buparlisib and Leukemia--Promyelocytic--Acute

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.

Topics: Aminopyridines; Antineoplastic Agents; Apoptosis; Arsenic Trioxide; Caspase 3; Cell Cycle; Cell Proliferation; Dose-Response Relationship, Drug; Drug Interactions; Gene Expression Regulation, Neoplastic; HL-60 Cells; Humans; Intracellular Space; Leukemia, Promyelocytic, Acute; Morpholines; Phosphatidylinositol 3-Kinases; Reactive Oxygen Species; Signal Transduction

The intertwining between cancer pathogenesis and perturbation of multitude signaling pathways ushered the cancer therapeutic approaches into an unbounded route of targeted therapies. For the nonce and among the plethora of promising inhibitors, intense interest has focused on small molecules targeting different component of PI3K axis. Intrigued by the constant activation of PI3K in leukemia, this study aimed to investigate the effects of BKM120, as the excelled member of pan PI3K inhibitors, in a panel of hematologic malignant cell lines. The resulting data showed that BKM120 exerted a concentration-dependent growth suppressive effect; however, IC

Topics: Aminopyridines; Apoptosis; Caspase 3; Cell Line, Tumor; Cell Proliferation; Cell Survival; DNA; Enzyme Activation; Enzyme Inhibitors; Humans; Leukemia, Promyelocytic, Acute; Morpholines; NF-kappa B; Phosphoinositide-3 Kinase Inhibitors; S Phase; Signal Transduction; Telomerase