Synthetic polyamines activating autophagy: Effects on cancer cell death

The ability of symmetrically substituted long chain polymethylene tetramines, methoctramine (1) and its analogues 2-4 to kill cancer cells was studied. We found that an elevated cytotoxicity was correlated with a 12 methylene chain length separating the inner amine functions (6-12-6 carbon backbone), together with the introduction of diphenylethyl moietieson the terminal nitrogen atoms (compound 4) of a tetramine backbone. Compound 4 triggered dissipation of mitochondrial transmembrane potential and increased intracellular peroxide levels, leading to a caspase-independent HeLa cell death associated with a rapid activation of autophagy. The antioxidant N-acetylcysteine inhibited cell death and activation of autophagy, indicating a link between oxidative stress and autophagy. Autophagy was rapidly triggered even by tetramines 2 and 3, indicating that is related to their polyamine structure. Autophagy did not protect HeLa cells against cytotoxicity elicited by compound 4. The present studyshows that, by modifications of the methoctramine structure, it is possible to design polyamine derivatives highly cytotoxic against tumor cells and that the appropriate design of molecules bearing polyamine-like structures leads to powerful inducers of autophagy.