26 results on '"Nutlin-3a"'
Search Results
2. MDM2 up-regulates the energy metabolism in NSCLC in a p53-independent manner.
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Fefilova, Elizaveta, Kirdeeva, Yulia, Parfenyev, Sergey, Daks, Alexandra, Fedorova, Olga, Sorokina, Margarita, Ha, Nguyen Xuan, Huong, Tran Thu, Loc, Vu Thanh, Hai, Pham The, Cuong, Nguyen Manh, Barlev, Nickolai, and Shuvalov, Oleg more...
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ENERGY metabolism , *UBIQUITIN ligases , *ELECTRON transport , *MEMBRANE potential , *MITOCHONDRIAL membranes , *BERBERINE , *P53 antioncogene - Abstract
Although an E3 ligase MDM2 is the major negative regulator of the p53 tumor suppressor, a growing body of evidence suggests its p53-independent oncogenic properties. In particular, MDM2 has been shown to regulate serine metabolism independently of p53 status in several types of neoplasia, including NSCLC. Using the GSEA approach and publicly available molecular data on NSCLC tumors, our bioinformatics data suggest that MDM2 affects a number of metabolic genes, particularly those encoding components of the electron transport chain (ETC). To experimentally elucidate the role of MDM2 in respiration and energy metabolism of NSCLC cell models, we established NSCLC cell lines (WT p53+ A549 and p53-null H1299) overexpressing wild-type MDM2, or its catalytically deficient (C464A) mutant (MUT), or the control vector. Using TMRE staining and SeaHorse energy profiling, we demonstrated that wild-type MDM2, but not its catalytically inactive mutant, significantly increased mitochondrial membrane potential (MMP), glycolysis, respiration, and ATP production in a p53-independent manner. Further, we compared MDM2-associated effects of two natural compounds that, according to our docking experiment data, bind MDM2 with affinities similar to nutlin-3A, ganoderic acid A and berberine. Despite the fact that both nutlin-3A and berberine stabilized the MDM2 protein, they displayed differential effects on energy metabolism. Taken together, our data argue that MDM2 affects energy metabolism likely in a p53-independent manner. These results also highlight another pharmacological dimension of using MDM2-targeting compounds as potent inhibitors of glycolysis and respiration in tumor cells. • In NSCLC, MDM2 up-regulates metabolic genes, especially those encoding components of the electron transport chain. • Only WT MDM2, but not its catalytically deficient mutant, stimulates the energy metabolism in a p53-independent manner. • Despite stabilizing MDM2, nutlin-3a inhibits energy metabolism in wild-type p53-bearing A549 cells. • Berberine suppresses energy metabolism in p53- H1299 cells, but induces compensatory glycolysis in p53+ A549 cells. [ABSTRACT FROM AUTHOR] more...
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- 2025
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Catalog
3. Resistance mechanisms to inhibitors of p53-MDM2 interactions in cancer therapy: can we overcome them?
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Lucia Haronikova, Ondrej Bonczek, Pavlina Zatloukalova, Filip Kokas-Zavadil, Martina Kucerikova, Philip J. Coates, Robin Fahraeus, and Borivoj Vojtesek
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p53 ,MDM2 ,MDM2 inhibitor ,Nutlin-3a ,Resistance ,Combination therapy ,Cytology ,QH573-671 - Abstract
Abstract Since the discovery of the first MDM2 inhibitors, we have gained deeper insights into the cellular roles of MDM2 and p53. In this review, we focus on MDM2 inhibitors that bind to the p53-binding domain of MDM2 and aim to disrupt the binding of MDM2 to p53. We describe the basic mechanism of action of these MDM2 inhibitors, such as nutlin-3a, summarise the determinants of sensitivity to MDM2 inhibition from p53-dependent and p53-independent points of view and discuss the problems with innate and acquired resistance to MDM2 inhibition. Despite progress in MDM2 inhibitor design and ongoing clinical trials, their broad use in cancer treatment is not fulfilling expectations in heterogenous human cancers. We assess the MDM2 inhibitor types in clinical trials and provide an overview of possible sources of resistance to MDM2 inhibition, underlining the need for patient stratification based on these aspects to gain better clinical responses, including the use of combination therapies for personalised medicine. more...
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- 2021
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4. Resistance mechanisms to inhibitors of p53-MDM2 interactions in cancer therapy: can we overcome them?
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Haronikova, Lucia, Bonczek, Ondrej, Zatloukalova, Pavlina, Kokas-Zavadil, Filip, Kucerikova, Martina, Coates, Philip J., Fahraeus, Robin, and Vojtesek, Borivoj
- Abstract
Since the discovery of the first MDM2 inhibitors, we have gained deeper insights into the cellular roles of MDM2 and p53. In this review, we focus on MDM2 inhibitors that bind to the p53-binding domain of MDM2 and aim to disrupt the binding of MDM2 to p53. We describe the basic mechanism of action of these MDM2 inhibitors, such as nutlin-3a, summarise the determinants of sensitivity to MDM2 inhibition from p53-dependent and p53-independent points of view and discuss the problems with innate and acquired resistance to MDM2 inhibition. Despite progress in MDM2 inhibitor design and ongoing clinical trials, their broad use in cancer treatment is not fulfilling expectations in heterogenous human cancers. We assess the MDM2 inhibitor types in clinical trials and provide an overview of possible sources of resistance to MDM2 inhibition, underlining the need for patient stratification based on these aspects to gain better clinical responses, including the use of combination therapies for personalised medicine. [ABSTRACT FROM AUTHOR] more...
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- 2021
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5. Nutlin‐3a as a novel anticancer agent for adrenocortical carcinoma with CTNNB1 mutation
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Wen Hui, Shenghua Liu, Jie Zheng, Zujun Fang, Qiang Ding, and Chenchen Feng
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Adrenocortical carcinoma ,CTNNB1 ,MDM2 ,Nutlin‐3a ,TP53 ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Abstract Adrenocortical carcinoma (ACC) is a rare malignancy, and CTNNB1 is frequently mutated in ACC. Our study aims to screen for effective agents with antineoplastic activity against ACC with CTNNB1 mutation. In‐silico screening of the Genomics of Drug Sensitivity in Cancer (GDSC) database was conducted. Drug sensitivity in cells with CTNNB1 mutation was analyzed and further in vitro and in vivo studies were performed using the compound. Only one compound, Nutlin‐3a, an MDM2 inhibitor, was significantly sensitive in 18 cancer cells with CTNNB1 mutation. Further analysis of the 18 cells revealed no significant efficacy between cells with both CTNNB1 and TP53 mutations indicating concomitant TP53 mutation did not impact on drug efficacy. We verified that Nutlin‐3a inhibited cellular proliferation in ACC cell line NCI‐H295R which harbored CTNNB1 mutation but not in SW13 cells which did not. Nutlin‐3a induced cell apoptosis and G1 cell‐cycle arrest in NCI‐H295R cells. Nutlin‐3a also decreased cellular migration and inhibited epithelial‐to‐mesenchymal transition (EMT) process in terms of EMT index. Nutlin‐3a resulted in decreased β‐catenin level independent of p53 level in NCI‐H295R but not SW13 cells. We also evaluated the effect of Nutlin‐3a on hormonal secretion of NCI‐H295R cells and found it resulted in decreased levels of cortisol, androgen, and progesterone. Nutlin‐3a treatment inhibited ACC tumor growth with no observed toxicity in mice in vivo. Our study has revealed that Nutlin‐3a potently inhibits ACC with CTNNB1 mutation. How p53/MDM2 axis coordinates with Wnt/beta‐Catenin signaling in ACC warrants further study. more...
