Miller M C, Woods C M, Murphy M E, Elkins A, Spielvogel B F, Hall I H
Division of Medicinal Chemistry and Natural Products, School of Pharmacy, University of North Carolina, Chapel Hill 27599-7360, USA.
Biomed Pharmacother. 1998;52(4):169-79. doi: 10.1016/s0753-3322(98)80207-2.
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.
结果表明，胺基羧基硼烷在细胞毒性以及对特定类型癌细胞DNA合成的抑制方面，与肿瘤坏死因子α（TNFα）具有协同作用，这取决于细胞表面是否存在TNFα高亲和力受体。最初，TNFα和胺基羧基硼烷均会减少钙的内流，但随后会导致细胞内钙显著增加。这种内流与胺基羧基硼烷激活肿瘤细胞中的降钙素受体无关。这两种药物和TNFα均不会直接抑制DNA拓扑异构酶II的活性，但两者都会导致该酶被蛋白激酶C（PKC）磷酸化的程度降低。这两种药物产生了协同抑制作用。这一现象与DNA蛋白连接断裂、DNA片段化及细胞死亡增加相关。这些蛋白连接断裂与依托泊苷的作用相加，但后者的作用机制与拓扑异构酶II的磷酸化不同。没有证据表明这些癌细胞中的DNA片段化是由钙诱导的核酸内切酶引起的。低分子量胺基羧基硼烷在导致DNA断裂和片段化以引发细胞凋亡方面，似乎与TNFα发挥相同的作用。
