The basic and clinical implications of ABC transporters, Y‐box‐binding protein‐1 (YB‐1) and angiogenesis‐related factors in human malignancies

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. Angiogene‐sis 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. (Cancer Sci 2003; 94: 9–14)