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- 2018
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6. MDM2/p53通路对多发性骨髓瘤RPMI 8226 细胞凋亡的调控.
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梁 昊, 廖 灿, 李 红, and 刘文龙
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Objective To study the regulatory effect and mechanism of MDM2/p53 pathway on apoptosis in multiple myeloma (MM). Methods RPMI8226 cells were cultured in vitro and divided into Nutlin-3a group, control group and blank group. CCK-8 method was used to detect the cell inhibition rate, Western blot was used to detect the expression of apoptosis-related protein, and flow cytometry was used to detect the apoptosis in the two groups. Results Compared with that in control group, the inhibition rate of cells in the experimental group increased significantly at 24h, 48h and 72h (P<0.05). Compared with those in the control group, the expression levels of MDM2 and Bcl-2 in the experimental group decreased significantly (P<0.05), while the expression level of p53 increased significantly (P<0.05). The apoptosis rate was significantly higher in the experimental group than in the control group at 24h, 48h and 72h (38.42%, 82.26% and 82.74% vs. 4.80%, 8.06% and 14.69%). Conclusion The degradation trans-activation pathway between MDM2 and p53 affects the expression of Bcl-2, inhibits the proliferation of MM cells, and promotes the apoptosis of MM cells. [ABSTRACT FROM AUTHOR] more...
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- 2020
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7. An Mdm2 antagonist, Nutlin-3a, induces p53-dependent and proteasome-mediated poly(ADP-ribose) polymerase1 degradation in mouse fibroblasts
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Matsushima, Shingo, Okita, Naoyuki, Oku, Misako, Nagai, Wataru, Kobayashi, Masaki, and Higami, Yoshikazu
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- 2011
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8. Inhibition of Transglutaminase 2 but Not of MDM2 Has a Significant Therapeutic Effect on Renal Cell Carcinoma
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Joon Hee Kang, Seon-Hyeong Lee, Jae-Seon Lee, Su-Jin Oh, Ji Sun Ha, Hyun-Jung Choi, and Soo-Youl Kim
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MDM2 ,p53 ,transglutaminase 2 ,nutlin-3a ,Cytology ,QH573-671 - Abstract
More than 50% of human cancers harbor TP53 mutations and increased expression of Mouse double minute 2 homolog (MDM2), which contribute to cancer progression and drug resistance. Renal cell carcinoma (RCC) has an unusually high incidence of wild-type p53, with a mutation rate of less than 4%. MDM2 is master regulator of apoptosis in cancer cells, which is triggered through proteasomal degradation of wild-type p53. Recently, we found that p53 protein levels in RCC are regulated by autophagic degradation. Transglutaminase 2 (TGase 2) was responsible for p53 degradation through this pathway. Knocking down TGase 2 increased p53-mediated apoptosis in RCC. Therefore, we asked whether depleting p53 from RCC cells occurs via MDM2-mediated proteasomal degradation or via TGase 2-mediated autophagic degradation. In vitro gene knockdown experiments revealed that stability of p53 in RCC was inversely related to levels of both MDM2 and TGase 2 protein. Therefore, we examined the therapeutic efficacy of inhibitors of TGase 2 and MDM2 in an in vivo model of RCC. The results showed that inhibiting TGase 2 but not MDM2 had efficient anticancer effects. more...
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- 2020
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9. Nutlin‐3a as a novel anticancer agent for adrenocortical carcinoma with <italic>CTNNB1</italic> mutation.
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Hui, Wen, Liu, Shenghua, Zheng, Jie, Fang, Zujun, Ding, Qiang, and Feng, Chenchen
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ANTINEOPLASTIC agents , *ADRENAL tumors , *GENETIC mutation , *DRUG efficacy , *CANCER genetics , *PROGNOSIS , *TUMOR treatment - Abstract
Abstract: Adrenocortical carcinoma (ACC) is a rare malignancy, and
CTNNB1 is frequently mutated in ACC. Our study aims to screen for effective agents with antineoplastic activity against ACC withCTNNB1 mutation. In‐silico screening of the Genomics of Drug Sensitivity in Cancer (GDSC) database was conducted. Drug sensitivity in cells withCTNNB1 mutation was analyzed and further in vitro and in vivo studies were performed using the compound. Only one compound, Nutlin‐3a, an MDM2 inhibitor, was significantly sensitive in 18 cancer cells withCTNNB1 mutation. Further analysis of the 18 cells revealed no significant efficacy between cells with bothCTNNB1 and TP53 mutations indicating concomitantTP53 mutation did not impact on drug efficacy. We verified that Nutlin‐3a inhibited cellular proliferation in ACC cell line NCI‐H295R which harboredCTNNB1 mutation but not in SW13 cells which did not. Nutlin‐3a induced cell apoptosis and G1 cell‐cycle arrest in NCI‐H295R cells. Nutlin‐3a also decreased cellular migration and inhibited epithelial‐to‐mesenchymal transition (EMT) process in terms of EMT index. Nutlin‐3a resulted in decreased β‐catenin level independent of p53 level in NCI‐H295R but not SW13 cells. We also evaluated the effect of Nutlin‐3a on hormonal secretion of NCI‐H295R cells and found it resulted in decreased levels of cortisol, androgen, and progesterone. Nutlin‐3a treatment inhibited ACC tumor growth with no observed toxicity in mice in vivo. Our study has revealed that Nutlin‐3a potently inhibits ACC withCTNNB1 mutation. How p53/MDM2 axis coordinates with Wnt/beta‐Catenin signaling in ACC warrants further study. [ABSTRACT FROM AUTHOR] more...- Published
- 2018
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10. P53-MDM2 PATHWAY: EVIDENCES FOR A NEW TARGETED THERAPEUTIC APPROACH IN B-ACUTE LYMPHOBLASTIC LEUKEMIA
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Stefania Trino, Luciana De Luca, Ilaria Laurenzana, Antonella Caivano, Luigi Del Vecchio, Giovanni Martinelli, and Pellegrino Musto
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Acute Lymphoblastic Leukemia ,p53 ,target therapy ,MDM2 ,Nutlin-3a ,Therapeutics. Pharmacology ,RM1-950 - Abstract
The tumor suppressor p53 is a canonical regulator of different biological functions, like apoptosis, cell cycle arrest, DNA repair and genomic stability. This gene is frequently altered in human tumors generally by point mutations or deletions. Conversely, in acute lymphoblastic leukemia (ALL) genomic alterations of TP53 are rather uncommon, and prevalently occur in patients at relapse or with poor prognosis. On the other hand, p53 pathway is often compromised by the inactivation of its regulatory proteins, as MDM2 and ARF. MDM2 inhibitor molecules are able to antagonize p53-MDM2 interaction allowing p53 to exert tumor suppressor transcriptional regulation and to induce apoptotic pathways. Recent preclinical and clinical studies propose that MDM2 targeted therapy represents a promising anticancer strategy restoring p53 dependent mechanisms in ALL disease. Here, we discussed the use of new small molecule targeting p53 pathways as a promising drug target therapy in ALL. more...
