We found a match
Your institution may have access to this item. Find your institution then sign in to continue.
- Title
Combined Application of Pan-AKT Inhibitor MK-2206 and BCL-2 Antagonist Venetoclax in B-Cell Precursor Acute Lymphoblastic Leukemia.
- Authors
Richter, Anna; Fischer, Elisabeth; Holz, Clemens; Schulze, Julia; Lange, Sandra; Sekora, Anett; Knuebel, Gudrun; Henze, Larissa; Roolf, Catrin; Escobar, Hugo Murua; Junghanss, Christian; Martinelli, Giovanni; Cerchione, Claudio; Daver, Naval
- Abstract
Aberrant PI3K/AKT signaling is a hallmark of acute B-lymphoblastic leukemia (B-ALL) resulting in increased tumor cell proliferation and apoptosis deficiency. While previous AKT inhibitors struggled with selectivity, MK-2206 promises meticulous pan-AKT targeting with proven anti-tumor activity. We herein, characterize the effect of MK-2206 on B-ALL cell lines and primary samples and investigate potential synergistic effects with BCL-2 inhibitor venetoclax to overcome limitations in apoptosis induction. MK-2206 incubation reduced AKT phosphorylation and influenced downstream signaling activity. Interestingly, after MK-2206 mono application tumor cell proliferation and metabolic activity were diminished significantly independently of basal AKT phosphorylation. Morphological changes but no induction of apoptosis was detected in the observed cell lines. In contrast, primary samples cultivated in a protective microenvironment showed a decrease in vital cells. Combined MK-2206 and venetoclax incubation resulted in partially synergistic anti-proliferative effects independently of application sequence in SEM and RS4;11 cell lines. Venetoclax-mediated apoptosis was not intensified by addition of MK-2206. Functional assessment of BCL-2 inhibition via Bax translocation assay revealed slightly increased pro-apoptotic signaling after combined MK-2206 and venetoclax incubation. In summary, we demonstrate that the pan-AKT inhibitor MK-2206 potently blocks B-ALL cell proliferation and for the first time characterize the synergistic effect of combined MK-2206 and venetoclax treatment in B-ALL.
- Subjects
LYMPHOBLASTIC leukemia; ACUTE leukemia; CELL proliferation; CELL lines; FUNCTIONAL assessment
- Publication
International Journal of Molecular Sciences, 2021, Vol 22, Issue 5, p2771
- ISSN
1661-6596
- Publication type
Article
- DOI
10.3390/ijms22052771