Antimyeloma Activity of the Orally Bioavailable Dual Phosphatidylinositol 3-Kinase/Mammalian Target of Rapamycin Inhibitor NVP-BEZ235

• Published in: Cancer research (Chicago, Ill.) Vol. 69; no. 14; pp. 5835 - 5842
• Main Authors: MCMILLIN, Douglas W, OOI, Melissa, MUNSHI, Nikhil C, RICHARDSON, Paul G, ANDERSON, Kenneth C, MITSIADES, Constantine S, DELMORE, Jake, NEGRI, Joseph, HAYDEN, Patrick, MITSIADES, Nicolas, JAKUBIKOVA, Jana, MAIRA, Sauveur-Michel, GARCIA-ECHEVERRIA, Carlos, SCHLOSSMAN, Robert
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 15-07-2009
• Subjects: Administration, Oral; Animals; Antineoplastic agents; Antineoplastic Agents - administration & dosage; Antineoplastic Agents - pharmacokinetics; Antineoplastic Agents - pharmacology; Apoptosis - drug effects; Biological and medical sciences; Biological Availability; Cell Cycle - drug effects; Cell Line; Cell Line, Tumor; Cell Survival - drug effects; Hematologic and hematopoietic diseases; Humans; Imidazoles - administration & dosage; Imidazoles - pharmacokinetics; Imidazoles - pharmacology; Immunoblotting; Immunodeficiencies. Immunoglobulinopathies; Immunoglobulinopathies; Immunopathology; Insulin-Like Growth Factor I - pharmacology; Interleukin-6 - pharmacology; Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis; Medical sciences; Mice; Mice, Nude; Multiple Myeloma - drug therapy; Multiple Myeloma - metabolism; Multiple Myeloma - pathology; Pharmacology. Drug treatments; Phosphatidylinositol 3-Kinases - antagonists & inhibitors; Phosphatidylinositol 3-Kinases - metabolism; Phosphorylation - drug effects; Protein Kinase Inhibitors - administration & dosage; Protein Kinase Inhibitors - pharmacokinetics; Protein Kinase Inhibitors - pharmacology; Protein Kinases - metabolism; Proto-Oncogene Proteins c-akt - metabolism; Proto-Oncogene Proteins c-bcl-2 - metabolism; Quinolines - administration & dosage; Quinolines - pharmacokinetics; Quinolines - pharmacology; Signal Transduction - drug effects; TOR Serine-Threonine Kinases; Tumors; Xenograft Model Antitumor Assays; Immunopathology; Enzyme; Transferases; Oral administration; Malignant hemopathy; Myeloma; Biological activity; 1-Phosphatidylinositol 3-kinase; Immunoglobulinopathy; Lymphoproliferative syndrome; Mammalian target of rapamycin; Inhibitor; Cancer
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/0008-5472.CAN-08-4285

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.