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- 2016
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11. P53-MDM2 Pathway: Evidences for A New Targeted Therapeutic Approach in B-Acute Lymphoblastic Leukemia.
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Trino, Stefania, De Luca, Luciana, Laurenzana, Ilaria, Caivano, Antonella, Del Vecchio, Luigi, Martinelli, Giovanni, and Musto, Pellegrino
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LYMPHOBLASTIC leukemia ,LYMPHOCYTIC leukemia - Abstract
The tumor suppressor p53 is a canonical regulator of different biological functions, like apoptosis, cell cycle arrest, DNA repair, and genomic stability. This gene is frequently altered in human tumors generally by point mutations or deletions. Conversely, in acute lymphoblastic leukemia (ALL) genomic alterations of TP53 are rather uncommon, and prevalently occur in patients at relapse or with poor prognosis. On the other hand, p53 pathway is often compromised by the inactivation of its regulatory proteins, as MDM2 and ARF. MDM2 inhibitor molecules are able to antagonize p53-MDM2 interaction allowing p53 to exert tumor suppressor transcriptional regulation and to induce apoptotic pathways. Recent preclinical and clinical studies propose that MDM2 targeted therapy represents a promising anticancer strategy restoring p53 dependent mechanisms in ALL disease. Here, we discussed the use of new small molecule targeting p53 pathways as a promising drug target therapy in ALL. [ABSTRACT FROM AUTHOR] more...
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- 2016
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12. Inhibition of Transglutaminase 2 but Not of MDM2 Has a Significant Therapeutic Effect on Renal Cell Carcinoma
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Jae Seon Lee, Ji Sun Ha, Su-Jin Oh, Joonhee Kang, Soo-Youl Kim, Seon-Hyeong Lee, and Hyun-Jung Choi
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0301 basic medicine ,p53 ,Tissue transglutaminase ,Apoptosis ,urologic and male genital diseases ,Piperazines ,Article ,03 medical and health sciences ,0302 clinical medicine ,MDM2 ,In vivo ,GTP-Binding Proteins ,Cell Line, Tumor ,medicine ,Autophagy ,Humans ,Protein Glutamine gamma Glutamyltransferase 2 ,lcsh:QH301-705.5 ,Carcinoma, Renal Cell ,neoplasms ,Gene knockdown ,Transglutaminases ,biology ,integumentary system ,Chemistry ,Cancer ,Proto-Oncogene Proteins c-mdm2 ,General Medicine ,medicine.disease ,transglutaminase 2 ,Kidney Neoplasms ,030104 developmental biology ,lcsh:Biology (General) ,nutlin-3a ,030220 oncology & carcinogenesis ,Cancer cell ,Cancer research ,biology.protein ,Mdm2 - Abstract
More than 50% of human cancers harbor TP53 mutations and increased expression of Mouse double minute 2 homolog (MDM2), which contribute to cancer progression and drug resistance. Renal cell carcinoma (RCC) has an unusually high incidence of wild-type p53, with a mutation rate of less than 4%. MDM2 is master regulator of apoptosis in cancer cells, which is triggered through proteasomal degradation of wild-type p53. Recently, we found that p53 protein levels in RCC are regulated by autophagic degradation. Transglutaminase 2 (TGase 2) was responsible for p53 degradation through this pathway. Knocking down TGase 2 increased p53-mediated apoptosis in RCC. Therefore, we asked whether depleting p53 from RCC cells occurs via MDM2-mediated proteasomal degradation or via TGase 2-mediated autophagic degradation. In vitro gene knockdown experiments revealed that stability of p53 in RCC was inversely related to levels of both MDM2 and TGase 2 protein. Therefore, we examined the therapeutic efficacy of inhibitors of TGase 2 and MDM2 in an in vivo model of RCC. The results showed that inhibiting TGase 2 but not MDM2 had efficient anticancer effects. more...
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- 2020
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13. Effects of the MDM2 inhibitor Nutlin-3a on sensitivity of pancreatic cancer cells to berberine and modified berberines in the presence and absence of WT-TP53
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Paolo Lombardi, Giuseppe Montalto, Lucio Cocco, Massimo Libra, Matilde L. Follo, James A. McCubrey, Shaw M. Akula, Stephen L. Abrams, Luca Falzone, Linda S. Steelman, Melchiorre Cervello, Saverio Candido, Stefano Ratti, Alberto M. Martelli, Abrams S.L., Akula S.M., Steelman L.S., Follo M.Y., Cocco L., Ratti S., Martelli A.M., Libra M., Falzone L., Candido S., Montalto G., Cervello M., Lombardi P., and McCubrey J.A. more...
