Correlation between the inhibition of cell growth by bis(ethyl)polyamine analogues and the decrease in the function of mitochondria

Abstract

The antiproliferating effect of nine kinds of bis(ethy1)polyamine analogues [three kinds each of bis(ethyl)triamine, bis(ethy1)tetraamine and bis(ethy1)pentaaminel was compared using FM3 A cells.The inhibitory effect was in the order BE4444 > BE3443 > BE4334ZBE444 > BE343 > BE333 > BE44 > BE34 > BE33. Our results indicate that not only polyamine deficiency but also the accumulation of polyamine analogues is involved in the inhibition of cell growth. Accumulation of bis(ethy1)polyamine analogues caused the inhibition of protein synthesis and the decrease in the ATP content. The protein synthetic system in mitochondria was more strongly inhibited by bis(ethy1)polyamine analogues than that in the cytoplasm. Under conditions such that cytoplasmic protein synthesis was inhibited by 50% by bis(ethy1)polyamine analogues, mitochondrial protein synthesis was almost completely inhibited. Mitochondria1 Ile-tRNA formation was inhibited by bis(ethy1)polyamine analogues at the concentrations that cytoplasmic Ile-tRNA formation was stimulated. This may be one of the reasons for the selective inhibition of mitochondrial protein synthesis. This inhibition was followed by the decrease in ATP content, swelling of mitochondria and depletion of mitochondrial DNA. These results suggest that the early event of metabolic change caused by bis(ethy1)polyamine analogues in cells is the inhibition of protein synthesis, especially of mitochondrial protein synthesis.Since the polyamines putrescine, spermidine and spermine are essential for the maintenance of eukaryotic cell proliferation [ 11, inhibitors of polyamine biosynthesis to deplete cellular polyamines have been developed as antiproliferative reagents [2, 31. Bis(ethy1)polyamine analogues have also been developed as antiproliferative reagents [4, 51. These reagents can not only negatively regulate the synthesis of omithine decarboxylase (OmDC) and S-adenosylmethionine decarboxylase (AdoMetDC) [6], but can also induce spermidinekpermine A"-acetyltransferase (SSAT) activity [7, 81. Thus, the analogues can deplete intracellular polyamines almost completely, and they are thought to inhibit cell growth through this process. We found that A", W'-bis(ethyl)spermine (BE343) can substitute for the functions of spermine in various aspects and accumulate in cells at a concentration fivefold that of spermine in control cells [9, lo], and suggested that not only polyamine deficiency but also the accumulation of BE343 may be involved in the inhibition of cell growth [lo]. Recently, it has been reported that the inhibition of cell growth by BE343 correlated with the intracellular acCorrespondence to K. Igarashi, Faculty of Pharmaceutical Sciences, Chiba University, 1-33 Yayoi-cho, Inage-ku, Chiba, Japan 263Fax: +81 43 290 2900. Abbreviations. OmDC, ornithine decarboxylase; AdoMetDC, S-adenosylmethionine decarboxylase; SSAT, spermidinehpermine W-acetyltransferase.Enzymes. Ornithine decarboxylase (EC 4.1.1.17) ; S-adenosylmethionine decarboxylase (EC 4.1.1.50) ; spermidinehpermine W-acetyltransferase...

Antizyme protects against abnormal accumulation and toxicity of polyamines in ornithine decarboxylase-overproducing cells.

“…Although there was an initial time lag, the decrease in polyamine content eventually became nearly parallel with the recovery of cell growth. The ATP content was seen to decrease upon the addition of spermine or spermidine (data not shown), as has been observed when cell growth is inhibited by polyamines or polyamine derivatives such as N1,N12-bis(ethyl)spermine (18,29,30). The ATP content then also recovered as cell culture was extended.…”

“…Sensitivity to spermine was slightly different in the EXOD-1 and AZ-2 cells in the absence of dexamethasone. Partial cell death of EXOD-1 was observed with 30 pM spermine (Fig. 1), and that of AZ-2 cells was observed with 10 ,uM spermine (Fig.…”

“…Accordingly, sensitivity to polyamine toxicity of EXOD-1 cells increased 70-to 100-fold over the parent FM3A cells. Moreover, when the concentrations of spermine and spermidine in the medium were increased to 30 AuM and 90 AuM, respectively, a transient decrease in cell number was seen to occur on day 1. Table 1 shows polyamine contents in EXOD-1 cells.…”

Putrescine analogue cytotoxicity against Trypanosoma cruzi

“…Furthermore, polyamine depletion may shift drug-induced programmed cell death to necrosis (Monti et al 2004), and the absence of nuclear fragmentation or chromatin condensation in our experiments reinforces the inference of a necrotic process rather than an apoptotic process. Nevertheless, bis(ethyl)-polyamine analogues produced mitochondrial swelling associated with a decreased ATP content in mammalian cells (Fukuchi et al 1992;He et al 1994), and the organelle was severely injured (Fukuchi et al 1992;Snyder et al 1994). DAB-induced mitochondrial dysfunction was confirmed by MTT reduction as that in Leishmania (Valentim et al, unpublished).…”

Antitumor activity of the polyamine analog N1,N11-diethylnorspermine against human prostate carcinoma cells

“…In these studies, the cellular responses to these compounds were 1) downregulation of polyamine biosynthesis, 2) high increase of SSAT activity, and 3) decrease of the natural polyamine pools. The mechanisms of action of these compounds have been investigated [25][26][27][28], but the exact mode of action remains unclear. The huge induction of SSAT, which is directly or indirectly related to the sensitivity of the cells for the drugs, can have potential chemotherapeutic benefits.…”