The pan-BCL-2-blocker obatoclax (GX15-070) and the PI3-kinase/mTOR-inhibitor BEZ235 produce cooperative growth-inhibitory effects in ALL cells

// Gabriele Stefanzl 1, 2, * , Daniela Berger 1, * , Sabine Cerny-Reiterer 1, 2 , Katharina Blatt 1, 2 , Gregor Eisenwort 1, 2 , Wolfgang R. Sperr 1, 2 , Gregor Hoermann 2, 3 , Karin Lind 4 , Alexander W. Hauswirth 1, 2 , Peter Bettelheim 5 , Heinz Sill 4 , Junia V. Melo 6 , Ulrich Jager 1, 2 and Peter Valent 1, 2 1 Department of Internal Medicine I, Division of Hematology & Hemostaseology, Medical University of Vienna, Vienna, Austria 2 The Ludwig Boltzmann Cluster Oncology, Medical University of Vienna, Vienna, Austria 3 Department of Laboratory Medicine, Medical University of Vienna, Vienna, Austria 4 Department of Internal Medicine, Division of Hematology, Medical University of Graz, Graz, Austria 5 Division of Laboratory Medicine, Elisabethinen Hospital Linz, Linz, Austria 6 Faculty of Health and Medical Sciences, University of Adelaide, Adelaide, Australia * These authors have contributed equally to this work Correspondence to: Peter Valent, email: peter.valent@meduniwien.ac.at Keywords: ALL, targeting-concepts, BCL-2 family members, PI3-Kinase, mTOR Received: December 21, 2016      Accepted: June 02, 2017      Published: June 28, 2017 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 3 H-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 IC 50 : 0.01-5 μM; BEZ235, IC 50 : 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.