NVP-BKM120 is a novel
phosphatidylinositol 3-kinase (PI3K) inhibitor and is currently being investigated in phase I clinical trials in solid
tumors. This study aimed to evaluate the therapeutic efficacy of
BKM120 in
multiple myeloma (MM).
BKM120 induces cell growth inhibition and apoptosis in both MM cell lines and freshly isolated primary MM cells. However,
BKM120 only shows limited cytotoxicity toward normal lymphocytes. The presence of MM bone marrow stromal cells,
insulin-like growth factor, or
interleukin-6 does not affect BKM120-induced
tumor cell apoptosis. More importantly,
BKM120 treatment significantly inhibits
tumor growth in vivo and prolongs the survival of myeloma-bearing mice. In addition,
BKM120 shows synergistic cytotoxicity with
dexamethasone in
dexamethasone-sensitive MM cells. Low doses of
BKM120 and
dexamethasone, each of which alone has limited cytotoxicity, induce significant cell apoptosis in MM.1S and ARP-1. Mechanistic study shows that
BKM120 exposure causes cell cycle arrest by upregulating p27 (Kip1) and downregulating
cyclin D1 and induces caspase-dependent apoptosis by downregulating antiapoptotic XIAP and upregulating expression of cytotoxic small
isoform of Bim, BimS. In summary, our findings demonstrate the in vitro and in vivo anti-MM activity of
BKM120 and suggest that
BKM120 alone or together with other MM chemotherapeutics, particularly
dexamethasone, may be a promising treatment for MM.