Abstract
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.
Highlights
The polyamines spermidine (Spd) and spermine (Spm) and their diamine precursor putrescine (Put) (Figure 1, Figure S1) are cationic regulators of many important cellular functions such as proliferation and differentiation [1]
Activation of polyamine biosynthesis is associated with carcinogenesis, whereas polyamine depletion leads to cytostasis or cytotoxicity. α-Difluoromethylornithine (DFMO, Eflornithine®, Figure S1) is an irreversible inhibitor of ornithine decarboxylase (ODC), the key polyamine biosynthetic enzyme
We and others have shown that the treatment with DFMO leads to the cessation of cell growth in two distinct phases; the early phase, which can be reversed by the natural polyamines and many of their analogs, and the late phase, which can be reversed only by Spd and some of its functionally active mimetics such as (S)-1-methylspermidine (MeSpd, Figure S1) [2]
Summary
The polyamines spermidine (Spd) and spermine (Spm) and their diamine precursor putrescine (Put) (Figure 1, Figure S1) are cationic regulators of many important cellular functions such as proliferation and differentiation [1]. It was shown that while the drug efficacy was the greatest in subjects with a low Spd/Spm ratio in rectal mucosa at the beginning of the trial, no relationship was found between DFMO/sulindac-induced changes in polyamine levels and drug efficacy [7]. 70% and reductions in the such incidences of adenomas and adenomas, respectively [6].ofItother was that while the efficacy thespecific greatest midine is a general feature cell shown lines, or whether it isdrug restricted towas some in lines, subjects with low Spd/Spm rectal beginning of the trial,ofno cell such as acolon carcinomaratio cell in lines. It was shown that exogenous thymidine supplementation could partially prevent DFMO-induced cytostasis without affecting the intracellular polyamine pools in HT-29, SW480, and LoVo colorectal cancer cells. We found no evidence of the ability of thymidine to rescue DFMO-induced growth inhibition either in CaCo2 or HT-29 colon carcinoma cells or in any other of the eight tested cell lines
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