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It is generally accepted that the cancer cells, which have adapted to hypoxic environment in tumor tissues, aggravate the pathology of cancer by promoting tumor growth, angiogenesis, metastasis and drug resistance. Therefore the compounds that selectively inhibit growth of cancer cells under hypoxic environment are expected to be new leads promising for molecular targeted anti-cancer drugs. So far, we have reported that furospinosulin-1 (1), a marine spongean furanosesterterpene, showed selective anti-proliferative activity under hypoxic condition. Compound 1 also exhibited anti-tumor activity by oral administration in a mouse model inoculated mouse sarcoma S180 cells. A mechanistic analysis revealed that 1 suppressed transcription of insulin-like growth factor (IGF)-2 gene, which is selectively induced under hypoxic condition, by inhibiting complex formation between nuclear protein and the oligonucleotide containing Sp1-like consensus sequence.
In this paper, we proved that 1 showed anti-tumor activity via acting on the hypoxic region in tumor tissue as well as in vitro property of 1. Moreover, two transcriptional regulators, p54nrb and LEDGF were figured out as the binding protein of 1 by using the oligonucleotide probe containing Sp1-like consensus sequence and the furospinosulin-1 (1) probe, and we then clarified that hypoxia-selective growth inhibition was observed in both p54nrbgene-knockdown and LEDGFgene-knockdown DU145 cells.
