p53, Mdm2, and c‐Myc overexpression is associated with a poor prognosis in aggressive non‐Hodgkin's lymphomas

Pagnano, Katia B; Vassallo, José; Lorand‐Metze, Irene; Costa, Fernando Ferreira; Saad, Sara Teresinha Olalla

doi:10.1002/ajh.1084

Cited by 44 publications

(31 citation statements)

References 45 publications

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“…c-Myc is overexpressed in numerous cancers, including prostate, gynecological, lung, pancreatic, breast, and colon cancers, B-cell lymphoma, and leukemias. Alterations in c-Myc often are associated with cancer aggressiveness and poor treatment prognosis (Fleming et al, 1986;Nesbit et al, 1999;Pagnano et al, 2001;McNeil et al, 2006). It has been estimated that approximately one-seventh of cancer deaths in the United States per year can be associated with tumors that have changes in the c-Myc gene or its expression (Dang, 1999).…”

Section: Introductionmentioning

confidence: 99%

In Vitro Cytotoxicity and In Vivo Efficacy, Pharmacokinetics, and Metabolism of 10074-G5, a Novel Small-Molecule Inhibitor of c-Myc/Max Dimerization

Clausen

Guo²,

Parise³

et al. 2010

J Pharmacol Exp Ther

103

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The c-Myc oncoprotein is overexpressed in many tumors and is essential for maintaining the proliferation of transformed cells. To function as a transcription factor, c-Myc must dimerize with Max via the basic helix-loop-helix leucine zipper protein (bHLH-ZIP) domains in each protein. The small molecule 7-nitro-N-(2-phenylphenyl)-2,1,3-benzoxadiazol-4-amine (10074-G5) binds to and distorts the bHLH-ZIP domain of c-Myc, thereby inhibiting c-Myc/Max heterodimer formation and inhibiting its transcriptional activity. We report in vitro cytotoxicity and in vivo efficacy, pharmacodynamics, pharmacokinetics, and metabolism of 10074-G5 in human xenograft-bearing mice. In vitro, 10074-G5 inhibited the growth of Daudi Burkitt's lymphoma cells and disrupted c-Myc/Max dimerization. 10074-G5 had no effect on the growth of Daudi xenografts in C.B-17 SCID mice that were treated with 20 mg/kg 10074-G5 intravenously for 5 consecutive days. Inhibition of c-Myc/Max dimerization in Daudi xenografts was not seen 2 or 24 h after treatment. Concentrations of 10074-G5 in various matrices were determined by high-performance liquid chromatography-UV, and metabolites of 10074-G5 were identified by liquid chromatography/tandem mass spectrometry. The plasma half-life of 10074-G5 in mice treated with 20 mg/kg i.v. was 37 min, and peak plasma concentration was 58 M, which was 10-fold higher than peak tumor concentration. The lack of antitumor activity probably was caused by the rapid metabolism of 10074-G5 to inactive metabolites, resulting in tumor concentrations of 10074-G5 insufficient to inhibit c-Myc/Max dimerization. Our identification of 10074-G5 metabolites in mice will help design new, more metabolically stable small-molecule inhibitors of c-Myc.

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Section: Introductionmentioning

confidence: 99%

In Vitro Cytotoxicity and In Vivo Efficacy, Pharmacokinetics, and Metabolism of 10074-G5, a Novel Small-Molecule Inhibitor of c-Myc/Max Dimerization

Clausen

Guo²,

Parise³

et al. 2010

J Pharmacol Exp Ther

103

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“…Results of expression analyses using Northern blot (Hernandez et al, 1999), in situ hybridization (Greil et al, 1991), and immunohistochemistry (IHC) (Chang et al, 2000;Pagnano et al, 2001) coincide in showing that c-myc overexpression is a common observation in BL and DLBCL. Despite this, there is striking variability in the reported c-myc protein cellular localization and intensity of c-myc expression in reactive and tumoral lymphoid tissue (Chang et al, 2000;Jack et al, 1986;Loke et al, 1988;Pagnano et al, 2001). Despite the significant role that c-myc seems to play in lymphomagenesis, the difficulties for demonstrating c-myc expression at the protein or RNA level has impeded our gaining a deeper understanding of the mechanism regulating c-myc expression and the identification of c-myc targets in lymphoma tumoral specimens.…”

mentioning

confidence: 96%

“…Furthermore, regulatory elements of promoters and enhancers of Ig and c-myc genes have been shown to contribute to this deregulation (Gerbitz et al, 1999;Ji et al, 1994;Kanda et al, 2000;Madisen and Groudine, 1994). Results of expression analyses using Northern blot (Hernandez et al, 1999), in situ hybridization (Greil et al, 1991), and immunohistochemistry (IHC) (Chang et al, 2000;Pagnano et al, 2001) coincide in showing that c-myc overexpression is a common observation in BL and DLBCL. Despite this, there is striking variability in the reported c-myc protein cellular localization and intensity of c-myc expression in reactive and tumoral lymphoid tissue (Chang et al, 2000;Jack et al, 1986;Loke et al, 1988;Pagnano et al, 2001).…”

mentioning

confidence: 99%

Development of a Real-Time Reverse Transcription Polymerase Chain Reaction Assay for c-myc Expression That Allows the Identification of a Subset of c-myc+ Diffuse Large B-Cell Lymphoma

