PI3Kδ inhibitor YY-20394 synergizes with Bcl-2 inhibitor ABT199 to induce apoptosis in AML cells

Acute myeloid leukemia (AML) remains a challenging hematological malignancy, often requiring novel therapeutic strategies. While ABT199 (venetoclax), a Bcl-2 inhibitor, shows promise, its monotherapy effects in AML are limited, highlighting the need for more effective combinatorial approaches. Targeting the PI3Kδ pathway is an emerging strategy, with YY-20394 (linperlisib) showing efficacy in other hematological cancers. This study explores combining these two mechanisms to overcome resistance and enhance therapeutic outcomes in AML.

Researchers evaluated the drug sensitivity and synergistic effects of YY-20394 and ABT199 in three AML cell lines: MV-4-11, U937, and THP-1. Cell viability was assessed using a Cell Counting Kit-8 assay. Apoptosis and cell cycle distribution were analyzed via dual acridine orange/ethidium bromide staining and flow cytometry. Expression levels of Bcl-2 family members, c-Myc, Akt, and ERK were quantified using reverse transcription-quantitative PCR and western blot analyses.

YY-20394 inhibited the viability of MV-4-11, U937, and THP-1 cells in a concentration-dependent manner. In U937 cells, which exhibited the highest IC50 value, YY-20394 effectively suppressed proliferation, induced apoptosis, and caused cell cycle arrest. Compared with the negative control, levels of c-Myc and Akt phosphorylation were significantly reduced in the YY-20394 group, with these inhibitory effects retained in the combination group.

The combination of YY-20394 and ABT199 demonstrated a synergistic effect in MV-4-11 cells, significantly enhancing apoptosis compared to either agent alone. Interestingly, ERK phosphorylation was significantly increased in the combination group. However, alterations in the Bcl-2 pathways did not show a pattern consistent with the observed apoptotic phenotype, suggesting alternative mechanisms.