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Bortezomib and Arsenic Trioxide Activity on a Myelodysplastic Cell Line (P39): A Gene Expression Study.

Savlı H, Galimberti S, Sünnetçi D, Canesastraro M, Palumbo G, Nagy B, Di Raimondo F, Petrini M - Turk J Haematol (2015)

Bottom Line: Combination treatment of the two compounds showed gene expression deregulations in concordance by the results of single bortezomib treatment.Especially, P53 was a pathway more significantly modified and a gene network centralized around the beta estradiol gene.Beta estradiol, BRCA2, and FOXA1 genes were remarkable deregulations in our findings.

View Article: PubMed Central - PubMed

ABSTRACT

Introduction: We aimed to understand the molecular pathways affected by bortezomib and arsenic trioxide treatment on myelomonocytoid cell line P39.

Methods: Oligonucleotide microarray platforms were used for gene expression and pathway analysis. Confirmation studies were performed using quantitative real time PCR.

Results: Bortezomib treatment has shown upregulated DIABLO and NF-κBIB (a NF-κB inhibitor) and downregulated NF-κB1, NF-κB2, and BIRC1 gene expressions. Combination treatment of the two compounds showed gene expression deregulations in concordance by the results of single bortezomib treatment. Especially, P53 was a pathway more significantly modified and a gene network centralized around the beta estradiol gene. Beta estradiol, BRCA2, and FOXA1 genes were remarkable deregulations in our findings.

Discussion and conclusion: Results support the suggestions about possible use of proteasome inhibitors in the treatment of high-risk myelodysplastic syndrome (MDS). NF-κB was observed as an important modulator in leukemic transformation of MDS.

No MeSH data available.


Related in: MedlinePlus

ROS production after bortezomib treatment. Exposure of cells with and without bortezomib after which they were labeled with dihydrorhodamine 123 and analyzed by flow cytometry, to determine the percentage of cells displaying an increase in reactive oxygen species production (∗p<0.05 with respect to control; #p<0.05 with respect to bortezomib alone; Fisher’s exact test). Columns, means of at least three separate experiments; bars, SD. (b) Role of ROS in ATO/bortezomib-mediated lethality in HL60 cells. Bortezomib induces a significant ROS production after 48 hours incubation period. First column (CTRL) indicates the control sample without bortezomib.
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f4: ROS production after bortezomib treatment. Exposure of cells with and without bortezomib after which they were labeled with dihydrorhodamine 123 and analyzed by flow cytometry, to determine the percentage of cells displaying an increase in reactive oxygen species production (∗p<0.05 with respect to control; #p<0.05 with respect to bortezomib alone; Fisher’s exact test). Columns, means of at least three separate experiments; bars, SD. (b) Role of ROS in ATO/bortezomib-mediated lethality in HL60 cells. Bortezomib induces a significant ROS production after 48 hours incubation period. First column (CTRL) indicates the control sample without bortezomib.

Mentions: Bortezomib inactivated NF-kB and exerted an anti-proliferative (Figure 1) and pro-apoptotic effect (Figure 2) by blocking cell cycle in the G2 phase (Figure 3). It increased the release of reactive oxygen species (Figure 4) and down-regulated the WT1 expression (Figure 5). In the untreated P39, 84 of the 93 genes involved in the apoptosis pathway and representation in the Taqman Low-Density Arrays were expressed. After treatment, bortezomib had up-regulated DIABLO and NFkBIB (NF-kB inhibitor), and down-regulated the NF-kB1, NF-kB2, and BIRC1, an anti-apoptotic gene (Figure 5). Seven gene pathways (P53, PPAR, IL6, IL2, hypoxia, Huntington’s disease, TLR) were found most significantly de-regulated in our microarray analysis.


Bortezomib and Arsenic Trioxide Activity on a Myelodysplastic Cell Line (P39): A Gene Expression Study.

Savlı H, Galimberti S, Sünnetçi D, Canesastraro M, Palumbo G, Nagy B, Di Raimondo F, Petrini M - Turk J Haematol (2015)

ROS production after bortezomib treatment. Exposure of cells with and without bortezomib after which they were labeled with dihydrorhodamine 123 and analyzed by flow cytometry, to determine the percentage of cells displaying an increase in reactive oxygen species production (∗p<0.05 with respect to control; #p<0.05 with respect to bortezomib alone; Fisher’s exact test). Columns, means of at least three separate experiments; bars, SD. (b) Role of ROS in ATO/bortezomib-mediated lethality in HL60 cells. Bortezomib induces a significant ROS production after 48 hours incubation period. First column (CTRL) indicates the control sample without bortezomib.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4563195&req=5

f4: ROS production after bortezomib treatment. Exposure of cells with and without bortezomib after which they were labeled with dihydrorhodamine 123 and analyzed by flow cytometry, to determine the percentage of cells displaying an increase in reactive oxygen species production (∗p<0.05 with respect to control; #p<0.05 with respect to bortezomib alone; Fisher’s exact test). Columns, means of at least three separate experiments; bars, SD. (b) Role of ROS in ATO/bortezomib-mediated lethality in HL60 cells. Bortezomib induces a significant ROS production after 48 hours incubation period. First column (CTRL) indicates the control sample without bortezomib.
Mentions: Bortezomib inactivated NF-kB and exerted an anti-proliferative (Figure 1) and pro-apoptotic effect (Figure 2) by blocking cell cycle in the G2 phase (Figure 3). It increased the release of reactive oxygen species (Figure 4) and down-regulated the WT1 expression (Figure 5). In the untreated P39, 84 of the 93 genes involved in the apoptosis pathway and representation in the Taqman Low-Density Arrays were expressed. After treatment, bortezomib had up-regulated DIABLO and NFkBIB (NF-kB inhibitor), and down-regulated the NF-kB1, NF-kB2, and BIRC1, an anti-apoptotic gene (Figure 5). Seven gene pathways (P53, PPAR, IL6, IL2, hypoxia, Huntington’s disease, TLR) were found most significantly de-regulated in our microarray analysis.

Bottom Line: Combination treatment of the two compounds showed gene expression deregulations in concordance by the results of single bortezomib treatment.Especially, P53 was a pathway more significantly modified and a gene network centralized around the beta estradiol gene.Beta estradiol, BRCA2, and FOXA1 genes were remarkable deregulations in our findings.

View Article: PubMed Central - PubMed

ABSTRACT

Introduction: We aimed to understand the molecular pathways affected by bortezomib and arsenic trioxide treatment on myelomonocytoid cell line P39.

Methods: Oligonucleotide microarray platforms were used for gene expression and pathway analysis. Confirmation studies were performed using quantitative real time PCR.

Results: Bortezomib treatment has shown upregulated DIABLO and NF-κBIB (a NF-κB inhibitor) and downregulated NF-κB1, NF-κB2, and BIRC1 gene expressions. Combination treatment of the two compounds showed gene expression deregulations in concordance by the results of single bortezomib treatment. Especially, P53 was a pathway more significantly modified and a gene network centralized around the beta estradiol gene. Beta estradiol, BRCA2, and FOXA1 genes were remarkable deregulations in our findings.

Discussion and conclusion: Results support the suggestions about possible use of proteasome inhibitors in the treatment of high-risk myelodysplastic syndrome (MDS). NF-κB was observed as an important modulator in leukemic transformation of MDS.

No MeSH data available.


Related in: MedlinePlus