Targeting the Bcl-2 family of proteins in Hodgkin lymphoma: in vitro cytotoxicity, target modulation and drug combination studies of the Bcl-2 homology 3 mimetic ABT-737

被引:19
作者
Jayanthan, Aarthi [1 ,2 ]
Howard, Scott C. [3 ]
Trippett, Tanya [4 ]
Horton, Terzah [5 ]
Whitlock, James A. [6 ]
Daisley, Lara [1 ,2 ]
Lewis, Victor [1 ,2 ]
Narendran, Aru [1 ,2 ]
机构
[1] Alberta Childrens Prov Gen Hosp, Div Pediat Oncol, Calgary, AB T3B 6A8, Canada
[2] Alberta Childrens Prov Gen Hosp, Hughes Childrens Canc Res Ctr, Calgary, AB T3B 6A8, Canada
[3] St Jude Childrens Hosp, Memphis, TN 38105 USA
[4] Mem Sloane Kettering Canc Ctr, New York, NY USA
[5] Baylor Coll Med, Houston, TX 77030 USA
[6] Vanderbilt Univ, Med Ctr, Nashville, TN USA
关键词
Hodgkin lymphoma; ABT-737; Bcl-2; apoptosis; targeted therapeutics; ACUTE LYMPHOBLASTIC-LEUKEMIA; REED-STEMBERG CELLS; EPSTEIN-BARR-VIRUS; NF-KAPPA-B; MULTIPLE-MYELOMA; INHIBITOR ABT-737; APOPTOTIC PATHWAY; STERNBERG CELLS; EXPRESSION; PROLIFERATION;
D O I
10.1080/10428190902943069
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
With currently available treatment, patients with refractory Hodgkin lymphoma (HL) or those who relapse multiple times have an extremely poor prognosis. Therefore, new agents and novel therapeutic approaches are urgently needed. Antiapoptotic proteins such as Bcl-2 and Bcl-x have been associated with the growth and survival of Hodgkin Reed-Sternberg cells and are potential therapeutic targets. ABT-737 is a small molecule that inhibits the Bcl-2 family of apoptosis regulators. In this study, we show the concentration-dependent and time-dependent cytotoxicity of ABT-737 against cell lines derived from patients with HL. A concurrent reduction in a number of intracellular cell growth and survival related molecules, such as Bcl-2, Bcl-xl, NF-kappa B and survivin was also seen. Drug combination studies using a panel of conventional and novel therapeutic agents show that ABT-737 potentiates the activity of agents that have inherent anti-lymphoma activity and provide support for the evaluation of ABT-737 in the clinical setting.
引用
收藏
页码:1174 / 1182
页数:9
相关论文
共 53 条
[1]   Bcl-2-regulated apoptosis: mechanism and therapeutic potential [J].
Adams, Jerry M. ;
Cory, Suzanne .
CURRENT OPINION IN IMMUNOLOGY, 2007, 19 (05) :488-496
[2]   A NEW RAPID AND SIMPLE NONRADIOACTIVE ASSAY TO MONITOR AND DETERMINE THE PROLIFERATION OF LYMPHOCYTES - AN ALTERNATIVE TO [H-3] THYMIDINE INCORPORATION ASSAY [J].
AHMED, SA ;
GOGAL, RM ;
WALSH, JE .
JOURNAL OF IMMUNOLOGICAL METHODS, 1994, 170 (02) :211-224
[3]  
Aktas Safiye, 2007, Lymphatic Research and Biology, V5, P175, DOI 10.1089/lrb.2007.5305
[4]   A novel B-cell line (U-2932) established from a patient with diffuse large B-cell lymphoma following Hodgkin lymphoma [J].
Amini, RM ;
Berglund, M ;
Rosenquist, R ;
Von Heideman, A ;
Lagercrantz, S ;
Thunberg, U ;
Bergh, J ;
Sundström, C ;
Glimelius, B ;
Enblad, G .
LEUKEMIA & LYMPHOMA, 2002, 43 (11) :2179-2189
[5]   Expression of bcl2 family proteins and active caspase 3 in classical Hodgkin's lymphomas [J].
Bai, Maria ;
Papoudou-Bai, Alexandra ;
Horianopoulos, Nikolaos ;
Grepi, Constantina ;
Agnantis, Niki John ;
Kanavaros, Panagiotis .
HUMAN PATHOLOGY, 2007, 38 (01) :103-113
[6]   Constitutive nuclear factor-κB-RelA activation is required for proliferation and survival of Hodgkin's disease tumor cells [J].
Bargou, RC ;
Emmerich, F ;
Krappmann, D ;
Bommert, K ;
Mapara, MY ;
Arnold, W ;
Royer, HD ;
Grinstein, E ;
Greiner, A ;
Scheidereit, C ;
Dörken, B .
JOURNAL OF CLINICAL INVESTIGATION, 1997, 100 (12) :2961-2969
[7]   High-level nuclear NF-kappa B and Oct-2 is a common feature of cultured Hodgkin/Reed-Sternberg cells [J].
Bargou, RC ;
Leng, C ;
Krappmann, D ;
Emmerich, F ;
Mapara, MY ;
Bommert, K ;
Royer, HD ;
Scheidereit, C ;
Dorken, B .
BLOOD, 1996, 87 (10) :4340-4347
[8]   The role of NF-κB-1 and NF-κB-2-mediated resistance to apoptosis in lymphornas [J].
Bernal-Mizrachi, Leon ;
Lovly, Christine M. ;
Ratner, Lee .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2006, 103 (24) :9220-9225
[9]   No influence of bcl-2, p53, and p21waf1 protein expression on the outcome of pediatric Hodgkin lymphomas [J].
Chabay, Paola ;
Pesce, Pablo ;
De Matteo, Elena ;
Lombardi, Mercedes Garcia ;
Rey, Guadalupe ;
Preciado, Maria Victoria .
JOURNAL OF PEDIATRIC HEMATOLOGY ONCOLOGY, 2006, 28 (09) :552-558
[10]   A novel Bcl-2/Bcl-XL/Bcl-w inhibitor ABT-737 as therapy in multiple myeloma [J].
Chauhan, D. ;
Velankar, M. ;
Brahmandam, M. ;
Hideshima, T. ;
Podar, K. ;
Richardson, P. ;
Schlossman, R. ;
Ghobrial, I. ;
Raje, N. ;
Munshi, N. ;
Anderson, K. C. .
ONCOGENE, 2007, 26 (16) :2374-2380