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Nutlin-3a ,Cancer Research ,Berberine ,endocrine system diseases ,Tumor suppressor gene ,NAX compounds ,Apoptosis ,Piperazines ,Targeted therapy ,Gene product ,Cell Line, Tumor ,Pancreatic cancer ,Genetics ,medicine ,Humans ,TP53 ,neoplasms ,Molecular Biology ,Regulator gene ,NAX compunds ,biology ,Chemistry ,Imidazoles ,PDAC ,Cancer ,Proto-Oncogene Proteins c-mdm2 ,PDCA ,medicine.disease ,Ubiquitin ligase ,Pancreatic Neoplasms ,Cell culture ,biology.protein ,Cancer research ,NAX compound ,Molecular Medicine ,Mdm2 ,Tumor Suppressor Protein p53 ,Signal Transduction - Abstract
Approaches to improve pancreatic cancer therapy are essential as this disease has a very bleak outcome. Approximately 80% of pancreatic cancers are pancreatic ductal adenocarcinomas (PDAC). A key regulatory gene frequently mutated (∼75%) in PDAC is the TP53 tumor suppressor gene which controls the transcription of multiple genes involved in cell cycle progression, apoptosis, cancer progression and other growth regulatory processes. The mouse double minute 2 homolog (MDM2) gene product is a nuclear-localized E3 ubiquitin ligase and negatively regulates the TP53 protein which results in its proteasomal degradation. Various MDM2 inhibitors have been isolated and examined in clinical trials, especially in patients with hematological malignancies. Nutlin-3a is one of the first MDM2 inhibitors isolated. Berberine (BBR) is a natural product found in many fruits and berries and used in traditional medicine for centuries. It has many biological effects, and some are anti-proliferative in nature. BBR may activate the expression of TP53 and inhibit cell cycle progression as well as other events important in cell growth. To understand more about the potential of compounds like BBR and chemical modified BBRs (NAX compounds) to sensitize PDAC cells to MDM2 inhibitors, we introduced either WT-TP53 or the pLXSN empty vector control into two PDAC cell lines, one lacking expression of TP53 (PANC-28) and one with gain-of-function mutant TP53 on both alleles (MIA-PaCa-2). Our results indicate that nutlin-3a was able to increase the sensitivity to BBR and certain NAX compounds. The effects of nutlin-3a were usually more substantial in those cells containing an introduced WT TP53 gene. These results highlight the importance of knowledge of the type of TP53 mutation that is present in cancer patients before the administration of drugs which function by stabilization of the TP53 protein. more...
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- 2022
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14. The structure of an MDM2-Nutlin-3a complex solved by the use of a validated MDM2 surface-entropy reduction mutant.
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Anil, Burcu, Riedinger, Christiane, Endicott, Jane A., and Noble, Martin E. M.
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FLUORIMETRY , *BINDING sites , *ENTROPY , *LIGAND binding (Biochemistry) , *TRANSCRIPTION factors - Abstract
The p53-binding site of MDM2 holds great promise as a target for therapeutic intervention in MDM2-amplified p53 wild-type forms of cancer. Despite the extensive validation of this strategy, there are relatively few crystallographically determined co-complex structures for small-molecular inhibitors of the MDM2-p53 interaction available in the PDB. Here, a surface-entropy reduction mutant of the N-terminal domain of MDM2 that has been designed to enhance crystallogenesis is presented. This mutant has been validated by comparative ligand-binding studies using differential scanning fluorimetry and fluorescence polarization anisotropy and by cocrystallization with a peptide derived from p53. Using this mutant, the cocrystal structure of MDM2 with the benchmark inhibitor Nutlin-3a has been determined, revealing subtle differences from the previously described co-complex of MDM2 with Nutlin-2. [ABSTRACT FROM AUTHOR] more...
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- 2013
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15. Mouse double minute antagonist Nutlin-3a enhances chemotherapy-induced apoptosis in cancer cells with mutant p53 by activating E2F1.
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Ambrosini, G., Sambol, E. B., Carvajal, D., Vassilev, L. T., Singer, S., and Schwartz, G. K.
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TUMOR suppressor proteins , *CANCER cells , *DNA damage , *APOPTOSIS , *CELL death , *DRUG therapy - Abstract
MDM2 is a critical negative regulator of the p53 tumor suppressor protein. Recently, small-molecule antagonists of MDM2, the Nutlins, have been developed to inhibit the p53-MDM2 interaction and activate p53 signaling. However, half of human cancers have mutated p53 and they are resistant to Nutlin treatment. Here, we report that treatment of the p53-mutant malignant peripheral nerve sheath (MPNST) and p53-null HCT116 cells with cisplatin (Cis) and Nutlin-3a induced a degree of apoptosis that was significantly greater than either drug alone. Nutlin-3a also increased the cytotoxicity of both carboplatin and doxorubicin in a series of p53-mutant human tumor cell lines. In the human dedifferentiated liposarcoma cell line (LS141) and the p53 wild-type HCT116 cells, Nutlin-3a induced downregulation of E2F1 and this effect appeared to be proteasome dependent. In contrast, in MPNST and HCTp53−/− cells, Nutlin-3a inhibited the binding of E2F1 to MDM2 and induced transcriptional activation of free E2F1 in the presence of Cis-induced DNA damage. Downregulation of E2F1 by small interfering RNA significantly decreased the level of apoptosis induced by Cis and Nutlin-3a treatment. Moreover, expression of a dominant-negative form of E2F1 rescued cells from apoptosis, whereas cells overexpressing wild-type E2F1 showed an increase in cell death. This correlated with the induction of the proapoptotic proteins p73α and Noxa, which are both regulated by E2F1. These results indicate that antagonism of MDM2 by Nutlin-3a in cells with mutant p53 enhances chemosensitivity in an E2F1-dependent manner. Nutlin-3a therefore may provide a therapeutic benefit in tumors with mutant p53 provided it is combined with chemotherapy.Oncogene (2007) 26, 3473–3481. doi:10.1038/sj.onc.1210136; published online 4 December 2006 [ABSTRACT FROM AUTHOR] more...
- Published
- 2007
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16. Nutlin-3a suppresses poly (ADP-ribose) polymerase 1 by mechanisms different from conventional PARP1 suppressors in a human breast cancer cell line
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Yoshikazu Higami, Ryoma Tagawa, Naoyuki Okita, Yuka Ishizaki, Yoko Matsumoto, Shunsuke Hoshino, Yuri Kakiyama, Kazunori Akimoto, Mika Owaki, Masaki Kobayashi, and Yuka Sudo
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Gene knockdown ,proteasomal degradation ,biology ,Poly ADP ribose polymerase ,PARP1 ,Cell biology ,chemistry.chemical_compound ,breast cancer ,Oncology ,chemistry ,Ubiquitin ,nutlin-3a ,MG132 ,CHFR ,Proteasome inhibitor ,medicine ,biology.protein ,Mdm2 ,autoPARylation ,medicine.drug ,Research Paper - Abstract
Poly (ADP-ribose) polymerase 1 (PARP1) plays important roles in single strand DNA repair. PARP1 inhibitors enhance the effects of DNA damaging drugs in homologous recombination-deficient tumors including tumors with breast cancer susceptibility gene (BRCA1) mutation. Nutlin-3a, an analog of cis-imidazoline, inhibits degradation of murine double minute 2 (MDM2) and stabilizes p53. We previously reported that nutlin-3a induces PARP1 degradation in p53-dependent manner in mouse fibroblasts, suggesting nutlin-3a may be a PARP1 suppressor. Here, we investigated the effects of nutlin-3a on PARP1 in MCF-7, a human breast cancer cell line. Consistent with our previous results, nutlin-3a reduced PARP1 levels in dose- and time-dependent manners in MCF-7 cells, but this reduction was suppressed in p53 knockdown cells. RITA, a p53 stabilizer that binds to p53 itself, failed to reduce PARP1 protein levels. Moreover, transient MDM2 knockdown repressed nutlin-3a-mediated PARP1 reduction. The MG132 proteasome inhibitor, and knockdown of checkpoint with forkhead and ring finger domains (CHFR) and ring finger protein 146 (RNF146), E3 ubiquitin ligases targeting PARP1, suppressed nutlin-3a-induced PARP1 reduction. Short-term nutlin-3a treatment elevated the levels of PARylated PARP1, suggesting nutlin-3a promoted PARylation of PARP1, thereby inducing its proteasomal degradation. Furthermore, nutlin-3a-induced PARP1 degradation enhanced DNA-damaging effects of cisplatin in BRCA1 knockdown cells. Our study revealed that nutlin-3a is a PARP1 suppressor that induces PARP1 proteasomal degradation by binding to MDM2 and promoting autoPARylation of PARP1. Further analysis of the mechanisms in nutlin-3a-induced PARP1 degradation may lead to the development of novel PARP1 suppressors applicable for cancers with BRCA1 mutation. more...
