Simultaneous targeting of PI3K and mTOR with NVP-BGT226 is highly effective in multiple myeloma

Philipp Baumann, Laura Schneider, Sonja Mandl-Weber, Fuat Oduncu, Ralf Schmidmaier
Anti-cancer Drugs 2012, 23 (1): 131-8
Multiple myeloma is still uncurable. Myeloma cells become resistant to common drugs and patients eventually die of tumour progression. Therefore, new targets and drugs are urgently needed. NVP-BGT226 is a novel, orally bioavailable small-molecule inhibitor of phosphoinositol-3-kinase and mammalian target of rapamycin. Here, we show that NVP-BGT226 inhibits growth in common myeloma cell lines and primary myeloma cells at nanomolar concentrations in a time-dependent and dose-dependent manner. Western blots for the detection of caspase 3 cleavage and annexin-V-fluorescein isothiocyanate/propidium iodide assays revealed induction of apoptosis in common myeloma cells lines. Induction of apoptosis was accompanied by upregulation of proapoptotic Bim and a moderate upregulation of Mcl-1 and Bad and a downregulation of Bcl-2, Bax and Bcl-Xl. Inhibition of cell growth was mainly due to inhibition of myeloma cell proliferation, as shown by the 5-bromo-2'-deoxyuridine assay. Cell cycle analysis revealed induction of cell cycle arrest in the G1 phase, which was due to downregulation of cyclin D1, cyclin D2, pRb and cdc25a. NVP-BGT226 inhibited phosphorylation of protein kinase B (Akt), P70S6k and 4E-BP-1 in a time-dependent and dose-dependent manner. Furthermore, we show that the stimulatory effect of insulin-like growth factor 1, interleukin-6 and conditioned medium of HS-5 stromal cells on myeloma cell growth is completely abrogated by NVP-BGT226. Overall, inhibition of phosphoinositol-3-kinase/mammalian target of rapamycin by NVP-BGT226 is highly effective, and NVP-BGT226 represents a potential new candidate for targeted therapy in multiple myeloma.

Full Text Links

Find Full Text Links for this Article


You are not logged in. Sign Up or Log In to join the discussion.

Related Papers

Remove bar
Read by QxMD icon Read

Save your favorite articles in one place with a free QxMD account.


Search Tips

Use Boolean operators: AND/OR

diabetic AND foot
diabetes OR diabetic

Exclude a word using the 'minus' sign

Virchow -triad

Use Parentheses

water AND (cup OR glass)

Add an asterisk (*) at end of a word to include word stems

Neuro* will search for Neurology, Neuroscientist, Neurological, and so on

Use quotes to search for an exact phrase

"primary prevention of cancer"
(heart or cardiac or cardio*) AND arrest -"American Heart Association"