TY - JOUR T1 - The Dual Kinase Inhibitor NVP-BEZ235 in Combination with Cytotoxic Drugs Exerts Anti-proliferative Activity towards Acute Lymphoblastic Leukemia Cells JF - Anticancer Research JO - Anticancer Res SP - 463 LP - 474 VL - 32 IS - 2 AU - CATRIN SCHULT AU - MEIKE DAHLHAUS AU - AENNE GLASS AU - KRISTIN FISCHER AU - SANDRA LANGE AU - MATHIAS FREUND AU - CHRISTIAN JUNGHANSS Y1 - 2012/02/01 UR - http://ar.iiarjournals.org/content/32/2/463.abstract N2 - Background: Inhibition of signal transduction pathways has been successfully introduced into cancer treatment. The dual phosphatidylinositol 3-kinase (PI3K) and mammalian target of rapamycin (mTOR) inhibitor NVP-BEZ235 has antitumor activity in vitro against solid tumors. Here, we examined the activity of NVP-BEZ235 in acute lymphoblastic leukemia (ALL) cells and the best modalities for combination approaches. Materials and Methods: ALL cell lines (SEM, RS4;11, Jurkat and MOLT4) were treated with NVP-BEZ235 alone, or in combination with cytarabine (AraC), doxorubicin (Doxo) or dexamethasone (Dexa). Results: NVP-BEZ235 potently inhibited the proliferation and metabolic activity of ALL cells. Antiproliferative effects were associated with G0/G1 arrest and reduced levels of cyclin-dependent kinase 4 (CDK4) and cyclin D3. Inhibition of PI3K and mTOR activity was detected at 10 and 100 nM. NVP-BEZ235 combined with AraC, Doxo or Dexa synergistically enhanced the cytotoxicity compared to single-drug treatment, even in glucocorticoid-resistant cells. Conclusion: NVP-BEZ235 displays pronounced antiproliferative effects in ALL cells and might therefore be a useful drug in the treatment of ALL. ER -