Repurposing Cationic Amphiphilic Drugs and Derivatives to Engage Lysosomal Cell Death in Cancer Treatment

Abstract

A major confounding issue in the successful treatment of cancer is the existence of tumor cell populations that resist therapeutic agents and regimens. While tremendous effort has gone into understanding the biochemical mechanisms underlying resistance to each traditional and targeted therapeutic, a broader approach to the problem may emerge from the recognition that existing anti-cancer agents elicit their cytotoxic effects almost exclusively through apoptosis. Considering the myriad mechanisms cancer cells employ to subvert apoptotic death, an attractive alternative approach would leverage programmed necrotic mechanisms to side-step therapeutic resistance to apoptosis-inducing agents. Lysosomal cell death (LCD) is a programmed necrotic cell death mechanism that is engaged upon the compromise of the limiting membrane of the lysosome, a process called lysosomal membrane permeabilization (LMP). The release of lysosomal components into the cytosol upon LMP triggers biochemical cascades that lead to plasma membrane rupture and necrotic cell death. Interestingly, the process of cellular transformation appears to render the limiting lysosomal membranes of tumor cells more fragile than non-transformed cells, offering a potential therapeutic window for drug development. Here we outline the concepts of LMP and LCD, and discuss strategies for the development of agents to engage these processes. Importantly, the potential exists for existing cationic amphiphilic drugs such as antidepressants, antibiotics, antiarrhythmics, and diuretics to be repurposed to engage LCD within therapy-resistant tumor cell populations.

Targeting plasma membrane and mitochondrial instability in breast cancer cells and breast epithelial to mesenchymal transition-model cells by adamantyl diaza-crown ether ZG613

“…Recently, it was shown that small molecules can trigger pyroptosis in breast tumour cells 78 . In addition, cationic amphiphilic drugs could be repurposed to induce lysosomal cell death in cancer 20 . Pyroptosis and lysosomal cell death overlap or culminate with non-regulated necrotic cell death and therefore couldn't be absolutely excluded.…”

“…Cancer membrane targeting is currently developing as an effective therapeutic strategy [10][11][12] . Antimicrobial drugs with ionophoric properties as salinomycin [13][14][15] , monensin 16,17 , azurin 4 and gramicidin 18,19 , as well as amphiphilic drugs with potential to locally perturb composition of lipid bilayers throughout the cell 11,20 , have been repurposed to target membranes in cancer. One of the most promising approaches involves drugs with heterogeneous anticancer activity that simultaneously hit multiple membrane-related targets within the cell.…”

Engaging the Lysosome and Lysosome-Dependent Cell Death in Cancer

“…Lysosome-dependent cell death (LDCD), characterized by lysosomal destabilization and requiring LMP, is now distinguished as a subclass of programmed cell death (153). Though lysosomal rupture has been observed as an ultimate consequence of canonical cell death processes (154), primary LMP activates a death program in LDCD and can be differentiated by novel assay systems (155,156). LMP does not generate defining morphological alterations (157) and is therefore classified at the molecular level by release of lysosomal luminal contents including proteolytic cathepsin enzymes to the cytosol, where cathepsins function in a variety of contexts as cell death executioners (158).…”

The Cationic Amphiphilic Drug Hexamethylene Amiloride Eradicates Bulk Breast Cancer Cells and Therapy-Resistant Subpopulations with Similar Efficiencies

“…We have reported that 5-(N,N-hexamethylene) amiloride (HMA), a derivative of the FDA-approved potassium-sparing diuretic amiloride and a member of the broader class of cationic amphiphilic drugs (CADs) [ 14 , 15 , 16 ], is cytotoxic toward cultured breast cancer cells independent of caspase activity [ 17 ]. HMA reduces the viability of breast cancer cells of differing molecular profiles with equal efficiency [ 17 ], which is significant as breast cancer subtypes (luminal or basal, estrogen/progesterone receptor-positive (ER/PR+), HER2−amplified (HER2+), or receptor-negative (ER/PR/HER2−)) are variably resistant to chemotherapeutics and targeted drugs [ 18 ].…”