Abstract
Since apoptosis is impaired in malignant cells overexpressing prosurvival Bcl-2 proteins, drugs mimicking their natural antagonists, BH3-only proteins, might overcome chemoresistance. Of seven putative BH3 mimetics tested, only ABT-737 triggered Bax/Bak-mediated apoptosis. Despite its high affinity for Bcl-2, Bcl-x(L), and Bcl-w, many cell types proved refractory to ABT-737. We show that this resistance reflects ABT-737's inability to target another prosurvival relative, Mcl-1. Downregulation of Mcl-1 by several strategies conferred sensitivity to ABT-737. Furthermore, enforced Mcl-1 expression in a mouse lymphoma model conferred resistance. In contrast, cells overexpressing Bcl-2 remained highly sensitive to ABT-737. Hence, ABT-737 should prove efficacious in tumors with low Mcl-1 levels, or when combined with agents that inactivate Mcl-1, even to treat those tumors that overexpress Bcl-2.
Publication types
-
Research Support, N.I.H., Extramural
-
Research Support, Non-U.S. Gov't
MeSH terms
-
Animals
-
Apoptosis*
-
Biphenyl Compounds / metabolism
-
Biphenyl Compounds / pharmacology*
-
Biphenyl Compounds / therapeutic use
-
Cells, Cultured
-
Cytokines / metabolism
-
Disease Models, Animal
-
Fibroblasts / cytology
-
Fibroblasts / metabolism
-
Humans
-
Leukemia, Myeloid, Acute / drug therapy*
-
Leukemia, Myeloid, Acute / metabolism
-
Leukemia, Myeloid, Acute / pathology*
-
Male
-
Mice
-
Mice, Inbred C57BL
-
Mice, Transgenic
-
Myeloid Cell Leukemia Sequence 1 Protein
-
Neoplasm Proteins / metabolism
-
Nitrophenols / metabolism
-
Nitrophenols / pharmacology*
-
Nitrophenols / therapeutic use
-
Piperazines / metabolism
-
Piperazines / pharmacology
-
Piperazines / therapeutic use
-
Protein Structure, Tertiary
-
Proto-Oncogene Proteins c-bcl-2 / antagonists & inhibitors*
-
Proto-Oncogene Proteins c-bcl-2 / chemistry
-
Proto-Oncogene Proteins c-bcl-2 / genetics
-
Proto-Oncogene Proteins c-bcl-2 / metabolism
-
RNA Interference
-
Recombinant Fusion Proteins / genetics
-
Recombinant Fusion Proteins / metabolism
-
Sulfonamides / metabolism
-
Sulfonamides / pharmacology*
-
Sulfonamides / therapeutic use
-
bcl-2 Homologous Antagonist-Killer Protein / genetics
-
bcl-2 Homologous Antagonist-Killer Protein / metabolism
-
bcl-2-Associated X Protein / chemistry
-
bcl-2-Associated X Protein / genetics
-
bcl-2-Associated X Protein / metabolism
Substances
-
ABT-737
-
Biphenyl Compounds
-
Cytokines
-
Mcl1 protein, mouse
-
Myeloid Cell Leukemia Sequence 1 Protein
-
Neoplasm Proteins
-
Nitrophenols
-
Piperazines
-
Proto-Oncogene Proteins c-bcl-2
-
Recombinant Fusion Proteins
-
Sulfonamides
-
bcl-2 Homologous Antagonist-Killer Protein
-
bcl-2-Associated X Protein