Bortezomib potentiates the antitumor effect of tributyltin(IV) ferulate in colon cancer cells exacerbating ER stress and promoting apoptosis

Abstract

Organotin(IV) complexes represent promising drugs in medicinal chemistry for their potential use in cancer therapy. We recently reported synthesis and characterization of a new organotin(IV) complex of ferulic acid (FA), tributyltin(IV) ferulate (TBT-F), showing its antitumor action in colon cancer cells. Here we provide evidence that the efficacy of this compound is strongly potentiated by the proteasome inhibitor bortezomib (BTZ). While low concentrations of tributyltin(IV) ferulate alone promoted autophagy without reducing cell viability, combination of the two compounds markedly affected colon cancer cell viability, cell morphology and exasperated endoplasmic reticulum (ER) stress, as revealed by a dramatic increase in Grp78 ER stress marker and consequent unfolded protein response (UPR) pathway components including PERK, eIF2α and downstream transcription factor CHOP. Our data also indicated that ER stress promoted by the TBT-F/BTZ combination leads to apoptosis, as shown by caspase 3 and caspase 7 activation, PARP cleavage, increase in p53 levels, chromatin condensation and prevention of the TBT-F effect by the caspase inhibitor zVAD-fmk.