RT Journal Article
SR Electronic
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
FD International Institute of Anticancer Research
SP 463
OP 474
VO 32
IS 2
A1 CATRIN SCHULT
A1 MEIKE DAHLHAUS
A1 AENNE GLASS
A1 KRISTIN FISCHER
A1 SANDRA LANGE
A1 MATHIAS FREUND
A1 CHRISTIAN JUNGHANSS
YR 2012
UL http://ar.iiarjournals.org/content/32/2/463.abstract
AB 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.