Abstract
ABT-737 and its orally active analog, ABT-263, are rationally designed inhibitors of BCL2 and BCL-X(L). ABT-263 shows promising activity in early phase 1 clinical trials in B-cell malignancies, particularly chronic lymphocytic leukemia (CLL). In vitro, peripheral blood CLL cells are extremely sensitive to ABT-737 (EC(50) approximately 7 nM), with rapid induction of apoptosis in all 60 patients tested, independent of parameters associated with disease progression and chemotherapy resistance. In contrast to data from cell lines, ABT-737-induced apoptosis in CLL cells was largely MCL1-independent. Because CLL cells within lymph nodes are more resistant to apoptosis than those in peripheral blood, CLL cells were cultured on CD154-expressing fibroblasts in the presence of interleukin-4 (IL-4) to mimic the lymph node microenvironment. CLL cells thus cultured developed an approximately 1000-fold resistance to ABT-737 within 24 hours. Investigations of the underlying mechanism revealed that this resistance occurred upstream of mitochondrial perturbation and involved de novo synthesis of the antiapoptotic proteins BCL-X(L) and BCL2A1, which were responsible for resistance to low and high ABT-737 concentrations, respectively. Our data indicate that after therapy with ABT-737-related inhibitors, resistant CLL cells might develop in lymph nodes in vivo and that treatment strategies targeting multiple BCL2 antiapoptotic members simultaneously may have synergistic activity.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Apoptosis / drug effects
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Biphenyl Compounds / pharmacology*
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Blotting, Western
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CD40 Ligand / genetics
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CD40 Ligand / metabolism
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Drug Resistance, Neoplasm*
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Fibroblasts / cytology
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Fibroblasts / drug effects
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Fibroblasts / metabolism
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Humans
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Immunoenzyme Techniques
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Immunoprecipitation
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Interleukin-4 / genetics
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Interleukin-4 / metabolism
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Leukemia, Lymphocytic, Chronic, B-Cell / drug therapy*
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Leukemia, Lymphocytic, Chronic, B-Cell / metabolism*
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Leukemia, Lymphocytic, Chronic, B-Cell / pathology
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Lymph Nodes / drug effects
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Lymph Nodes / metabolism
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Lymph Nodes / pathology
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Lymphocytes / drug effects
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Lymphocytes / metabolism
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Lymphocytes / pathology
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Minor Histocompatibility Antigens
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Mitochondria / drug effects
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Mitochondria / metabolism
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Myeloid Cell Leukemia Sequence 1 Protein
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Nitrophenols / pharmacology*
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Piperazines / pharmacology
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Protein Biosynthesis / drug effects
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Proto-Oncogene Proteins c-bcl-2 / antagonists & inhibitors
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Proto-Oncogene Proteins c-bcl-2 / genetics
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Proto-Oncogene Proteins c-bcl-2 / metabolism*
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RNA, Small Interfering / pharmacology
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Sulfonamides / pharmacology*
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Up-Regulation
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bcl-X Protein / antagonists & inhibitors
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bcl-X Protein / genetics
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bcl-X Protein / metabolism*
Substances
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ABT-737
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BCL2-related protein A1
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BCL2L1 protein, human
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Biphenyl Compounds
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Minor Histocompatibility Antigens
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Myeloid Cell Leukemia Sequence 1 Protein
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Nitrophenols
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Piperazines
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Proto-Oncogene Proteins c-bcl-2
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RNA, Small Interfering
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Sulfonamides
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bcl-X Protein
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CD40 Ligand
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Interleukin-4