- Published
- 2019
17. Effects of the MDM-2 inhibitor Nutlin-3a on PDAC cells containing and lacking WT-TP53 on sensitivity to chemotherapy, signal transduction inhibitors and nutraceuticals
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Paolo Lombardi, Weifeng Mao, Linda S. Steelman, Alberto M. Martelli, Ramiro Mendonça Murata, Stefano Ratti, Saverio Candido, Dariusz Rakus, Melchiorre Cervello, Kvin Lertpiriyapong, Severino Matias de Alencar, Heng-Liang Lin, Shaw M. Akula, Stephen L. Abrams, Agnieska Gizak, Bruno Bueno-Silva, Massimo Libra, James A. McCubrey, Giuseppe Montalto, Matilde Y. Follo, Pedro Luiz Rosalen, Lucio Cocco, Candido, Saverio, Abrams, Stephen L, Steelman, Linda S, Lertpiriyapong, Kvin, Martelli, Alberto M, Cocco, Lucio, Ratti, Stefano, Follo, Matilde Y, Murata, Ramiro M, Rosalen, Pedro L, Bueno-Silva, Bruno, de Alencar, Severino Matia, Lombardi, Paolo, Mao, Weifeng, Montalto, Giuseppe, Cervello, Melchiorre, Rakus, Dariusz, Gizak, Agnieska, Lin, Heng-Liang, Libra, Massimo, Akula, Shaw M, McCubrey, James A, and S. Candido, S.L. Abrams, L.S. Steelman, K. Lertpiriyapong, A.M. Martelli, L. Cocco, S. Ratti, M.Y. Follo, R.M. Murata, P.L. Rosalen, B. Bueno-Silva, S. Matias de Alencar, P. Lombardi, W. Mao, G. Montalto, M. Cervello, D. Rakus, A. Gizak, H.-L. Lin, M. Libra, S. Akula, J.A. McCubrey. more...
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0301 basic medicine ,Cancer Research ,Nutlin-3a ,Settore MED/09 - Medicina Interna ,endocrine system diseases ,medicine.medical_treatment ,medicine.disease_cause ,Piperazines ,Targeted therapy ,0302 clinical medicine ,TP53 ,Mutation ,biology ,Chemistry ,Imidazoles ,Proto-Oncogene Proteins c-mdm2 ,Oxaliplatin ,Targeted Therapeutics ,Drug sensitivity ,Nutraceuticals ,Targeted therapeutics ,030220 oncology & carcinogenesis ,Molecular Medicine ,Mdm2 ,Nutraceutical ,Signal transduction ,Carcinoma, Pancreatic Ductal ,Signal Transduction ,medicine.drug ,Antineoplastic Agents ,Irinotecan ,03 medical and health sciences ,Cell Line, Tumor ,Pancreatic cancer ,Genetics ,medicine ,Humans ,Molecular Biology ,neoplasms ,Chemotherapy ,medicine.disease ,digestive system diseases ,Pancreatic Neoplasms ,030104 developmental biology ,Cell culture ,Dietary Supplements ,biology.protein ,Cancer research ,TERAPÊUTICA MÉDICA ,Tumor Suppressor Protein p53 - Abstract
Mutations at the TP53 gene are readily detected (approximately 50–75%) in pancreatic ductal adenocarcinoma (PDAC) patients. TP53 was previously thought to be a difficult target as it is often mutated, deleted or inactivated on both chromosomes in certain cancers. In the following study, the effects of restoration of wild-type (WT) TP53 activity on the sensitivities of MIA-PaCa-2 pancreatic cancer cells to the MDM2 inhibitor nutlin-3a in combination with chemotherapy, targeted therapy, as well as, nutraceuticals were examined. Upon introduction of the WT-TP53 gene into MIA-PaCa-2 cells, which contain a TP53 gain of function (GOF) mutation, the sensitivity to the MDM2 inhibitor increased. However, effects of nutlin-3a were also observed in MIA-PaCa-2 cells lacking WT-TP53, as upon co-treatment with nutlin-3a, the sensitivity to certain inhibitors, chemotherapeutic drugs and nutraceuticals increased. Interestingly, co-treatment with nutlin-3a and certain chemotherapeutic drug such as irinotecan and oxaliplatin resulted in antagonistic effects in cells both lacking and containing WT-TP53 activity. These studies indicate the sensitizing abilities that WT-TP53 activity can have in PDAC cells which normally lack WT-TP53, as well as, the effects that the MDM2 inhibitor nutlin-3a can have in both cells containing and lacking WT-TP53 to various therapeutic agents. more...