Sáez¹,

Artiga

Romero

et al. 2003

Laboratory Investigation

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SUMMARY:Absence of a reliable method for determining the level of c-myc expression has impeded the analysis of its biological and clinical relevance in tumors. We have standardized the conditions for a real-time reverse transcription polymerase chain reaction analysis for c-myc expression, including the selection of an endogenous reference (18S rRNA), the adequate number of measurements for each sample (2 cDNA in triplicate), and suitable controls for determining inter-and intrarun variability (standard curve and calibrator). Subsequently, in a series of 56 non-Hodgkin's lymphomas, we analyzed the expression of c-myc mRNA, using real-time reverse transcription polymerase chain reaction, and of other functionally related proteins (bcl-6, p27, cyclin D3, and p53). As expected, all eight Burkitt's lymphoma cases analyzed had high levels of c-myc mRNA expression compared with that observed in reactive lymphoid tissue. There was a wider range of expression in diffuse large B-cell lymphoma, with 30% (15 of 48) of cases overexpressing c-myc. This overexpression was largely independent of c-myc translocations (4 of 5), as demonstrated by fluorescence in situ hybridization. In this large B-cell lymphoma series, a high level of c-myc expression predicted lower survival probability, irrespectively of the International Prognostic Index risk group classification. A slightly increased frequency of p53 inactivation was observed in the cases with c-myc overexpression, which suggests a growth advantage in lymphomas with concurrent deregulation of c-myc and p53. In addition, a moderate increase in bcl-6 protein expression was observed in the c-myc-positive cases, suggesting the existence of a complex interrelationship between these two genes. These findings suggest that c-myc may play a relevant role in the pathogenesis of a subset of large B-cell lymphoma and suggest the existence of additional regulatory mechanisms of c-myc expression to c-myc rearrangements. (Lab Invest 2003, 83:143-152). C-myc is a multifunctional gene involved in important cellular processes, such as cell proliferation, differentiation, and apoptosis. c-myc targets include critical genes involved in growth, the cell cycle, signaling, and adhesion (eg, cyclin D2, cyclin D3, DP1, p27 KIP1 , p21 CIP1 , AKT, Cul-1, TGFR-2, CDC25C, API2, BclII) (Coller et al, 2000;Eischen et al, 2001;Guo et al, 2000;Nasi et al, 2001;Neiman et al, 2001;Nesbit et al, 2000;O'Hagan et al, 2000;Schuhmacher et al, 2001).Although c-myc gene was initially described as being involved in t(8;14) in Burkitt's lymphoma (BL), overexpression of c-myc has been found in other solid tumors such as breast, prostate, and gastrointestinal carcinomas and in melanoma. In these neoplasias, c-myc expression has been shown to be dependent on amplifications of the gene or to be derived from deregulation of upstream genes in the c-myc pathway, such as BRCA1, PTEN, and ␤-catenin/APC (Nesbit et al, 1999). In addition, N-myc has been implicated in the pathogenesis of neuroblastomas (Fulda et al, 1999).c-myc ...

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“…The other four microRNAs encoded by these clusters, had P values of 0.067,0.087, cluster is encoded at the 13q31 locus, a region commonly amplified in lymphomas and ectopic expression of miR-17-92 greatly accelerated lymphogenesis in a murine model (He et al 2005). Moreover, direct binding of the c-myc protein up-regulates miR-17-92 expression (O'Donnell et al 2005) and overexpression of c-myc has been demonstrated in the majority (66.6%) of DLBCL cases (Aref et al 2004), which has also been associated with poorer outcome (Pagnano et al 2001). An increased level of this cluster in DLBCL compared to FL is consistent with a more aggressive clinical phenotype of DLBCL.…”

Section: Microrna Expression Is Distinct Between Dlbcl and Flmentioning

confidence: 99%

MicroRNA Expression in Follicular Lymphoma

Lawrie¹

2012

Hematology - Science and Practice

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p53, Mdm2, and c‐Myc overexpression is associated with a poor prognosis in aggressive non‐Hodgkin's lymphomas

Cited by 44 publications

References 45 publications

In Vitro Cytotoxicity and In Vivo Efficacy, Pharmacokinetics, and Metabolism of 10074-G5, a Novel Small-Molecule Inhibitor of c-Myc/Max Dimerization

In Vitro Cytotoxicity and In Vivo Efficacy, Pharmacokinetics, and Metabolism of 10074-G5, a Novel Small-Molecule Inhibitor of c-Myc/Max Dimerization

Development of a Real-Time Reverse Transcription Polymerase Chain Reaction Assay for c-myc Expression That Allows the Identification of a Subset of c-myc+ Diffuse Large B-Cell Lymphoma

MicroRNA Expression in Follicular Lymphoma

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