The
amine-carboxyboranes were shown to be synergistic with
tumor necrosis factor alpha (
TNF alpha) in cytotoxicity and inhibition of
DNA synthesis in select types of
cancer cells depending on the presence of a
TNF alpha high affinity receptor on the membrane of the cell. Initially both
TNF alpha and the
amine-carboxyboranes reduce the influx of
calcium but later cause a significant increase intracellularly. This influx is not linked with the
amine-carboxyborane activating the
calcitonin receptor in the
tumor cells. Neither the agents nor
TNF alpha directly inhibits
DNA topoisomerase II activity but both did cause decreased phosphorylation of the
enzyme by
protein kinase C (PKC). The two agents caused synergistic inhibition. This event correlated with increased
DNA protein linked breaks, DNA fragmentation and cell death. These
protein linked breaks are additive with
etoposide's effects but the latter agent's mechanism is different than phosphorylation of
topoisomerase II. There was no evidence that the DNA fragmentation was caused by a
calcium induced
endonuclease enzyme in these
cancer cells. The low-molecular weight
amine-carboxyboranes appear to play an identical function as
TNF alpha in its role to cause DNA breaks and fragmentation to cause apoptosis.