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- 2019
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18. Nutlin-3a as a novel anticancer agent for adrenocortical carcinoma with CTNNB1 mutation
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Shenghua Liu, Jie Zheng, Qiang Ding, Zujun Fang, Chenchen Feng, and Wen Hui
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0301 basic medicine ,Male ,Cancer Research ,Adrenocortical carcinoma ,Epithelial-Mesenchymal Transition ,Gene Expression ,Antineoplastic Agents ,medicine.disease_cause ,Piperazines ,03 medical and health sciences ,Mice ,0302 clinical medicine ,MDM2 ,In vivo ,Cell Movement ,Cell Line, Tumor ,medicine ,Animals ,Humans ,Radiology, Nuclear Medicine and imaging ,CTNNB1 ,Epithelial–mesenchymal transition ,TP53 ,beta Catenin ,Cell Proliferation ,Original Research ,Mutation ,Cell growth ,Chemistry ,Cell Cycle ,Imidazoles ,Cell cycle ,medicine.disease ,Xenograft Model Antitumor Assays ,Hormones ,Disease Models, Animal ,030104 developmental biology ,Oncology ,Cell culture ,Drug Resistance, Neoplasm ,030220 oncology & carcinogenesis ,Cancer cell ,Nutlin‐3a ,Cancer research ,Cancer Prevention - Abstract
Adrenocortical carcinoma (ACC) is a rare malignancy, and CTNNB1 is frequently mutated in ACC. Our study aims to screen for effective agents with antineoplastic activity against ACC with CTNNB1 mutation. In‐silico screening of the Genomics of Drug Sensitivity in Cancer (GDSC) database was conducted. Drug sensitivity in cells with CTNNB1 mutation was analyzed and further in vitro and in vivo studies were performed using the compound. Only one compound, Nutlin‐3a, an MDM2 inhibitor, was significantly sensitive in 18 cancer cells with CTNNB1 mutation. Further analysis of the 18 cells revealed no significant efficacy between cells with both CTNNB1 and TP53 mutations indicating concomitant TP53 mutation did not impact on drug efficacy. We verified that Nutlin‐3a inhibited cellular proliferation in ACC cell line NCI‐H295R which harbored CTNNB1 mutation but not in SW13 cells which did not. Nutlin‐3a induced cell apoptosis and G1 cell‐cycle arrest in NCI‐H295R cells. Nutlin‐3a also decreased cellular migration and inhibited epithelial‐to‐mesenchymal transition (EMT) process in terms of EMT index. Nutlin‐3a resulted in decreased β‐catenin level independent of p53 level in NCI‐H295R but not SW13 cells. We also evaluated the effect of Nutlin‐3a on hormonal secretion of NCI‐H295R cells and found it resulted in decreased levels of cortisol, androgen, and progesterone. Nutlin‐3a treatment inhibited ACC tumor growth with no observed toxicity in mice in vivo. Our study has revealed that Nutlin‐3a potently inhibits ACC with CTNNB1 mutation. How p53/MDM2 axis coordinates with Wnt/beta‐Catenin signaling in ACC warrants further study. more...
- Published
- 2017
19. Nutlin-3a Nanodisks Induce p53 Stabilization and Apoptosis in a Subset of Cultured Glioblastoma Cells
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Robert O. Ryan, Aparna Krishnamoorthy, and Andrzej Witkowski
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p53 ,Nutlin-3a ,Population ,Biomedical Engineering ,Phospholipid ,Pharmaceutical Science ,Medicine (miscellaneous) ,Bioengineering ,Apoptosis ,Biology ,Article ,chemistry.chemical_compound ,MDM2 ,Phosphatidylcholine ,education ,Lipid bilayer ,Polyacrylamide gel electrophoresis ,education.field_of_study ,Cell growth ,Molecular biology ,chemistry ,Nanodisk ,biology.protein ,Mdm2 ,Glioblastoma - Abstract
Nanodisks (ND) are ternary complexes of phospholipid, one or more hydrophobic bioactive agents and an apolipoprotein scaffold. These nanoscale assemblies are organized as a disk-shaped lipid bilayer whose perimeter is stabilized by an apolipoprotein scaffold. Solubilization of hydrophobic bioactive agents is achieved by their integration into the ND lipid milieu. When the cis-imidazoline, nutlin-3a, was incubated with phosphatidylcholine and apolipoprotein A-I, it was conferred with aqueous solubility as judged by spectroscopic analysis. Nondenaturing polyacrylamide gel electrophoresis yielded evidence of a homogeneous population of ND particles ~9 nm in diameter. Gel filtration chromatography experiments revealed the association of nutlin-3a with ND is reversible. Biological activity of nutlin-3a ND was examined in three distinct glioblastoma cell lines, U87MG, SF763 and SF767. Incubation of U87MG cells with nutlin-3a ND induced concentration-dependent cell growth arrest and apoptosis. SF763 cells demonstrated modest cell growth arrest only at high concentrations of nutlin-3a ND and no apoptosis. SF767 cells were unaffected by nutlin-3a ND. Immunoblot analysis revealed nutlin-3a ND induced time-dependent stabilization of the master tumor suppressor, p53, and up regulation of the E3 ubiquitin ligase, murine double minute 2 in U87MG cells, but not the other glioma cell lines. The nanoscale size of the formulation particles, their facile assembly and nutlin-3a solubilization capability suggest ND represent a potentially useful vehicle for in vivo administration of this anti-tumor agent. more...
- Published
- 2017
20. Nutlin-3a selects for cells harbouring TP53 mutations
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Jill E, Kucab, Monica, Hollstein, Volker M, Arlt, and David H, Phillips
- Subjects
0301 basic medicine ,Cancer Research ,endocrine system diseases ,Mutant ,Drug Resistance ,medicine.disease_cause ,Piperazines ,Mice ,Molecular Cancer Biology ,0302 clinical medicine ,Gene Knock-In Techniques ,TP53 ,Cells, Cultured ,Cell Line, Transformed ,Genetics ,Mutation ,Imidazoles ,Proto-Oncogene Proteins c-mdm2 ,3. Good health ,Cell Transformation, Neoplastic ,medicine.anatomical_structure ,Oncology ,030220 oncology & carcinogenesis ,Mdm2 ,immortalisation ,Signal Transduction ,Hupki ,Cell Survival ,Sequence analysis ,Mutagenesis (molecular biology technique) ,Biology ,03 medical and health sciences ,stomatognathic system ,medicine ,Animals ,Humans ,Selection, Genetic ,Fibroblast ,neoplasms ,Cell growth ,Fibroblasts ,Genes, p53 ,Molecular biology ,In vitro ,Clone Cells ,Oxygen ,030104 developmental biology ,Nutlin‐3a ,biology.protein - Abstract
TP53 mutations occur in half of all human tumours. Mutagen‐induced or spontaneous TP53 mutagenesis can be studied in vitro using the human TP53 knock‐in (Hupki) mouse embryo fibroblast (HUF) immortalisation assay (HIMA). TP53 mutations arise in up to 30% of mutagen‐treated, immortalised HUFs; however, mutants are not identified until TP53 sequence analysis following immortalisation (2–5 months) and much effort is expended maintaining TP53‐WT cultures. In order to improve the selectivity of the HIMA for HUFs harbouring TP53 mutations, we explored the use of Nutlin‐3a, an MDM2 inhibitor that leads to stabilisation and activation of wild‐type (WT) p53. First, we treated previously established immortal HUF lines carrying WT or mutated TP53 with Nutlin‐3a to examine the effect on cell growth and p53 activation. Nutlin‐3a induced the p53 pathway in TP53‐WT HUFs and inhibited cell growth, whereas most TP53‐mutated HUFs were resistant to Nutlin‐3a. We then assessed whether Nutlin‐3a treatment could discriminate between TP53‐WT and TP53‐mutated cells during the HIMA (n = 72 cultures). As immortal clones emerged from senescent cultures, each was treated with 10 µM Nutlin‐3a for 5 days and observed for sensitivity or resistance. TP53 was subsequently sequenced from all immortalised clones. We found that all Nutlin‐3a‐resistant clones harboured TP53 mutations, which were diverse in position and functional impact, while all but one of the Nutlin‐3a‐sensitive clones were TP53‐WT. These data suggest that including a Nutlin‐3a counter‐screen significantly improves the specificity and efficiency of the HIMA, whereby TP53‐mutated clones are selected prior to sequencing and TP53‐WT clones can be discarded., What's new? Because half of human tumors carry mutations in the TP53 tumor suppressor gene, a mammalian cell culture system reproducing the diverse mutations seen in patients is necessary to properly study functional impact. Here the authors report a significant improvement to an existing model system using fibroblasts from human TP53 knock‐in mice (HIMA). They show that treating cells with Nutlin‐3a, an inhibitor of the destabilizing cofactor MDM2, efficiently selects for the growth of TP53‐mutated immortalized cells, while selecting against TP53‐wild type cells, thus increasing specificity and efficiency of TP53 mutagenesis. more...
