Small-Molecule MDM2-p53 Inhibitors: Recent Advances

Zhang, Bian; Golding, Bernard T.; Hardcastle, Ian R.

doi:10.4155/fmc.15.13

Cited by 55 publications

(34 citation statements)

References 36 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…For example, recently described interactions of MM with core histones could account, in part, for repression of genes lacking prototypic SP1 or p53 recognition elements within their respective promoters {Banerjee, 2014 3218 /id}. Experiments are underway to examine these issues, and to ascertain if small molecule mdm2-p53 inhibitors {Zhang, 2015 3222 /id} or agents which inhibit p21 expression {Nguyen, 2004 1774 /id} can augment MM-mediated apoptosis in MPM cells.…”

Section: Discussionmentioning

confidence: 99%

Mithramycin Depletes Specificity Protein 1 and Activates p53 to Mediate Senescence and Apoptosis of Malignant Pleural Mesothelioma Cells

Rao

Atay

Shukla

et al. 2016

Clinical Cancer Research

View full text Add to dashboard Cite

Purpose Specificity protein 1 (SP1) is an oncogenic transcription factor over-expressed in various human malignancies. This study sought to examine SP1 expression in malignant pleural mesotheliomas (MPM), and ascertain the potential efficacy of targeting SP1 in these neoplasms. Experimental Design qRT-PCR, immunoblot and immunohistochemistry techniques were used to evaluate SP1 expression in cultured MPM cells and MPM specimens and normal mesothelial cells/pleura. MTS, chemotaxis, soft agar, ß-galactosidase and Apo-BrdU techniques were used to assess proliferation, migration, clonogenicity, senescence and apoptosis in MPM cells following SP1 knockdown, p53 over-expression, or mithramycin treatment. Murine subcutaneous and intraperitoneal (IP) xenograft models were used to examine effects of mithramycin on MPM growth in vivo. Microarray, qRT-PCR, immunoblot and chromatin immunoprecipitation techniques were used to examine gene expression profiles mediated by mithramycin and combined SP1 knockdown/p53 over-expression, and correlate these changes with SP1 and p53 levels within target gene promoters. Results MPM cells and tumors exhibited higher SP1 mRNA and protein levels relative to control cells/tissues. SP1 knockdown significantly inhibited proliferation, migration and clonogenicity of MPM cells. Mithramycin depleted SP1 and activated p53, dramatically inhibiting proliferation and clonogenicity of MPM cells. IP mithramycin significantly inhibited growth of subcutaneous MPM xenografts, and completely eradicated mesothelioma carcinomatosis in 75% of mice. Mithramycin modulated genes mediating oncogene signaling, cell cycle regulation, senescence and apoptosis in-vitro and in-vivo. The growth inhibitory effects of mithramycin in MPM cells were recapitulated by combined SP1 knockdown/p53 overexpression. Conclusions These findings provide preclinical rationale for phase II evaluation of mithramycin in mesothelioma patients.

show abstract

Section: Discussionmentioning

confidence: 99%

Mithramycin Depletes Specificity Protein 1 and Activates p53 to Mediate Senescence and Apoptosis of Malignant Pleural Mesothelioma Cells

Rao

Atay

Shukla

et al. 2016

Clinical Cancer Research

View full text Add to dashboard Cite

show abstract

“…Briefly, MDM2 is overexpressed in a variety of cancers and promotes tumorigenesis primarily by targeting the degradation of p53, although the regulation of other substrates by MDM2 may contribute 55 (Supplementary information S1 (table)). Inhibitors that disrupt the interaction between p53 and MDM2 and/or the homologue MDMX (also known as MDM4) were developed 57 , including the cis -imidazoline analogues (otherwise known as the nutlins) such as Nutlin-3 and RG7112, which are currently being assessed in clinical trials for haematological malignancies 58 .…”

Section: Ubiquitin Ligases In Genome Maintenancementioning

confidence: 99%

Ubiquitin ligases in oncogenic transformation and cancer therapy

2017

View full text Add to dashboard Cite

The cellular response to external stress signals and DNA damage depends on the activity of ubiquitin ligases (E3s), which regulate numerous cellular processes, including homeostasis, metabolism and cell cycle progression. E3s recognize, interact with and ubiquitylate protein substrates in a temporally and spatially regulated manner. The topology of the ubiquitin chains dictates the fate of the substrates, marking them for recognition and degradation by the proteasome or altering their subcellular localization or assembly into functional complexes. Both genetic and epigenetic alterations account for the deregulation of E3s in cancer. Consequently, the stability and/or activity of E3 substrates are also altered, in some cases leading to downregulation of tumour-suppressor activities and upregulation of oncogenic activities. A better understanding of the mechanisms underlying E3 regulation and function in tumorigenesis is expected to identify novel prognostic markers and to enable the development of the next generation of anticancer therapies. This Review summarizes the oncogenic and tumour-suppressor roles of selected E3s and highlights novel opportunities for therapeutic intervention.

show abstract

“…One may thus speculate that a local decrease in AMH would speed up the transition from primordial to primary stage and hasten the exhaustion of the follicle population. Finally, MDM2 inhibitors have been developed for cancer treatment [32,33] and based on our data, we may easily suspect that these may impair female fertility. In this regard, it will be important to further elucidate the process that mediates oocyte loss in the absence of Mdm2.…”

Section: No Detectable Increase In P53 and Apoptotic Markers In Oocytesmentioning

confidence: 99%

Loss of oocytes due to conditional ablation of Murine double minute 2 (Mdm2) gene is p53‐dependent and results in female sterility

et al. 2016

View full text Add to dashboard Cite

Murine double minute 2 and 4 (Mdm2, Mdm4) are major p53-negative regulators, preventing thus uncontrolled apoptosis induction in numerous cell types, although their function in the female germ line has received little attention. In the present work, we have generated mice with specific invalidation of Mdm2 and Mdm4 genes in the mouse oocyte (Mdm2 Ocko and Mdm4Ocko mice), to test their implication in survival of these germ cells. Most of the Mdm2 Ocko but not Mdm4 Ocko mice were sterile, with a dramatic reduction of the weight of ovaries and genital tract, a strong increase in follicle-stimulating hormone and luteinizing hormone serum levels, and a reduction of anti-mullerian hormone serum levels. Histological analyses revealed an obvious decrease of the number of growing follicles beyond the primary stage in Mdm2 Ocko ovaries in comparison to controls, with a pronounced increase in the apparition of primary atretic follicles, most being devoid of oocyte. Similar phenotypes were observed with Mdm2 Ocko Mdm4Ocko ovaries, with no worsening of the phenotype. However, we failed to detect any increase in p53 level in mutant oocytes, nor any other apoptotic marker, introgression of this targeted invalidation in p53À/À mice restored the fertility of females. This study is the first to show that Mdm2, but not Mdm4, has a critical role in oocyte survival and would be involved in premature ovarian insufficiency phenotype.

show abstract

Small-Molecule MDM2-p53 Inhibitors: Recent Advances

Cited by 55 publications

References 36 publications

Mithramycin Depletes Specificity Protein 1 and Activates p53 to Mediate Senescence and Apoptosis of Malignant Pleural Mesothelioma Cells

Mithramycin Depletes Specificity Protein 1 and Activates p53 to Mediate Senescence and Apoptosis of Malignant Pleural Mesothelioma Cells

Ubiquitin ligases in oncogenic transformation and cancer therapy

Loss of oocytes due to conditional ablation of Murine double minute 2 (Mdm2) gene is p53‐dependent and results in female sterility

Contact Info

Product

Resources

About