RELATIONSHIP BETWEEN AMINE-CARBOXYBORANES AND TNF-ALPHA FOR THE REGULATION OF CELL-GROWTH IN DIFFERENT TUMOR-CELL LINES

The amine-carboxyboranes were shown to be synergistic with tumor necro sis factor alpha (TNF alpha) in cytotoxicity and inhibition of DNA syn thesis in select types of cancer cells depending on the presence of a TNF alpha high affinity receptor on the membrane of the cell. Initiall y both TNF alpha and the amine-carboxyboranes reduce the influx of cal cium but later cause a significant increase intracellularly. This infl ux is not linked with the amine-carboxyborane activating the calcitoni n receptor in the tumor cells. Neither the agents nor TNF alpha, direc tly inhibits DNA topoisomerase II activity but both did cause decrease d phosphorylation of the enzyme by protein kinase C (PKC). The two age nts caused synergistic inhibition. This event correlated with increase d DNA protein linked breaks, DNA fragmentation and cell death. These p rotein linked breaks are additive with etoposide's effects but the lat ter agent's mechanism is different than phosphorylation of topoisomera se II. There was no evidence that the DNA fragmentation was caused by a calcium induced endonuclease enzyme in these cancer cells. The low-m olecular weight amine-carboxyboranes appear to play an identical funct ion as TNF alpha in its role to cause DNA breaks and fragmentation to cause apoptosis. (C) 1998 Elsevier, Paris.