- Published
- 2017
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21. Inhibition of Transglutaminase 2 but Not of MDM2 Has a Significant Therapeutic Effect on Renal Cell Carcinoma.
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Kang, Joon Hee, Lee, Seon-Hyeong, Lee, Jae-Seon, Oh, Su-Jin, Ha, Ji Sun, Choi, Hyun-Jung, and Kim, Soo-Youl
- Subjects
- *
RENAL cell carcinoma , *TREATMENT effectiveness , *DRUG resistance in cancer cells , *P53 protein , *CANCER cells - Abstract
More than 50% of human cancers harbor TP53 mutations and increased expression of Mouse double minute 2 homolog(MDM2), which contribute to cancer progression and drug resistance. Renal cell carcinoma (RCC) has an unusually high incidence of wild-type p53, with a mutation rate of less than 4%. MDM2 is master regulator of apoptosis in cancer cells, which is triggered through proteasomal degradation of wild-type p53. Recently, we found that p53 protein levels in RCC are regulated by autophagic degradation. Transglutaminase 2 (TGase 2) was responsible for p53 degradation through this pathway. Knocking down TGase 2 increased p53-mediated apoptosis in RCC. Therefore, we asked whether depleting p53 from RCC cells occurs via MDM2-mediated proteasomal degradation or via TGase 2-mediated autophagic degradation. In vitro gene knockdown experiments revealed that stability of p53 in RCC was inversely related to levels of both MDM2 and TGase 2 protein. Therefore, we examined the therapeutic efficacy of inhibitors of TGase 2 and MDM2 in an in vivo model of RCC. The results showed that inhibiting TGase 2 but not MDM2 had efficient anticancer effects. [ABSTRACT FROM AUTHOR] more...
- Published
- 2020
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22. Regulation of p53-dependent genes expression in multiple sclerosis: the effect of MDM2 inhibitor Nutlin-3a
- Author
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Valiullina Aigul Khabibullovna, Gomzikova Marina Olegovna, Khaibullin T., Rizvanov Albert Anatolevich, Bulatov Emil Rafaelevich, Институт фундаментальной медицины и биологии, and Казанский федеральный университет more...
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p53 ,Nutlin-3a ,MDM2 ,Биология ,multiple sclerosis - Published
- 2017
23. Targeting the p53-MDM2 interaction by the small-molecule MDM2 antagonist Nutlin-3a: A new challenged target therapy in adult Philadelphia positive acute lymphoblastic leukemia patients
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Luciana De Luca, Andrea Ghelli Luserna di Rorà, Annalisa Lonetti, Federica Cattina, Enrico Derenzini, Giovanni Martinelli, Cristina Papayannidis, Claudia Venturi, Domenico Russo, Giovanni Perini, Pellegrino Musto, Anna Maria Ferrari, Ilaria Iacobucci, Daniela Erriquez, Maria Chiara Abbenante, Ilaria Laurenzana, Emanuela Ottaviani, Stefania Trino, Giorgia Simonetti, Trino, Stefania, Iacobucci, Ilaria, Erriquez, Daniela, Laurenzana, Ilaria, De Luca, Luciana, Ferrari, Anna, Ghelli Luserna Di Rorà, Andrea, Papayannidis, Cristina, Derenzini, Enrico, Simonetti, Giorgia, Lonetti, Annalisa, Venturi, Claudia, Cattina, Federica, Ottaviani, Emanuela, Abbenante, Maria Chiara, Russo, Domenico, Perini, Giovanni, Musto, Pellegrino, and Martinelli, Giovanni more...
- Subjects
0301 basic medicine ,Adult ,Male ,p53 ,Pediatrics ,medicine.medical_specialty ,Nutlin-3a ,Cell cycle checkpoint ,Cell Survival ,Antineoplastic Agents ,Acute lymphoblastic leukemia ,medicine.disease_cause ,Piperazines ,03 medical and health sciences ,0302 clinical medicine ,Proto-Oncogene Proteins c-mdm2 ,MDM2 ,Precursor cell ,hemic and lymphatic diseases ,Tumor Cells, Cultured ,Medicine ,Humans ,Aged ,Mutation ,biology ,Oncology ,business.industry ,Antagonist ,Imidazoles ,Middle Aged ,Precursor Cell Lymphoblastic Leukemia-Lymphoma ,030104 developmental biology ,Cell culture ,Apoptosis ,030220 oncology & carcinogenesis ,biology.protein ,Cancer research ,Mdm2 ,Female ,Tumor Suppressor Protein p53 ,business ,Research Paper - Abstract
MDM2 is an important negative regulator of p53 tumor suppressor. In this study, we sought to investigate the preclinical activity of the MDM2 antagonist, Nutlin-3a, in Philadelphia positive (Ph+) and negative (Ph-) leukemic cell line models, and primary B-acute lymphoblastic leukemia (ALL) patient samples. We demonstrated that Nutlin-3a treatment reduced viability and induced p53-mediated apoptosis in ALL cells with wild-type p53 protein, in a time and dose-dependent manner, resulting in the increased expression of pro-apoptotic proteins and key regulators of cell cycle arrest. The dose-dependent reduction in cell viability was confirmed in primary blast cells from B-ALL patients, including Ph+ ALL resistant patients carrying the T315I BCR-ABL1 mutation. Our findings provide a strong rational for further clinical investigation of Nutlin-3a in Ph+ and Ph- ALL. more...
