A1 Refereed original research article in a scientific journal
Inhibition of PI3K signaling pathway enhances the chemosensitivity of APL cells to ATO: Proposing novel therapeutic potential for BKM120
Authors: Davood Bashash, Mahda Delshad, Niknam Riyahi, Ava Safaroghli-Azar, Atieh Pourbagheri-Sigaroodi, Majid Momeny
Publication year: 2018
Journal: European Journal of Pharmacology
Journal name in source: EUROPEAN JOURNAL OF PHARMACOLOGY
Journal acronym: EUR J PHARMACOL
Volume: 841
First page : 10
Last page: 18
Number of pages: 9
ISSN: 0014-2999
eISSN: 1879-0712
DOI: https://doi.org/10.1016/j.ejphar.2018.10.007
Abstract
The latest molecular investigations leading to the discovery of the brand-new mechanisms associated to immortalized nature of cancer cells have questioned the efficacy of the conventional therapies and have increased the demand for more influential approaches, especially in the context of synergistic strategies. In an effort to enhance the effectiveness of acute promyelocytic leukemia (APL) treatment and to investigate the potential therapeutic value of Phosphoinositide 3-kinase (PI3K) inhibition synergism with chemotherapy, we designed experiments to evaluate the effect of Arsenic trioxide (ATO) in combination with BKM120 for the treatment of APL-derived NB4 cells. The results of the present study highlighted the favorable outcome of the PI3K inhibition using BKM120 in potentiating the anti-cancer effect of ATO, while reducing its cytotoxic concentration. Investigating the molecular mechanisms leading to this synergistic effect showed that probably down-regulation of the transcription factor SIRT1 coupled with suppression of c-Myc might halt the progression of the cell cycle from the G1 phase, resulting in the enhanced growth suppressive effect in ATO-plus-BKM120 combination. Moreover, we found that the positive regulatory role of the PI3K inhibition in augmenting the intracellular level of reactive oxygen species disturbed the balance between the death promoter and death repressor genes, which in turn amplified the caspase-3-dependent apoptotic activity of ATO in NB4. By and large, this study laid a therapeutic value on BKM120 in combination with ATO and suggested this combination as a novel therapeutic strategy that may be clinically accessible in the near future.
The latest molecular investigations leading to the discovery of the brand-new mechanisms associated to immortalized nature of cancer cells have questioned the efficacy of the conventional therapies and have increased the demand for more influential approaches, especially in the context of synergistic strategies. In an effort to enhance the effectiveness of acute promyelocytic leukemia (APL) treatment and to investigate the potential therapeutic value of Phosphoinositide 3-kinase (PI3K) inhibition synergism with chemotherapy, we designed experiments to evaluate the effect of Arsenic trioxide (ATO) in combination with BKM120 for the treatment of APL-derived NB4 cells. The results of the present study highlighted the favorable outcome of the PI3K inhibition using BKM120 in potentiating the anti-cancer effect of ATO, while reducing its cytotoxic concentration. Investigating the molecular mechanisms leading to this synergistic effect showed that probably down-regulation of the transcription factor SIRT1 coupled with suppression of c-Myc might halt the progression of the cell cycle from the G1 phase, resulting in the enhanced growth suppressive effect in ATO-plus-BKM120 combination. Moreover, we found that the positive regulatory role of the PI3K inhibition in augmenting the intracellular level of reactive oxygen species disturbed the balance between the death promoter and death repressor genes, which in turn amplified the caspase-3-dependent apoptotic activity of ATO in NB4. By and large, this study laid a therapeutic value on BKM120 in combination with ATO and suggested this combination as a novel therapeutic strategy that may be clinically accessible in the near future.
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