Long chain diamines inhibit growth of C6 glioma cells according to their hydrophobicity. An in vitro and molecular modeling study.
Long chain diamines inhibit growth of C6 glioma cells according to their hydrophobicity. An in vitro and molecular modeling study.
复制标题
长链二胺根据其疏水性抑制 C6 神经胶质瘤细胞的生长。
DOI：
10.1007/s002109900188
复制
发表时间：
2000
期刊：
影响因子：
--
通讯作者：
Hermann,A
中科院分区：
文献类型：
--
作者：
Hochreiter,R;Weiger,TM;Colombatto,S;Langer,T;Thomas,TJ;Cabella,C;Heidegger,W;Grillo,MA;Hermann,A
与天然多胺相比，测试了一系列具有一般结构NH 2（CH 2）xNH 2（x=2-12）的二胺对培养的大鼠C6神经胶质瘤细胞的细胞增殖的潜在作用。长链二胺在培养48 h后减少细胞数量，顺序为1，12-十二烷二氨基（1，12-DD）> 1，10-癸二氨基> 1，9-壬二氨基。多胺（腐胺，亚精胺和精胺），以及二胺的CH 2-链长ofx=8被发现是无效的。精胺类似物1，12-DD是以不可逆的剂量依赖性方式减少细胞数量的最有效分子（在无血清条件下，EC 50 =3 µM）。在进一步的实验中，我们研究了1，12-DD的作用机制。该化合物对细胞周期只有轻微的影响，不影响游离内部钙浓度。在生理条件下，1，12-DD与三链DNA相互作用，但不与双链DNA相互作用。鸟氨酸脱羧酶的活性以及内部多胺的浓度被发现减少1，12-DD。然而，多胺应用不能逆转1，12-DD的作用，表明多胺独立或非竞争性作用机制。1，12-DD通过诱导细胞凋亡和坏死减少细胞数量。在分子模拟研究中发现，使二胺成为有效的细胞生长药物需要至少4 μ m的最小疏水性片段。这种大小的疏水间隙符合分子建模预期的最低要求，以提供与蛋白质部分（如CH 3-基团）的疏水相互作用的空间。我们的研究结果表明，1，12-DD作为一种有效的药物，减少C6胶质瘤细胞的数量，并表明其空间和疏水特性是其作用机制的原因。
A series of diamines with the general structure NH2(CH2)xNH2,x=2–12, was tested for their potential effects on cell proliferation of cultured rat C6 glioma cells in comparison to natural polyamines. Long chain diamines reduced cell number after 48 h in culture with a sequence of 1,12-diaminododecane (1,12-DD) >1,10-diaminodecane >1,9-diaminononane. Polyamines (putrescine, spermidine and spermine) as well as diamines up to a CH2-chain length ofx=8 were found to be ineffective. The spermine analogue 1,12-DD was the most effective molecule in reducing cell number in an irreversible, dose-dependent manner (EC50=3 µM under serum-free conditions).In further experiments we investigated the mechanisms of action of 1,12-DD. The compound had only a minor effect on cell cycle and did not affect free internal calcium concentration. Under physiological conditions 1,12-DD interacts with triplex DNA but not with duplex DNA. Ornithine decarboxylase activity as well as the concentration of internal polyamines were found to be reduced by 1,12-DD. Polyamine application, however, was not able to reverse the effect of 1,12-DD, indicating a polyamine-independent or non-competitive mechanism of action. 1,12-DD reduced cell number by induction of apoptosis as well as necrosis.In molecular modeling studies it was found that a minimal hydrophobic intersegment of at least 4 Å was required to make a diamine an effective drug in respect to cellular growth. A hydrophobic gap of this size fits the minimum requirement expected from molecular modeling to provide space for hydrophobic interactions with parts of proteins like a CH3-group. Our results show that 1,12-DD acts as a potent drug, reducing the number of C6 glioma cells, and suggest that its spatial and hydrophobic properties are responsible for its mechanism of action.