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1.
Cell Chem Biol ; 26(5): 711-723.e14, 2019 05 16.
Article in English | MEDLINE | ID: mdl-30880155

ABSTRACT

The transcription factor Max is a basic-helix-loop-helix leucine zipper (bHLHLZ) protein that forms homodimers or interacts with other bHLHLZ proteins, including Myc and Mxd proteins. Among this dynamic network of interactions, the Myc/Max heterodimer has crucial roles in regulating normal cellular processes, but its transcriptional activity is deregulated in a majority of human cancers. Despite this significance, the arsenal of high-quality chemical probes to interrogate these proteins remains limited. We used small molecule microarrays to identify compounds that bind Max in a mechanistically unbiased manner. We discovered the asymmetric polycyclic lactam, KI-MS2-008, which stabilizes the Max homodimer while reducing Myc protein and Myc-regulated transcript levels. KI-MS2-008 also decreases viable cancer cell growth in a Myc-dependent manner and suppresses tumor growth in vivo. This approach demonstrates the feasibility of modulating Max with small molecules and supports altering Max dimerization as an alternative approach to targeting Myc.


Subject(s)
Basic Helix-Loop-Helix Leucine Zipper Transcription Factors/metabolism , Lactams/pharmacology , Polycyclic Compounds/pharmacology , Proto-Oncogene Proteins c-myc/genetics , Repressor Proteins/metabolism , Small Molecule Libraries/pharmacology , Transcription, Genetic/drug effects , Animals , Basic Helix-Loop-Helix Leucine Zipper Transcription Factors/chemistry , Basic Helix-Loop-Helix Leucine Zipper Transcription Factors/genetics , Cell Line , Dimerization , Disease Models, Animal , Humans , Lactams/chemical synthesis , Lactams/therapeutic use , Male , Mice , Mice, Inbred NOD , Mice, SCID , Neoplasms/drug therapy , Polycyclic Compounds/chemical synthesis , Polycyclic Compounds/therapeutic use , Promoter Regions, Genetic , Protein Binding , Proto-Oncogene Proteins c-myc/metabolism , Rats , Repressor Proteins/chemistry , Repressor Proteins/genetics , Small Molecule Libraries/therapeutic use , Ultraviolet Rays
2.
Nat Cell Biol ; 20(7): 782-788, 2018 07.
Article in English | MEDLINE | ID: mdl-29941931

ABSTRACT

Defining the metabolic limitations of tumour growth will help to develop cancer therapies1. Cancer cells proliferate slower in tumours than in standard culture conditions, indicating that a metabolic limitation may restrict cell proliferation in vivo. Aspartate synthesis can limit cancer cell proliferation when respiration is impaired2-4; however, whether acquiring aspartate is endogenously limiting for tumour growth is unknown. We confirm that aspartate has poor cell permeability, which prevents environmental acquisition, whereas the related amino acid asparagine is available to cells in tumours, but cancer cells lack asparaginase activity to convert asparagine to aspartate. Heterologous expression of guinea pig asparaginase 1 (gpASNase1), an enzyme that produces aspartate from asparagine5, confers the ability to use asparagine to supply intracellular aspartate to cancer cells in vivo. Tumours expressing gpASNase1 grow at a faster rate, indicating that aspartate acquisition is an endogenous metabolic limitation for the growth of some tumours. Tumours expressing gpASNase1 are also refractory to the growth suppressive effects of metformin, suggesting that metformin inhibits tumour growth by depleting aspartate. These findings suggest that therapeutic aspartate suppression could be effective to treat cancer.


Subject(s)
Aspartic Acid/metabolism , Cell Proliferation , Energy Metabolism , Neoplasms/metabolism , Animals , Antineoplastic Agents/pharmacology , Asparaginase/genetics , Asparaginase/metabolism , Cell Proliferation/drug effects , Drug Resistance, Neoplasm , Guinea Pigs , HCT116 Cells , HEK293 Cells , HeLa Cells , Humans , Male , Metabolomics/methods , Metformin/pharmacology , Mice, Nude , Mice, Transgenic , Neoplasms/drug therapy , Neoplasms/genetics , Neoplasms/pathology , Signal Transduction , Time Factors , Tumor Burden , Tumor Microenvironment , Xenograft Model Antitumor Assays
3.
Proc Natl Acad Sci U S A ; 112(11): E1288-96, 2015 Mar 17.
Article in English | MEDLINE | ID: mdl-25737542

