多胺亚精胺是真核细胞增殖所必需的。施用多胺生物合成抑制剂α-二氟甲基鸟氨酸(DFMO)诱导细胞停滞,发生在两个阶段;早期阶段,可以通过亚精胺逆转,精胺,和他们的一些类似物,以及晚期阶段,其特征是细胞亚精胺池几乎完全耗尽。晚期细胞的生长可以被亚精胺和很少的其类似物逆转,包括(S)-1-甲基亚精胺。以前曾报道过(Witherspoon等人。CancerDiscovery3(9);1072-81,2013)thatDFMO治疗导致细胞胸苷池耗尽,并且外源性胸苷补充部分防止DFMO诱导的细胞停滞,而不影响HT-29,SW480和LoVo结直肠癌细胞中的细胞内多胺库。在这里,我们显示胸苷并不能防止DU145,LNCaP中DFMO诱导的细胞停滞,MCF7,CaCo2,BT4C,SV40MES13,HepG2,HEK293,NIH3T3,ARPE19或HT-29细胞系,而给予亚精胺的功能活性模拟物,(S)-1-甲基亚精胺,did.因此,胸苷的作用似乎仅对某些细胞系具有特异性。我们得出的结论是,多胺水平的降低以及叶酸依赖性代谢物库的扭曲也可能介导DFMO的抗增殖作用。然而,多胺是必要的,足以克服DFMO诱导的细胞停滞,而胸苷一般不是。
Polyamine spermidine is essential for the proliferation of eukaryotic cells. Administration of polyamine biosynthesis inhibitor α-difluoromethylornithine (DFMO) induces cytostasis that occurs in two phases; the early phase which can be reversed by spermidine, spermine, and some of their analogs, and the late phase which is characterized by practically complete depletion of cellular spermidine pool. The growth of cells at the late phase can be reversed by spermidine and by very few of its analogs, including (S)-1-methylspermidine. It was reported previously (Witherspoon et al. Cancer Discovery 3(9); 1072-81, 2013) that DFMO treatment leads to depletion of cellular thymidine pools, and that exogenous thymidine supplementation partially prevents DFMO-induced cytostasis without affecting intracellular polyamine pools in HT-29, SW480, and LoVo colorectal cancer cells. Here we show that thymidine did not prevent DFMO-induced cytostasis in DU145, LNCaP, MCF7, CaCo2, BT4C, SV40MES13, HepG2, HEK293, NIH3T3, ARPE19 or HT-29 cell lines, whereas administration of functionally active mimetic of spermidine, (S)-1-methylspermidine, did. Thus, the effect of thymidine seems to be specific only for certain cell lines. We conclude that decreased polyamine levels and possibly also distorted pools of folate-dependent metabolites mediate the anti-proliferative actions of DFMO. However, polyamines are necessary and sufficient to overcome DFMO-induced cytostasis, while thymidine is generally not.