Anovel Aurora-A kinase inhibitor MLN8237 induces cytotoxicity and cell-cycle arrest in multiple myeloma

被引：244

作者：

Goerguen, Guellue ^{[1
]}

Calabrese, Elisabetta ^{[1
]}

Hideshima, Teru ^{[1
]}

Ecsedy, Jeffrey ^{[2
]}

Perrone, Giulia ^{[1
]}

Mani, Mala ^{[1
]}

Ikeda, Hiroshi ^{[1
]}

Bianchi, Giada ^{[1
]}

Hu, Yiguo ^{[1
]}

Cirstea, Diana ^{[1
]}

Santo, Loredana ^{[1
]}

Tai, Yu-Tzu ^{[1
]}

Nahar, Sabikun ^{[1
]}

Zheng, Mei ^{[3
]}

Bandi, Madhavi ^{[1
]}

Carrasco, Ruben D. ^{[1
]}

Raje, Noopur ^{[4
]}

Munshi, Nikhil ^{[1
,5
]}

Richardson, Paul ^{[1
]}

Anderson, Kenneth C. ^{[1
]}

机构：

[1] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA

[2] Millennium Pharmaceut Inc, Cambridge, MA USA

[3] Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA

[4] Massachusetts Gen Hosp, Boston, MA 02114 USA

[5] Boston Vet Adm Hlth Care Syst, Boston, MA USA

来源：

BLOOD | 2010年 / 115卷 / 25期

基金：

美国国家卫生研究院;

关键词：

PROTEIN-KINASE; G2; CHECKPOINT; BONE-MARROW; CANCER; OVEREXPRESSION; ACTIVATION; TARGETS; AGENTS; EVENT;

D O I：

10.1182/blood-2009-12-259523

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

Aurora-A is a mitotic kinase that regulates mitotic spindle formation and segregation. In multiple myeloma (MM), high Aurora-A gene expression has been correlated with centrosome amplification and proliferation; thus, inhibition of Aurora-A in MM may prove to be therapeutically beneficial. Here we assess the in vitro and in vivo anti-MM activity of MLN8237, a small-molecule Aurora-A kinase inhibitor. Treatment of cultured MM cells with MLN8237 results in mitotic spindle abnormalities, mitotic accumulation, as well as inhibition of cell proliferation through apoptosis and senescence. In addition, MLN8237 up-regulates p53 and tumor suppressor genes p21 and p27. Combining MLN8237 with dexamethasone, doxorubicin, or bortezomib induces synergistic/additive anti-MM activity in vitro. In vivo anti-MM activity of MLN8237 was confirmed using a xenograft-murine model of human-MM. Tumor burden was significantly reduced (P = .007) and overall survival was significantly increased (P<.005) in animals treated with 30 mg/kg MLN8237 for 21 days. Induction of apoptosis and cell death by MLN8237 were confirmed in tumor cells excised from treated animals by TdT-mediated dUTP nick end labeling assay. MLN8237 is currently in phase 1 and phase 2 clinical trials in patients with advanced malignancies, and our preclinical results suggest that MLN8237 may be a promising novel targeted therapy in MM. (Blood. 2010;115(25):5202-5213)

引用

页码：5202 / 5213

页数：12

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