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NF-κB-dependent Mechanism of Action of c-Myc Inhibitor 10058-F4: Highlighting a Promising Effect of c-Myc Inhibition in Leukemia Cells, Irrespective of p53 Status

Due to the frequent contribution in the pathogenesis of different human malignancies, c-Myc is among those transcription factors that are believed to be pharmacologically targeted for cancer therapeutic approaches. In the present study, we examined the anti-leukemic effect of a well-known c-Myc inhi...

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Autores principales: Sayyadi, Mohammad, Safaroghli-Azar, Ava, Safa, Majid, Abolghasemi, Hassan, Momeny, Majid, Bashash, Davood
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Shaheed Beheshti University of Medical Sciences 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7462502/
https://www.ncbi.nlm.nih.gov/pubmed/32922477
http://dx.doi.org/10.22037/ijpr.2020.112926.14018
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author Sayyadi, Mohammad
Safaroghli-Azar, Ava
Safa, Majid
Abolghasemi, Hassan
Momeny, Majid
Bashash, Davood
author_facet Sayyadi, Mohammad
Safaroghli-Azar, Ava
Safa, Majid
Abolghasemi, Hassan
Momeny, Majid
Bashash, Davood
author_sort Sayyadi, Mohammad
collection PubMed
description Due to the frequent contribution in the pathogenesis of different human malignancies, c-Myc is among those transcription factors that are believed to be pharmacologically targeted for cancer therapeutic approaches. In the present study, we examined the anti-leukemic effect of a well-known c-Myc inhibitor 10058-F4 on a panel of hematologic malignant cells harboring either mutant or wild-type p53. Notably, we found that the suppression of c-Myc was coupled with the reduction in the survival of all the tested leukemic cells; however, as far as we are aware, this study suggests for the first time that the cytotoxic effect of 10058-F4 was not significantly affected by the molecular status of p53. Delving into the molecular mechanisms of the inhibitor in the most sensitive cell line revealed that 10058-F4 could induce apoptotic cell death in mutant p53-expressing NB4 cells through the suppression of NF-κB pathway coupled with a significant induction of intracellular reactive oxygen species (ROS). In addition, we found that the anti-leukemic effect of 10058-F4 was overshadowed, at least partially, through the compensatory activation of the PI3K signaling pathway; highlighting a plausible attenuating role of this axis on 10058-F4 cytotoxicity. In conclusion, the results of the present study shed light on the favorable anti-leukemic effect of 10058-F4, especially in combination with PI3K inhibitors in acute promyelocytic leukemia; however, further investigations should be accomplished to determine the efficacy of the inhibitor, either as a single agent or in a combined-modal strategy, in leukemia treatment.
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spelling pubmed-74625022020-09-11 NF-κB-dependent Mechanism of Action of c-Myc Inhibitor 10058-F4: Highlighting a Promising Effect of c-Myc Inhibition in Leukemia Cells, Irrespective of p53 Status Sayyadi, Mohammad Safaroghli-Azar, Ava Safa, Majid Abolghasemi, Hassan Momeny, Majid Bashash, Davood Iran J Pharm Res Original Article Due to the frequent contribution in the pathogenesis of different human malignancies, c-Myc is among those transcription factors that are believed to be pharmacologically targeted for cancer therapeutic approaches. In the present study, we examined the anti-leukemic effect of a well-known c-Myc inhibitor 10058-F4 on a panel of hematologic malignant cells harboring either mutant or wild-type p53. Notably, we found that the suppression of c-Myc was coupled with the reduction in the survival of all the tested leukemic cells; however, as far as we are aware, this study suggests for the first time that the cytotoxic effect of 10058-F4 was not significantly affected by the molecular status of p53. Delving into the molecular mechanisms of the inhibitor in the most sensitive cell line revealed that 10058-F4 could induce apoptotic cell death in mutant p53-expressing NB4 cells through the suppression of NF-κB pathway coupled with a significant induction of intracellular reactive oxygen species (ROS). In addition, we found that the anti-leukemic effect of 10058-F4 was overshadowed, at least partially, through the compensatory activation of the PI3K signaling pathway; highlighting a plausible attenuating role of this axis on 10058-F4 cytotoxicity. In conclusion, the results of the present study shed light on the favorable anti-leukemic effect of 10058-F4, especially in combination with PI3K inhibitors in acute promyelocytic leukemia; however, further investigations should be accomplished to determine the efficacy of the inhibitor, either as a single agent or in a combined-modal strategy, in leukemia treatment. Shaheed Beheshti University of Medical Sciences 2020 /pmc/articles/PMC7462502/ /pubmed/32922477 http://dx.doi.org/10.22037/ijpr.2020.112926.14018 Text en This is an Open Access article distributed under the terms of the Creative Commons Attribution License, (http://creativecommons.org/licenses/by/3.0/) which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Original Article
Sayyadi, Mohammad
Safaroghli-Azar, Ava
Safa, Majid
Abolghasemi, Hassan
Momeny, Majid
Bashash, Davood
NF-κB-dependent Mechanism of Action of c-Myc Inhibitor 10058-F4: Highlighting a Promising Effect of c-Myc Inhibition in Leukemia Cells, Irrespective of p53 Status
title NF-κB-dependent Mechanism of Action of c-Myc Inhibitor 10058-F4: Highlighting a Promising Effect of c-Myc Inhibition in Leukemia Cells, Irrespective of p53 Status
title_full NF-κB-dependent Mechanism of Action of c-Myc Inhibitor 10058-F4: Highlighting a Promising Effect of c-Myc Inhibition in Leukemia Cells, Irrespective of p53 Status
title_fullStr NF-κB-dependent Mechanism of Action of c-Myc Inhibitor 10058-F4: Highlighting a Promising Effect of c-Myc Inhibition in Leukemia Cells, Irrespective of p53 Status
title_full_unstemmed NF-κB-dependent Mechanism of Action of c-Myc Inhibitor 10058-F4: Highlighting a Promising Effect of c-Myc Inhibition in Leukemia Cells, Irrespective of p53 Status
title_short NF-κB-dependent Mechanism of Action of c-Myc Inhibitor 10058-F4: Highlighting a Promising Effect of c-Myc Inhibition in Leukemia Cells, Irrespective of p53 Status
title_sort nf-κb-dependent mechanism of action of c-myc inhibitor 10058-f4: highlighting a promising effect of c-myc inhibition in leukemia cells, irrespective of p53 status
topic Original Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7462502/
https://www.ncbi.nlm.nih.gov/pubmed/32922477
http://dx.doi.org/10.22037/ijpr.2020.112926.14018
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