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 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.
Division of Medicinal Chemistry and Natural Products, School of Pharmacy, University of North Carolina, Chapel Hill 27599-7360, USA.
M C
MC
Miller
C M
CM
Woods
M E
ME
Murphy
A
A
Elkins
B F
BF
Spielvogel
I H
IH
Hall
D000818:Animals; D000970:Antineoplastic Agents / Q000633:toxicity*; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D001896:Boron Compounds / Q000633:toxicity*; D002116:Calcitonin / Q000378:metabolism; D002455:Cell Division / Q000187:drug effects / Q000502:physiology*; D002470:Cell Survival / Q000187:drug effects; D053938:DNA Fragmentation; D004261:DNA Replication / Q000187:drug effects; D004250:DNA Topoisomerases, Type II / Q000378:metabolism; D004273:DNA, Neoplasm / Q000096:biosynthesis; D004357:Drug Synergism; D018922:HL-60 Cells / Q000187:drug effects; D006801:Humans; D007939:Leukemia L1210 / Q000473:pathology; D051379:Mice; D012516:Osteosarcoma; D011493:Protein Kinase C / Q000378:metabolism; D018003:Receptors, Calcitonin / Q000378:metabolism; D018124:Receptors, Tumor Necrosis Factor / Q000378:metabolism; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology* / Q000502:physiology
D000970:Antineoplastic Agents; D001896:Boron Compounds; D004273:DNA, Neoplasm; D018003:Receptors, Calcitonin; D018124:Receptors, Tumor Necrosis Factor; D014409:Tumor Necrosis Factor-alpha; D002116:Calcitonin; D011493:Protein Kinase C; D004250:DNA Topoisomerases, Type II