No abstract

No abstract

No abstract

Parasporin-2, a new crystal protein derived from noninsecticidal and nonhemolytic Bacillus thuringiensis, recognizes and kills human liver and colon cancer cells as well as some classes of human cultured cells. Here we report that a potent proteinase K-resistant parasporin-2 toxin shows specific binding to and a variety of cytocidal effects against human hepatocyte cancer cells. Cleavage of the N-terminal region of parasporin-2 was essential for the toxin activity, whereas C-terminal digestion was required for rapid cell injury. Protease-activated parasporin-2 induced remarkable morphological alterations, cell blebbing, cytoskeletal alterations, and mitochondrial and endoplasmic reticulum fragmentation. The plasma membrane permeability was increased immediately after the toxin treatment and most of the cytoplasmic proteins leaked from the cells, whereas mitochondrial and endoplasmic reticulum proteins remained in the intoxicated cells. Parasporin-2 selectively bound to cancer cells in slices of liver tumor tissues and susceptible human cultured cells and became localized in the plasma membrane until the cells were damaged. Thus, parasporin-2 acts as a cytolysin that permeabilizes the plasma membrane with target cell specificity and subsequently induces cell decay.

An approach to minimization of toxicity of a new compound is to elucidate the mechanisms of toxicity of analogous compounds and to clarify their structure-toxicity relationships. A problem with this approach, however, is that such elucidation remains difficult. For quinolones, some improvements in this mechanistic approach have been achieved in the central nervous system (CNS), particularly with regard to their interaction with non-steroidal anti-inflammatory drugs (NSAIDs), and in genotoxicity and phototoxicity studies, particularly in comparison with other toxicities, such as to the cardiovascular, gastrointestinal, bone, reproductive, and developmental systems. This review concentrates on a description of the known effects of quinolones on various organ systems in experimental animals and humans. Given the logarithmic increase in the synthesis of new quinolones, it is questionable whether these drugs share similar safety and efficacy. Nevertheless, this mechanistic approach to the investigation and minimization of toxicity has produced satisfactory results to date and deserves to be continued.