The novel orally bioavailable inhibitor of phosphoinositol-3-kinase and mammalian target of rapamycin, NVP-BEZ235, inhibits growth and proliferation in multiple myeloma

Journal Article · Sun Feb 01 04:00:00 EST 2009 · Experimental Cell Research

DOI:https://doi.org/10.1016/j.yexcr.2008.11.007· OSTI ID:21176172

Baumann, Philipp ^[1]; Mandl-Weber, Sonja; Oduncu, Fuat; Schmidmaier, Ralf ^[1]

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1. Department of Hematology and Oncology Medizinische Klinik Innenstadt, Klinikum der Universitaet Muenchen (Germany)

NVP-BEZ235 is a new inhibitor of phosphoinositol-3-kinase (PI3 kinase) and mammalian target of rapamycin (mTOR) whose efficacy in advanced solid tumours is currently being evaluated in a phase I/II clinical trial. Here we show that NVP-BEZ235 inhibits growth in common myeloma cell lines as well as primary myeloma cells at nanomolar concentrations in a time and dose dependent fashion. Further experiments revealed induction of apoptosis in three of four cell lines. Inhibition of cell growth was mainly due to inhibition of myeloma cell proliferation, as shown by the BrdU assay. Cell cycle analysis revealed induction of cell cycle arrest in the G1 phase, which was due to downregulation of cyclin D1, pRb and cdc25a. NVP-BEZ235 inhibited phosphorylation of protein kinase B (Akt), P70S6k and 4E-BP-1. Furthermore we show that the stimulatory effect of CD40-ligand (CD40L), insulin-like growth factor 1 (IGF-1), interleukin-6 (IL-6) and conditioned medium of HS-5 stromal cells on myeloma cell growth is completely abrogated by NVP-BEZ235. In addition, synergism studies revealed synergistic and additive activity of NVP-BEZ235 together with melphalan, doxorubicin and bortezomib. Taken together, inhibition of PI3 kinase/mTOR by NVP-BEZ235 is highly effective and NVP-BEZ235 represents a potential new candidate for targeted therapy in multiple myeloma.

• OSTI ID: 21176172
• Journal Information: Experimental Cell Research, Journal Name: Experimental Cell Research Journal Issue: 3 Vol. 315; ISSN 0014-4827; ISSN ECREAL
• Country of Publication: United States
• Language: English

Related Subjects

60 APPLIED LIFE SCIENCES
APOPTOSIS
CELL CYCLE
CELL PROLIFERATION
CLINICAL TRIALS
DOXORUBICIN
GROWTH FACTORS
INHIBITION
INSULIN
LIGANDS
PHOSPHORYLATION
THERAPY