Tributyltin(IV) ferulate, a novel synthetic ferulic acid derivative, induces autophagic cell death in colon cancer cells: From chemical synthesis to biochemical effects.

Ferulic acid (FA) is a natural phenolic phytochemical that has low toxicity and exhibits therapeutic effects against various diseases, behaving as an antioxidant. FA also displays modest antitumor properties that have been reported at relatively high concentrations. With the aim of improving the anti-tumor efficacy of FA, we synthesized the novel compound tributyltin(IV) ferulate (TBT-F). The coordination environment at the tin center was investigated spectroscopically. Following synthesis, chemical characterization and computational analysis, we evaluated TBT-F effects in colon cancer cells. The results showed that TBT-F, at nanomolar range concentrations, was capable of reducing the viability of HCT116, HT-29 and Caco-2 colon cancer cells. On the other hand, FA was completely inefficacious at the same treatment conditions. Cell viability reduction induced by TBT-F was associated with G2/M cell cycle arrest, increase in membrane permeabilization and appearance of typical morphological signs. TBT-F-induced cell death seemed not to involve apoptotic or necroptotic markers whereas autophagic vacuoles appearance and increase in LC3-II and p62 autophagic proteins were observed after treatment with the compound. The autophagy inhibitor bafylomicin A1 markedly prevented the effect of TBT-F on colon cancer cells, thus indicating that autophagy is triggered as a cell death process. Taken together, our results strongly suggest that the novel ferulic derivative TBT-F is a promising therapeutic agent for colon cancer since it is capable of triggering autophagic (type-II) cell death that may be important in case of resistance to classic apoptosis.