The Biochemical Mechanisms Involved in the Biological Effects Induced by Neocarzinostatin (NCS) and the NCS Chromophore

Abstract

Treatment of bacterial and mammalian cells with neocarzinostatin (NCS) results in selective inhibition of DNA synthesis and induction of DNA degradation. Before the discovery of the NCS chromophore (NCS-chrom), NCS was defined as an antitumor antibiotic composed of an acidic polypeptide (approximately 11000; pi 3.3). In 1990, a NCS-chrom associated with the NCS polypeptide (NCS-apoprotein) was discovered and identified as the molecule responsible for the biological effects of NCS. In 1993, the research group of Goldberg (Harvard University, USA) proposed a biochemical mechanism of NCS-chrom DNA degradation in vitro. In 1995, they also found the base-catalyzed (bc) cleavage of single-stranded DNA (ssDNA) with a bulge structure by NCS-chrom in the absence of thiols. Therefore, it is concluded that the ability of NCS-chrom to degrade DNA is its primary action, which selectively inhibits DNA synthesis in cultured cells. In addition, NCS-chrom induces blocking of the metaphase of the cell cycle and also inhibits protein phosphorylation involved in transcriptional regulation. Disruption of the repair systems by NCS-chrom results in the positive induction of apoptosis, because NCS-chrom (i) is greatly activated by thiols at the intracellular level and (ii) inhibits activation of transcriptional factors through their specific phosphorylation. Taken together, all these biological and biochemical data suggest that NCS-chrom could be an effective chemotherapeutic drug for human cancer if its toxicity can be appropriately controlled.