ABSTRACT

BH3 mimetics such as ABT-263 induce apoptosis in a subset of cancer models. However, these drugs have shown limited clinical efficacy as single agents in small-cell lung cancer (SCLC) and other solid tumor malignancies, and rational combination strategies remain underexplored. To develop a novel therapeutic approach, we examined the efficacy of ABT-263 across >500 cancer cell lines, including 311 for which we had matched expression data for select genes. We found that high expression of the proapoptotic gene Bcl2-interacting mediator of cell death (BIM) predicts sensitivity to ABT-263. In particular, SCLC cell lines possessed greater BIM transcript levels than most other solid tumors and are among the most sensitive to ABT-263. However, a subset of relatively resistant SCLC cell lines has concomitant high expression of the antiapoptotic myeloid cell leukemia 1 (MCL-1). Whereas ABT-263 released BIM from complexes with BCL-2 and BCL-XL, high expression of MCL-1 sequestered BIM released from BCL-2 and BCL-XL, thereby abrogating apoptosis. We found that SCLCs were sensitized to ABT-263 via TORC1/2 inhibition, which led to reduced MCL-1 protein levels, thereby facilitating BIM-mediated apoptosis. AZD8055 and ABT-263 together induced marked apoptosis in vitro, as well as tumor regressions in multiple SCLC xenograft models. In a Tp53; Rb1 deletion genetically engineered mouse model of SCLC, the combination of ABT-263 and AZD8055 significantly repressed tumor growth and induced tumor regressions compared with either drug alone. Furthermore, in a SCLC patient-derived xenograft model that was resistant to ABT-263 alone, the addition of AZD8055 induced potent tumor regression. Therefore, addition of a TORC1/2 inhibitor offers a therapeutic strategy to markedly improve ABT-263 activity in SCLC.


Subject(s)
Aniline Compounds/therapeutic use , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Lung Neoplasms/drug therapy , Small Cell Lung Carcinoma/drug therapy , Sulfonamides/therapeutic use , Aniline Compounds/pharmacology , Animals , Antineoplastic Combined Chemotherapy Protocols/pharmacology , Apoptosis/drug effects , Apoptosis Regulatory Proteins/metabolism , Bcl-2-Like Protein 11 , Cell Line, Tumor , Dose-Response Relationship, Drug , Genetic Engineering , Humans , Inhibitory Concentration 50 , Lung Neoplasms/pathology , Mechanistic Target of Rapamycin Complex 1 , Mechanistic Target of Rapamycin Complex 2 , Membrane Proteins/metabolism , Mice , Morpholines/pharmacology , Morpholines/therapeutic use , Multiprotein Complexes/antagonists & inhibitors , Multiprotein Complexes/metabolism , Myeloid Cell Leukemia Sequence 1 Protein/metabolism , Proto-Oncogene Proteins/metabolism , Remission Induction , Small Cell Lung Carcinoma/pathology , Sulfonamides/pharmacology , TOR Serine-Threonine Kinases/antagonists & inhibitors , TOR Serine-Threonine Kinases/metabolism , Xenograft Model Antitumor Assays
4.
Am J Pathol ; 177(2): 575-85, 2010 Aug.
Article in English | MEDLINE | ID: mdl-20566748

ABSTRACT

Postmortem, genetic, brain imaging, and peripheral cell studies all support decreased mitochondrial activity as a factor in the manifestation of Bipolar Disorder (BD). Because abnormal mitochondrial morphology is often linked to altered energy metabolism, we investigated whether changes in mitochondrial structure were present in brain and peripheral cells of patients with BD. Mitochondria from patients with BD exhibited size and distributional abnormalities compared with psychiatrically-healthy age-matched controls. Specifically, in brain, individual mitochondria profiles had significantly smaller areas, on average, in BD samples (P = 0.03). In peripheral cells, mitochondria in BD samples were concentrated proportionately more within the perinuclear region than in distal processes (P = 0.0008). These mitochondrial changes did not appear to be correlated with exposure to lithium. Also, these abnormalities in brain and peripheral cells were independent of substantial changes in the actin or tubulin cytoskeleton with which mitochondria interact. The observed changes in mitochondrial size and distribution may be linked to energy deficits and, therefore, may have consequences for cell plasticity, resilience, and survival in patients with BD, especially in brain, which has a high-energy requirement. The findings may have implications for diagnosis, if they are specific to BD, and for treatment, if they provide clues as to the underlying pathophysiology of BD.


Subject(s)
Bipolar Disorder/pathology , Mitochondria/pathology , Prefrontal Cortex , Adenosine Triphosphate/metabolism , Adult , Aged , Aged, 80 and over , Antidepressive Agents/pharmacology , Cell Line , Cytochromes c/metabolism , Cytoskeleton/ultrastructure , Energy Metabolism , Female , Fibroblasts/drug effects , Fibroblasts/ultrastructure , Humans , Lithium Carbonate/pharmacology , Male , Middle Aged , Mitochondria/ultrastructure , Prefrontal Cortex/cytology , Prefrontal Cortex/metabolism , Young Adult
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