title: 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.
abstract: 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. Anti-apoptotic 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-kappaB 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.
authors: Hughes' Children's Cancer Research Centre, Division of Pediatric Oncology, Alberta Children's Hospital, Calgary, Alberta, Canada.
authors: Aarthi
authors: A
authors: Jayanthan
authors: Scott C
authors: SC
authors: Howard
authors: Tanya
authors: T
authors: Trippett
authors: Terzah
authors: T
authors: Horton
authors: James A
authors: JA
authors: Whitlock
authors: Lara
authors: L
authors: Daisley
authors: Victor
authors: V
authors: Lewis
authors: Aru
authors: A
authors: Narendran
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis; D001713:Biphenyl Compounds / Q000494:pharmacology*; D015153:Blotting, Western; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D004305:Dose-Response Relationship, Drug; D006689:Hodgkin Disease / Q000378:metabolism*; D006801:Humans; D020128:Inhibitory Concentration 50; D016328:NF-kappa B / Q000378:metabolism; D009596:Nitrophenols / Q000494:pharmacology*; D010879:Piperazines / Q000494:pharmacology; D011379:Prognosis; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism*; D013449:Sulfonamides / Q000494:pharmacology*; D013997:Time Factors; D051020:bcl-X Protein / Q000235:genetics
chemical_list: C501332:ABT-737; D000970:Antineoplastic Agents; D001713:Biphenyl Compounds; D016328:NF-kappa B; D009596:Nitrophenols; D010879:Piperazines; D019253:Proto-Oncogene Proteins c-bcl-2; D013449:Sulfonamides; D051020:bcl-X Protein