators.

The CERS6-AS1/miR-30b-3p/MDM2/p53 signaling axis may play key roles in regulating HCC progression. CERS6-AS1 may exert as a novel biomarker or therapeutic target for HCC.

In xenograft models, ZLM-7 treatment significantly inhibited tumor growth while the inhibition was attenuated when 14-3-3 sigma was silenced. Collectively, ZLM-7 could inhibit MDM2 via upregulating 14-3-3 sigma expression, thereby blocking the breast cancer progression.

Here, we demonstrated that BBR inhibited cell proliferation and acted synergistically with bortezomib in MM.1S cells...BBR treatment induced the degradation of MDM2 through the ubiquitin-proteasome system and reactivated P53/P21 in MM cells. Overall, our data has illustrated that MDM2, as a binding protein of BBR for the first time, may serve as a potential therapeutic option for MM.

Anticancer drugs that significantly reduced the proliferation of NCC-DDLPS6-C1 cells were identified by drug library screening. Thus, NCC-DDLPS6-C1 may recapitulate the original genotypes and phenotypes, and we conclude that the NCC-DDLPS6-C1 cell line is a useful resource for the study of DDLPS.

FXR inhibits cervical cancer by upregulating the p14-MDM2-p53 pathway. Activation of FXR may be a potential strategy for the treatment of cervical cancer.

The combination of nutlin-3 with chemotherapeutic agents may become a novel therapeutic strategy in esophageal cancer over-expressing MDM2.

Furthermore, Nutlin-3, an inhibitor of MDM2, could counteract the promotive effects of PVT1 overexpression on ADM resistance of ADM-sensitive BC cell, the expression of multidrug-resistance-related proteins, and the inhibition of p53-mediated tumor suppressor genes. Mechanically, AURKB increased MDM2-mediated p53 ubiquitination. Taken together, PVT1 promoted BC cell proliferation and drug resistance via elevating MDM2 expression and AURKB-mediated p53 ubiquitination.