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SHR Neuro Cancer Cardio Lipid Metab Microb

Stefanzl, G; Berger, D; Cerny-Reiterer, S; Blatt, K; Eisenwort, G; Sperr, WR; Hoermann, G; Lind, K; Hauswirth, AW; Bettelheim, P; Sill, H; Melo, JV; Jager, U; Valent, P.
The pan-BCL-2-blocker obatoclax (GX15-070) and the PI3-kinase/mTOR-inhibitor BEZ235 produce cooperative growth-inhibitory effects in ALL cells
ONCOTARGET. 2017; 8(40): 67709-67722. Doi: 10.18632/oncotarget.18810 [OPEN ACCESS]
Web of Science PubMed FullText FullText_MUG

Co-authors Med Uni Graz: Lind Karin; Sill Heinz
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Abstract:: Acute lymphoblastic leukemia (ALL) is characterized by leukemic expansion of lymphoid blasts in hematopoietic tissues. Despite improved therapy only a subset of patients can be cured. Therefore, current research is focusing on new drug-targets. Members of the BCL-2 family and components of the PI3-kinase/mTOR pathway are critically involved in the regulation of growth and survival of ALL cells. We examined the effects of the pan-BCL-2 blocker obatoclax and the PI3-kinase/mTOR-inhibitor BEZ235 on growth and survival of ALL cells. In 3H-thymidine uptake experiments, both drugs suppressed the in vitro proliferation of leukemic cells in all patients with Philadelphia chromosome-positive (Ph+) ALL and Ph- ALL (obatoclax IC50: 0.01-5 μM; BEZ235, IC50: 0.01-1 μM). Both drugs were also found to produce growth-inhibitory effects in all Ph+ and all Ph- cell lines tested. Moreover, obatoclax and BEZ235 induced apoptosis in ALL cells. In drug-combination experiments, obatoclax and BEZ235 exerted synergistic growth-inhibitory effects on ALL cells. Finally, we confirmed that ALL cells, including CD34+/CD38- stem cells and all cell lines express transcripts for PI3-kinase, mTOR, BCL-2, MCL-1, and BCL-xL. Taken together, this data shows that combined targeting of the PI3-kinase/mTOR-pathway and BCL-2 family-members is a potent approach to counteract growth and survival of ALL cells.
Find related publications in this database (Keywords): ALL; targeting-concepts; BCL-2 family members; PI3-Kinase; mTOR