The role of autophagy and lysosomal stability in the anti-cancer activity of the novel thiosemicarbazone, DP44MT

Abstract

Autophagy functions as a survival mechanism during cellular stress and contributes to resistance against anti-cancer agents. The selective anti-tumour and anti-metastatic chelator, di-2-pyridylketone 4,4-dimethyl-3-thiosemicarbazone (Dp44mT), which localises in lysosomes and induces tumour cell death through lysosomal membrane permeabilisation (LMP), affects autophagy by two mechanisms. First, concurrent with its anti-proliferative activity, Dp44mT induced autophagosome synthesis as a result of its redox activity. Second, this effect was supplemented by a reduction in autophagosome degradation due to LMP induced by Dp44mT. The resulting accumulation of autophagosomes leads to a build-up of cellular debris that are lethal to the tumour cells and, thus, potentiates the LMP-induced apoptotic cell death caused by Dp44mT. Lysosomal membrane stability was found to be important in the anti-tumour activity of Dp44mT, where increased lysosomal membrane rigidity markedly decreased its anti-tumour activity by inhibiting LMP and preventing its ability to overcome pro-survival autophagy. These results indicate a new mechanism by which Dp44mT induces tumour cell death and affirms the role of lysosome-dependent cell death as an alternative strategy for the treatment of apoptosis- and multi-drug-resistant cancers. This study highlights the importance of understanding the regulation of LMP to allow the optimal design of therapies targeting lysosomal-dependent cell death.