TY - JOUR
T1 - Novel phosphatidylinositol 3-kinase inhibitor NVP-BKM120 induces apoptosis in myeloma cells and shows synergistic anti-myeloma activity with dexamethasone
AU - Zheng, Yuhuan
AU - Yang, Jing
AU - Qian, Jianfei
AU - Zhang, Liang
AU - Lu, Yong
AU - Li, Haiyan
AU - Lin, Heather
AU - Lan, Yongsheng
AU - Liu, Zhiqiang
AU - He, Jin
AU - Hong, Sungyoul
AU - Thomas, Sheeba
AU - Shah, Jatin
AU - Baladandayuthapani, Veera
AU - Kwak, Larry W.
AU - Yi, Qing
N1 - Funding Information:
Grant support This work was supported by the National Cancer Institute R01 CA138402, R01 CA138398, and P50 CA142509, the Leukemia and Lymphoma Society Translational Research Grants, Multiple Myeloma Research Foundation, Commonwealth Foundation for Cancer Research, and the Center for Targeted Therapy of The University of Texas MD Anderson Cancer Center.
Copyright:
Copyright 2012 Elsevier B.V., All rights reserved.
PY - 2012/6
Y1 - 2012/6
N2 - 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.
AB - 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.
KW - Apoptosis
KW - BKM120
KW - Chemotherapy
KW - Multiple myeloma
KW - PI3K
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U2 - 10.1007/s00109-011-0849-9
DO - 10.1007/s00109-011-0849-9
M3 - Article
C2 - 22207485
AN - SCOPUS:84862701242
VL - 90
SP - 695
EP - 706
JO - Journal of Molecular Medicine
JF - Journal of Molecular Medicine
SN - 0946-2716
IS - 6
ER -