- Published
- 2016
24. Nutlin-3a is a potential therapeutic for Ewing sarcoma
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Kathleen I. Pishas, Paul M. Neilsen, David F. Callen, Irene Zinonos, Michael P. Brown, Andreas Evdokiou, Fares Al-Ejeh, Raman Kumar, Pishas, Kathleen I, Al-Ejeh, Fares, Zinonos, Irene, Kumar, Raman, Evdokiou, Andreas, Brown, Michael P, Callen, David F, and Neilsen, Paul M more...
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p53 ,Cancer Research ,Vincristine ,Nutlin-3a ,Cell cycle checkpoint ,medicine.medical_treatment ,Apoptosis ,Cell Cycle Proteins ,Sarcoma, Ewing ,Biology ,Piperazines ,Cell Line, Tumor ,Proto-Oncogene Proteins ,Antineoplastic Combined Chemotherapy Protocols ,medicine ,Humans ,cancer ,Doxorubicin ,Molecular Targeted Therapy ,TP53 ,Etoposide ,Chemotherapy ,Imidazoles ,Cancer ,Nuclear Proteins ,Drug Synergism ,Proto-Oncogene Proteins c-mdm2 ,medicine.disease ,Genes, p53 ,Oncology ,Immunology ,biology.protein ,Cancer research ,Mdm2 ,Sarcoma ,Ewing sarcoma ,medicine.drug - Abstract
Purpose: Although mutations in the TP53 gene occur in half of all cancers, approximately 90% of Ewing sarcomas retain a functional wild-type p53. The low frequency of TP53 alterations in Ewing sarcoma makes this tumor type an ideal candidate for p53-targeted therapies. In this study, we have examined the molecular and cellular responses of cultured Ewing sarcoma cell lines following exposure to Nutlin-3a, a recently developed MDM2 antagonist. Experimental Design: The ability of Nutlin-3a to impart apoptosis or cell cycle arrest in a p53-dependent manner was determined in a comprehensive panel of Ewing sarcoma cell lines. The capacity of Nutlin-3a to augment the antitumor activity of MDM4 antagonists and cytotoxic agents currently used in the clinical treatment of Ewing sarcoma was also investigated. Results: Apoptosis was the primary response of wild-type p53 expressing Ewing sarcoma cell lines. The cytotoxicity of Nultin-3a was also synergistic with the chemotherapeutic agents, vincristine, actinomycin D, doxorubicin, and etoposide in a concentration-dependent manner. Significant MDM4 protein overexpression was observed in Ewing sarcoma cell lines of wild-type p53 status, providing a mechanism through which Ewing sarcomas can develop in the absence of TP53 alterations. This study provides the first evidence of synergism between targeted inhibition of MDM2 and MDM4. Conclusion: Our findings suggest that p53-dependent apoptosis is the primary cellular response of Ewing sarcoma cell lines following exposure to Nutlin-3a. Furthermore, Nutlin-3a can synergize with the current Ewing sarcoma chemotherapy protocols, suggesting p53 activation as a novel systemic therapeutic approach for this disease. Clin Cancer Res; 17(3); 494–504. ©2010 AACR. more...
- Published
- 2011
25. Normal human mammary epithelial cells proliferate rapidly in the presence of elevated levels of the tumor suppressors p53 and p21WAF1/CIP1.
- Author
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Huschtscha, Lily I., Moore, Jonathan D., Noble, Jane R., Campbell, Hamish G., Royds, Janice A., Braithwaite, Antony W., and Reddel, Roger R.
- Subjects
- *
CELL proliferation , *EPITHELIAL cells , *TUMOR suppressor proteins , *DNA damage , *APOPTOSIS , *GENETIC mutation - Abstract
In normal cells, p53 protein is maintained at low levels, but the levels increase after stress or inappropriate growth signals to coordinate growth arrest or apoptosis. Human mammary epithelial cells (HMECs) are unusual in that they exhibit two phases of growth. The second growth phase, referred to as post-selection, follows a period of temporary growth arrest and is characterized by the absence of p16INK4a (also known as CDK4I and p16-INK4a) expression. Previously, we observed that post-selection HMECs have elevated levels of p53. Exogenous p16INK4a expression decreased levels of both p53 transcript and protein, and this effect was inhibited by nutlin-3a, indicating that p16INK4a can regulate p53 expression by affecting both p53 transcription and Mdm2-dependent degradation of p53. The p53 in post-selection HMECs was wild type and, as expected, increased p53 expression was associated with elevated p21WAF1/CIP1 and Mdm2 levels; the p53 response to DNA damage seemed normal. Despite elevated levels of wild-type p53 and p21WAF1/CIP1, post-selection cells grew more rapidly than their pre-selection HMEC precursors. We found that the post-selection HMECs contain a truncated Mdm2 protein (p60), which presumably lacks the p53 ubiquitylation domain. We propose that the increased levels of p53 in post-selection HMECs are due to the presence of an Mdm2 fragment that binds p53 but does not result in its degradation. [ABSTRACT FROM AUTHOR] more...
- Published
- 2009
- Full Text
- View/download PDF
26. Normal human mammary epithelial cells proliferate rapidly in the presence of elevated levels of the tumor suppressors p53 and p21WAF1/CIP1.
- Author
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Huschtscha, Lily I., Moore, Jonathan D., Noble, Jane R., Campbell, Hamish G., Royds, Janice A., Braithwaite, Antony W., and Reddel, Roger R.
- Subjects
CELL proliferation ,EPITHELIAL cells ,TUMOR suppressor proteins ,DNA damage ,APOPTOSIS ,GENETIC mutation - Abstract
In normal cells, p53 protein is maintained at low levels, but the levels increase after stress or inappropriate growth signals to coordinate growth arrest or apoptosis. Human mammary epithelial cells (HMECs) are unusual in that they exhibit two phases of growth. The second growth phase, referred to as post-selection, follows a period of temporary growth arrest and is characterized by the absence of p16
INK4a (also known as CDK4I and p16-INK4a) expression. Previously, we observed that post-selection HMECs have elevated levels of p53. Exogenous p16INK4a expression decreased levels of both p53 transcript and protein, and this effect was inhibited by nutlin-3a, indicating that p16INK4a can regulate p53 expression by affecting both p53 transcription and Mdm2-dependent degradation of p53. The p53 in post-selection HMECs was wild type and, as expected, increased p53 expression was associated with elevated p21WAF1/CIP1 and Mdm2 levels; the p53 response to DNA damage seemed normal. Despite elevated levels of wild-type p53 and p21WAF1/CIP1 , post-selection cells grew more rapidly than their pre-selection HMEC precursors. We found that the post-selection HMECs contain a truncated Mdm2 protein (p60), which presumably lacks the p53 ubiquitylation domain. We propose that the increased levels of p53 in post-selection HMECs are due to the presence of an Mdm2 fragment that binds p53 but does not result in its degradation. [ABSTRACT FROM AUTHOR] more...- Published
- 2009
- Full Text
- View/download PDF
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