Contributions
Abstract: PB1694
Type: Publication Only
Background
Interest into targeting PI3K pathway has elevated by the latest accomplishments which manifest that overexpression of PI3K not only is contributed to disease progression but also is associated with poor outcome in patients with leukemia. Despite the broad spectrum efficacies, drug resistance on account of multiple interfering factors, such as overexpression of c-Myc is known to be still a daunting challenge for the successful application of PI3K inhibitors.
Aims
To delve into whether c-Myc suppression could intensify the anti-tumoral effects of PI3K inhibitor in AML cells, U937 and KG1 cells were subjected to treatment with CAL-101 and 10058-F4.
Methods
Cell viability, growth kinetics, DNA synthesis rate, induction of apoptosis, and caspase-3 activity were assessed after exposing the cells with both individual and combination treatments of the drugs. Moreover, gene expression analyses by using quantitative real-time PCR were applied to examine the effects and molecular mechanisms of CAL-101 and 10058-F4 combination.
Results
Our results demonstrated that single agent of CAL-101, as the excelled member of PI3Kδ inhibitor, induced cytotoxic and growth suppressive effects through shifting the ratio of death promoters to death repressors via amendment of pro- and anti-apoptotic genes expression. Moreover, PI3K inhibition resulted in a concentration-dependent induction of apoptosis coupled with the enzymatic augmentation of caspase-3, as a substantial executioner of the apoptotic pathway. Noteworthy, the apoptotic effect was even more evident in combinational treatment, as the percentage of apoptotic dead cells was robustly higher in the cultures of AML cells co-treated with CAL-101 and 10058-F4. To investigate whether the augmentative impact of c-Myc inhibitor is a general feature in PI3K inhibition, we evaluated the effect of 10058-F4 in combination with pan-PI3K inhibitor BKM120. Of particular interest and in agreement with the results of CAL-101, it became evident that abrogation of c-Myc using 10058-F4 could enhance the tumor suppressive assets of the PI3K inhibition in acute myeloid leukemia.
Conclusion
Taken together, our findings not only highlighted that PI3K inhibition is a promising approach in AML but also illustrated the favorable therapeutic prospective for PI3K inhibitors in combination with 10058-F4.
Session topic: 3. Acute myeloid leukemia - Biology & Translational Research
Keyword(s): Acute Myeloid Leukemia, c-Myc, PI3K, Targeted therapy
Abstract: PB1694
Type: Publication Only
Background
Interest into targeting PI3K pathway has elevated by the latest accomplishments which manifest that overexpression of PI3K not only is contributed to disease progression but also is associated with poor outcome in patients with leukemia. Despite the broad spectrum efficacies, drug resistance on account of multiple interfering factors, such as overexpression of c-Myc is known to be still a daunting challenge for the successful application of PI3K inhibitors.
Aims
To delve into whether c-Myc suppression could intensify the anti-tumoral effects of PI3K inhibitor in AML cells, U937 and KG1 cells were subjected to treatment with CAL-101 and 10058-F4.
Methods
Cell viability, growth kinetics, DNA synthesis rate, induction of apoptosis, and caspase-3 activity were assessed after exposing the cells with both individual and combination treatments of the drugs. Moreover, gene expression analyses by using quantitative real-time PCR were applied to examine the effects and molecular mechanisms of CAL-101 and 10058-F4 combination.
Results
Our results demonstrated that single agent of CAL-101, as the excelled member of PI3Kδ inhibitor, induced cytotoxic and growth suppressive effects through shifting the ratio of death promoters to death repressors via amendment of pro- and anti-apoptotic genes expression. Moreover, PI3K inhibition resulted in a concentration-dependent induction of apoptosis coupled with the enzymatic augmentation of caspase-3, as a substantial executioner of the apoptotic pathway. Noteworthy, the apoptotic effect was even more evident in combinational treatment, as the percentage of apoptotic dead cells was robustly higher in the cultures of AML cells co-treated with CAL-101 and 10058-F4. To investigate whether the augmentative impact of c-Myc inhibitor is a general feature in PI3K inhibition, we evaluated the effect of 10058-F4 in combination with pan-PI3K inhibitor BKM120. Of particular interest and in agreement with the results of CAL-101, it became evident that abrogation of c-Myc using 10058-F4 could enhance the tumor suppressive assets of the PI3K inhibition in acute myeloid leukemia.
Conclusion
Taken together, our findings not only highlighted that PI3K inhibition is a promising approach in AML but also illustrated the favorable therapeutic prospective for PI3K inhibitors in combination with 10058-F4.
Session topic: 3. Acute myeloid leukemia - Biology & Translational Research
Keyword(s): Acute Myeloid Leukemia, c-Myc, PI3K, Targeted therapy