ABT-199, a BH3 mimetic that specifically targets Bcl-2, enhances the antitumor activity of chemotherapy, bortezomib and JQ1 in "double hit" lymphoma cells.
Double hit lymphoma (DHL) is a recently recognized lymphoma with a survival of less than 2 years. Both ABT-737, a Bcl-2/Bcl-XL inhibitor, and ABT-199, which selectively targets Bcl-2, were potently cytotoxic against DHL cell lines Sc-1 and OcI-LY18, the RL cell line and primary human DHL cells, but not Ramos cells, which lack Bcl-2 expression. ABT-199 was more potent than ABT-737, and is the most promising of the BH3 mimetics to date. The DHL cell lines were also sensitive (< 200 nM) to doxorubicin, methotrexate, cytarabine and the proteosome inhibitor, bortezomib. The combination of chemotherapy with ABT-199 and doxorubicin or cytarabine, bortezomib, YM-155 and JQ1 produced synergistic cell kill against the DHL cell lines. Cells from a patient with DHL were also sensitive to JQ1 and bortezomib, providing a rationale for a clinical trial of these combinations in patients with relapsed DHL.
Rutgers Cancer Institute of New Jersey and the Robert Wood Johnson School of Medicine , New Brunswick, NJ , USA.
Nadine
N
Johnson-Farley
Jonny
J
Veliz
S
S
Bhagavathi
Joseph R
JR
Bertino
D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D001381:Azepines / Q000008:administration & dosage; D032701:Biomimetics; D015153:Blotting, Western; D000069286:Bortezomib / Q000008:administration & dosage; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000008:administration & dosage; D049109:Cell Proliferation / Q000187:drug effects*; D004357:Drug Synergism; D006801:Humans; D008223:Lymphoma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology*; D010446:Peptide Fragments / Q000008:administration & dosage; D011518:Proto-Oncogene Proteins / Q000008:administration & dosage; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000037:antagonists & inhibitors*; D013449:Sulfonamides / Q000008:administration & dosage; D014230:Triazoles / Q000008:administration & dosage; D014407:Tumor Cells, Cultured
C561695:(+)-JQ1 compound; D001381:Azepines; C474007:Bax protein (53-86); D019086:Bridged Bicyclo Compounds, Heterocyclic; D010446:Peptide Fragments; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D013449:Sulfonamides; D014230:Triazoles; D000069286:Bortezomib; C579720:venetoclax
Cell lines and animal models; chemotherapeutic approaches; lymphoma and Hodgkin disease