[Biochemical mechanisms of NCS-chromophore-induced DNA cleavage and inhibition of protein kinase activity].
A NCS-chromophore (molecular weight: approximately 695) can be extracted from an antitumor antibiotic neocarzinostatin (NCS) (approximately 11,000, pI 3.3) with methanol as a DNA cleavaging molecule. Recently, the Goldberg research group (Harvard University, USA) proposed two distinct mechanisms of DNA cleavages (thiol-dependent DNA cleavage and thiol-independent base-catalyzed (bc) cleavage of ssDNA) by NCS-chromophore in vitro. Therefore, it is concluded that the ability of NCS-chromophore to cleave DNA is its primary action, which selectively inhibits DNA synthesis in cultured cells. Furthermore, we found that NCS-chromophore inhibits protein phosphorylation by CK-II (casein kinase II) involved in transcriptional regulation in a dose-dependent manner. Disruption of the repair systems of the NCS-chromophore-induced biological damages results in the positive induction of apoptosis, because the drug is greatly activated by thiols at the intracellular level, and it inhibits the activities of several transcriptional factors through their specific phosphorylation by nuclear kinases, such as CK-II. Taken together, all these biological and biochemical data suggest that the NCS-chromophore could be an effective chemotherapeutic drug for human cancer if its toxicity can be appropriately controlled.
Ohtsuki
K
K
Laboratory of Genetical Biochemistry, Kitasato University, School of Allied Health Sciences.
Tanoue
S
S
Karino
A
A
D000903:Antibiotics, Antineoplastic / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D053938:DNA Fragmentation / Q000187:drug effects*; D053281:Enediynes; D006801:Humans; D010766:Phosphorylation / Q000187:drug effects; D011494:Protein Kinases / Q000187:drug effects / Q000378:metabolism*; D014407:Tumor Cells, Cultured / Q000378:metabolism / Q000473:pathology; D009353:Zinostatin / Q000031:analogs & derivatives / Q000737:chemistry / Q000494:pharmacology
D000903:Antibiotics, Antineoplastic; D053281:Enediynes; C032372:neocarzinostatin chromophore; D009353:Zinostatin; D011494:Protein Kinases