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1.
Curr Opin Physiol ; 3: 71-81, 2018 Jun.
Article in English | MEDLINE | ID: mdl-30334018

ABSTRACT

Mitochondria play key roles in mammalian apoptosis, a highly regulated genetic program of cell suicide. Multiple apoptotic signals culminate in mitochondrial outer membrane permeabilization (MOMP), which not only couples the mitochondria to the activation of caspases but also initiates caspase-independent mitochondrial dysfunction. The BCL-2 family proteins are central regulators of MOMP. Multidomain pro-apoptotic BAX and BAK are essential effectors responsible for MOMP, whereas anti-apoptotic BCL-2, BCL-XL, and MCL-1 preserve mitochondrial integrity. The third BCL-2 subfamily of proteins, BH3-only molecules, promotes apoptosis by either activating BAX and BAK or inactivating BCL-2, BCL-XL, and MCL-1. Through an interconnected hierarchical network of interactions, the BCL-2 family proteins integrate developmental and environmental cues to dictate the survival versus death decision of cells by regulating the integrity of the mitochondrial outer membrane. Over the past 30 years, research on the BCL-2-regulated apoptotic pathway has not only revealed its importance in both normal physiological and disease processes, but has also resulted in the first anti-cancer drug targeting protein-protein interactions.

2.
Nat Commun ; 8: 16078, 2017 07 17.
Article in English | MEDLINE | ID: mdl-28714472

ABSTRACT

BCL-2 family proteins are central regulators of mitochondrial apoptosis and validated anti-cancer targets. Using small cell lung cancer (SCLC) as a model, we demonstrated the presence of differential addiction of cancer cells to anti-apoptotic BCL-2, BCL-XL or MCL-1, which correlated with the respective protein expression ratio. ABT-263 (navitoclax), a BCL-2/BCL-XL inhibitor, prevented BCL-XL from sequestering activator BH3-only molecules (BH3s) and BAX but not BAK. Consequently, ABT-263 failed to kill BCL-XL-addicted cells with low activator BH3s and BCL-XL overabundance conferred resistance to ABT-263. High-throughput screening identified anthracyclines including doxorubicin and CDK9 inhibitors including dinaciclib that synergized with ABT-263 through downregulation of MCL-1. As doxorubicin and dinaciclib also reduced BCL-XL, the combinations of BCL-2 inhibitor ABT-199 (venetoclax) with doxorubicin or dinaciclib provided effective therapeutic strategies for SCLC. Altogether, our study highlights the need for mechanism-guided targeting of anti-apoptotic BCL-2 proteins to effectively activate the mitochondrial cell death programme to kill cancer cells.


Subject(s)
Antineoplastic Agents/pharmacology , Apoptosis/drug effects , Lung Neoplasms/metabolism , Myeloid Cell Leukemia Sequence 1 Protein/drug effects , Proto-Oncogene Proteins c-bcl-2/drug effects , Small Cell Lung Carcinoma/metabolism , bcl-X Protein/drug effects , Aniline Compounds/pharmacology , Apoptosis Regulatory Proteins/antagonists & inhibitors , Apoptosis Regulatory Proteins/drug effects , Apoptosis Regulatory Proteins/metabolism , Bridged Bicyclo Compounds, Heterocyclic/pharmacology , Cell Line, Tumor , Cyclic N-Oxides , Cyclin-Dependent Kinase 9/antagonists & inhibitors , Doxorubicin/pharmacology , Drug Resistance, Neoplasm , Drug Synergism , High-Throughput Screening Assays , Humans , Indolizines , Lung Neoplasms/drug therapy , Molecular Targeted Therapy , Myeloid Cell Leukemia Sequence 1 Protein/antagonists & inhibitors , Myeloid Cell Leukemia Sequence 1 Protein/metabolism , Protein Kinase Inhibitors/pharmacology , Proto-Oncogene Proteins c-bcl-2/antagonists & inhibitors , Proto-Oncogene Proteins c-bcl-2/metabolism , Pyridinium Compounds/pharmacology , Small Cell Lung Carcinoma/drug therapy , Sulfonamides/pharmacology , bcl-X Protein/antagonists & inhibitors , bcl-X Protein/metabolism
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