Abstract
In our laboratories, we have been studying molecular targets which might be advantageous for novel cancer therapeutics. In this review, we focus on how ATP-binding cassette (ABC) transporter superfamily genes, Y-box-binding protein-1 (YB-1), and tumor angiogenesis-associated factors could contribute to the development of novel strategies for molecular cancer therapeutics. ABC transporters such as P-glycoprotein/MDR1 and several MRP family proteins function to protect cells from xenobiotics, drugs and poisons, suggesting that ABC transporters are a double-edged sword. In this regard, P-glycoprotein/MDR1 is a representative ABC transporter which plays a critical role in the efflux of a wide range of drugs. We have reported that gene amplification, gene rearrangements, transcription factor YB-1 and CpG methylation on the promoter are involved in MDR1 gene overexpression in cultured cancer cells. Among them, two mechanisms appear to be relevant to the up-regulation of MDR1 gene in human malignancies. We first reported that MDR1 gene promoter is activated in response to environmental stimuli, and is modulated by methylation/demethylation of CpG sites on the MDR1 promoter. We also demonstrated that YB-1 modulates not only transcription of various genes associated with cell growth, drug resistance and DNA synthesis, but also translation, mRNA stabilization and DNA repair/self-defense processes. Angiogenesis is also involved in tumor growth, invasion and metastasis of various malignancies, and so angiogenesis-related molecules also offer novel molecular targets for anticancer therapeutics.
Publication types
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Research Support, Non-U.S. Gov't
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Review
MeSH terms
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ATP Binding Cassette Transporter, Subfamily B, Member 1 / physiology
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ATP-Binding Cassette Transporters / physiology*
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Angiogenesis Inhibitors / pharmacology
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Angiogenesis Inhibitors / therapeutic use
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Antineoplastic Agents / pharmacokinetics
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Antineoplastic Agents / pharmacology
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Antineoplastic Agents / therapeutic use
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Biological Transport
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CCAAT-Enhancer-Binding Proteins / physiology*
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CpG Islands
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DNA Methylation
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DNA-Binding Proteins*
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Drug Design
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Drug Resistance, Multiple / genetics
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Drug Resistance, Neoplasm / genetics
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Endothelial Growth Factors / physiology*
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Gene Amplification
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Gene Expression Regulation, Neoplastic
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Genes, MDR
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Humans
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Intercellular Signaling Peptides and Proteins / physiology*
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Lymphokines / physiology*
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NFI Transcription Factors
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Neoplasm Proteins / physiology*
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Neoplasms / blood supply
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Neoplasms / drug therapy
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Neoplasms / genetics
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Neoplasms / metabolism*
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Neovascularization, Pathologic / drug therapy
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Neovascularization, Pathologic / physiopathology
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Nuclear Proteins
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Promoter Regions, Genetic / genetics
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Transcription Factors*
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Transcription, Genetic
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Vascular Endothelial Growth Factor A
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Vascular Endothelial Growth Factors
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Y-Box-Binding Protein 1
Substances
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ATP Binding Cassette Transporter, Subfamily B, Member 1
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ATP-Binding Cassette Transporters
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Angiogenesis Inhibitors
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Antineoplastic Agents
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CCAAT-Enhancer-Binding Proteins
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DNA-Binding Proteins
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Endothelial Growth Factors
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Intercellular Signaling Peptides and Proteins
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Lymphokines
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NFI Transcription Factors
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Neoplasm Proteins
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Nuclear Proteins
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Transcription Factors
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Vascular Endothelial Growth Factor A
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Vascular Endothelial Growth Factors
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Y-Box-Binding Protein 1
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YBX1 protein, human