Antimyeloma activity of the orally bioavailable dual phosphatidylinositol 3-kinase/mammalian target of rapamycin inhibitor NVP-BEZ235.
The phosphatidylinositol 3-kinase (PI3K)-Akt-mammalian target of rapamycin (mTOR) pathway mediates proliferation, survival, and drug resistance in multiple myeloma (MM) cells. Here, we tested the anti-MM activity of NVP-BEZ235 (BEZ235), which inhibits PI3K/Akt/mTOR signaling at the levels of PI3K and mTOR. 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide colorimetric survival assays showed that MM cell lines exhibited dose- and time-dependent decreased viability after exposure to BEZ235 (IC(50), 25-800 nmol/L for 48 hours). MM cells highly sensitive (IC(50), <25 nmol/L) to BEZ235 (e.g., MM.1S, MM.1R, Dox40, and KMS-12-PE) included both lines sensitive and resistant to conventional (dexamethasone, cytotoxic chemotherapeutics) agents. Pharmacologically relevant BEZ235 concentrations (25-400 nmol/L) induced rapid commitment to and induction of MM.1S and OPM-2 cell death. Furthermore, normal donor peripheral blood mononuclear cells were less sensitive (IC(50), >800 nmol/L) than the majority of MM cell lines tested, suggesting a favorable therapeutic index. In addition, BEZ235 was able to target MM cells in the presence of exogenous interleukin-6, insulin-like growth factor-1, stromal cells, or osteoclasts, which are known to protect against various anti-MM agents. Molecular profiling revealed that BEZ235 treatment decreased the amplitude of transcriptional signatures previously associated with myc, ribosome, and proteasome function, as well as high-risk MM and undifferentiated human embryonic stem cells. In vivo xenograft studies revealed significant reduction in tumor burden (P = 0.011) and survival (P = 0.028) in BEZ235-treated human MM tumor-bearing mice. Combinations of BEZ235 with conventional (e.g., dexamethasone and doxorubicin) or novel (e.g., bortezomib) anti-MM agents showed lack of antagonism. These results indicate that BEZ235 merits clinical testing, alone and in combination with other agents, in MM.
McMillin
Douglas W
DW
Jerome Lipper Multiple Myeloma Center, Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA.
Ooi
Melissa
M
Delmore
Jake
J
Negri
Joseph
J
Hayden
Patrick
P
Mitsiades
Nicolas
N
Jakubikova
Jana
J
Maira
Sauveur-Michel
SM
Garcia-Echeverria
Carlos
C
Schlossman
Robert
R
Munshi
Nikhil C
NC
Richardson
Paul G
PG
Anderson
Kenneth C
KC
Mitsiades
Constantine S
CS
D000284:Administration, Oral; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D001682:Biological Availability; D002453:Cell Cycle / Q000187:drug effects; D002460:Cell Line; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D006801:Humans; D007093:Imidazoles / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D015151:Immunoblotting; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology; D015850:Interleukin-6 / Q000494:pharmacology; D051379:Mice; D008819:Mice, Nude; D009101:Multiple Myeloma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D011494:Protein Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D011804:Quinolines / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects; D058570:TOR Serine-Threonine Kinases; D023041:Xenograft Model Antitumor Assays
D000970:Antineoplastic Agents; D007093:Imidazoles; D007334:Insulin-Like Growth Factor I; D015850:Interleukin-6; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors; D011494:Protein Kinases; D051057:Proto-Oncogene Proteins c-akt; D019253:Proto-Oncogene Proteins c-bcl-2; D011804:Quinolines; D058570:TOR Serine-Threonine Kinases; C546842:MTOR protein, human; C546843:mTOR protein, mouse; C531198:dactolisib