Combination of novel proteasome inhibitor NPI-0052 and lenalidomide trigger in vitro and in vivo synergistic cytotoxicity in multiple myeloma

被引：97

作者：

Chauhan, Dharminder ^{[1
,2
]}

Singh, Ajita V. ^{[1
,2
]}

Ciccarelli, Bryan ^{[1
,2
]}

Richardson, Paul G. ^{[1
,2
]}

Palladino, Michael A. ^{[3
]}

Anderson, Kenneth C. ^{[1
,2
]}

机构：

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

[2] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Med Oncol,Jerome Lipper Myeloma Ctr, Boston, MA 02115 USA

[3] Nereus Pharmaceut, San Diego, CA USA

来源：

BLOOD | 2010年 / 115卷 / 04期

基金：

美国国家卫生研究院;

关键词：

MARROW STROMAL CELLS; BONE-MARROW; THERAPEUTIC APPLICATIONS; THALIDOMIDE ANALOGS; DRUG-RESISTANCE; BORTEZOMIB; APOPTOSIS; SURVIVAL; ACTIVATION; CASPASE-12;

D O I：

10.1182/blood-2009-03-213009

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

Our recent study demonstrated that a novel proteasome inhibitor NPI-0052 is distinct from bortezomib (Velcade) and, importantly, triggers apoptosis in multiple myeloma (MM) cells resistant to bortezomib. Here we demonstrate that combining NPI-0052 and lenalidomide (Revlimid) induces synergistic anti-MM activity in vitro using MM-cell lines or patient MM cells. NPI-0052 plus lenalidomide-induced apoptosis is associated with (1) activation of caspase-8, caspase-9, caspase-12, caspase-3, and poly(ADP) ribose polymerase; (2) activation of BH-3 protein BIM; (3) translocation of BIM to endoplasmic reticulum; (4) inhibition of migration of MM cells and angiogenesis; and (5) suppression of chymotrypsin-like, caspase-like, and trypsin-like proteasome activities. Importantly, blockade of BIM using siRNA significantly abrogates NPI-0052 plus lenalidomide-induced apoptosis. Furthermore, studies using biochemical inhibitors of caspase-8 versus caspase-9 demonstrate that NPI-0052 plus lenalidomide-triggered apoptosis is primarily dependent on caspase-8 signaling. In animal tumor model studies, low-dose combination of NPI-0052 and lenalidomide is well tolerated, significantly inhibits tumor growth, and prolongs survival. Taken together, our study provides the preclinical rationale for clinical protocols evaluating lenalidomide together with NPI-0052 to improve patient outcome in MM. (Blood. 2010;115:834-845)

引用

页码：834 / 845

页数：12

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