The pan-BCL-2-blocker obatoclax (GX15-070) and the PI3-kinase/mTOR-inhibitor BEZ235 produce cooperative growth-inhibitory effects in ALL cells
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Gabriele Stefanzl1,2,*, Daniela Berger1,*, Sabine Cerny-Reiterer1,2, Katharina Blatt1,2, Gregor Eisenwort1,2, Wolfgang R. Sperr1,2, Gregor Hoermann2,3, Karin Lind4, Alexander W. Hauswirth1,2, Peter Bettelheim5, Heinz Sill4, Junia V. Melo6, Ulrich Jäger1,2 and Peter Valent1,2
1Department of Internal Medicine I, Division of Hematology & Hemostaseology, Medical University of Vienna, Vienna, Austria
2The Ludwig Boltzmann Cluster Oncology, Medical University of Vienna, Vienna, Austria
3Department of Laboratory Medicine, Medical University of Vienna, Vienna, Austria
4Department of Internal Medicine, Division of Hematology, Medical University of Graz, Graz, Austria
5Division of Laboratory Medicine, Elisabethinen Hospital Linz, Linz, Austria
6Faculty of Health and Medical Sciences, University of Adelaide, Adelaide, Australia
*These authors have contributed equally to this work
Peter Valent, email: [email protected]
Keywords: ALL, targeting-concepts, BCL-2 family members, PI3-Kinase, mTOR
Received: December 21, 2016 Accepted: June 02, 2017 Published: June 28, 2017
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.
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