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

The antiproliferating effect of nine kinds of bis(ethyl)polyamine analogues [three kinds each of bis(ethyl)triamine, bis(ethyl)tetraamine and bis(ethyl)pentaamine] was compared using FM3A cells. The inhibitory effect was in the order BE4444 > BE3443 > BE4334 > or = BE444 > 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(ethyl)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(ethyl)polyamine analogues than that in the cytoplasm. Under conditions such that cytoplasmic protein synthesis was inhibited by 50% by bis(ethyl)polyamine analogues, mitochondrial protein synthesis was almost completely inhibited. Mitochondrial Ile-tRNA formation was inhibited by bis(ethyl)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(ethyl)polyamine analogues in cells is the inhibition of protein synthesis, especially of mitochondrial protein synthesis.