Identification of Small Molecules That Induce Apoptosis in a Myc-Dependent Manner and Inhibit Myc-Driven Transformation

The Myc transcription factor plays a central role in the regulation of cell cycle progression, apoptosis, angiogenesis, and cellular transformation. Myc is a potent oncoprotein that is deregulated in a wide variety of human tumors and is therefore an attractive target for novel cancer therapies. Usi...

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Bibliographic Details
Published in:Proceedings of the National Academy of Sciences - PNAS 2006-04, Vol.103 (16), p.6344-6349
Main Authors: Mo, Hao, Henriksson, Marie
Format: Article
Language:English
Subjects:
Animals
Anthracenes - chemistry
Anthracenes - pharmacology
Antineoplastic Agents - chemistry
Antineoplastic Agents - pharmacology
Apoptosis
Apoptosis - genetics
B lymphocytes
Biological Sciences
Cancer
Cell cycle
Cell growth
Cell lines
Cell Transformation, Neoplastic - drug effects
Cell Transformation, Neoplastic - genetics
COS cells
Diamines - chemistry
Diamines - pharmacology
DNA
DNA - metabolism
Drug Screening Assays, Antitumor
Humans
Hydrazones - pharmacology
Oncogenes
Proteins
Proto-Oncogene Proteins c-myc - antagonists & inhibitors
Proto-Oncogene Proteins c-myc - metabolism
Purines - pharmacology
Rats
Transactivation
Transcription Factors - antagonists & inhibitors
Transcription Factors - metabolism
Transcriptional Activation - drug effects
Tumors
Viability
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Summary:The Myc transcription factor plays a central role in the regulation of cell cycle progression, apoptosis, angiogenesis, and cellular transformation. Myc is a potent oncoprotein that is deregulated in a wide variety of human tumors and is therefore an attractive target for novel cancer therapies. Using a cellular screening approach, we have identified low-molecular-weight compounds, Myc pathway response agents (MYRAs), that induce apoptosis in a c-Myc-dependent manner and inhibit Myc-driven cellular transformation. MYRA-A inhibits Myc transactivation and interferes with the DNA-binding activity of Myc family proteins but has no effect on the E-box-binding protein USF. In contrast, MYRA-B induces Myc-dependent apoptosis without affecting Myc transactivation or Myc/Max DNA binding. Our data show that cellular screening assays can be a powerful strategy for the identification of candidate substances that modulate the Myc pathway. These compounds can be useful tools for studying Myc function and may also be of therapeutic potential as leads for drug development.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.0601418103