Facilitated Anion Transport Induces Hyperpolarization of the Cell Membrane That Triggers Differentiation and Cell Death in Cancer Stem Cells

Abstract

Facilitated anion transport potentially represents a powerful tool to modulate various cellular functions. However, research into the biological effects of small molecule anionophores is still at an early stage. Here we have used two potent anionophore molecules inspired in the structure of marine metabolites tambjamines to gain insight into the effect induced by these compounds at the cellular level. We show how active anionophores, capable of facilitating the transmembrane transport of chloride and bicarbonate in model phospholipid liposomes, induce acidification of the cytosol and hyperpolarization of plasma cell membranes. We demonstrate how this combined effect can be used against cancer stem cells (CSCs). Hyperpolarization of cell membrane induces cell differentiation and loss of stemness of CSCs leading to effective elimination of this cancer cell subpopulation.

Synthetic tambjamine analogues induce mitochondrial swelling and lysosomal dysfunction leading to autophagy blockade and necrotic cell death in lung cancer

“…This tumour subpopulation possesses tumour-initiating and self-renewal capacities, and contributes to acquired chemotherapy resistance in cancer [25], thus these results are very promising for lung cancer treatment and the prevention of tumour recurrences. In this view, other anionophores such as the recently reported 2-pyrrolylindole tambjamine analogues or the cation selective ionophore salinomycin, also induce CSCspecific toxicity [20,26], indicating that the application of these kind of compounds might be a very promising therapy.…”

“…Diverse synthetic tambjamine analogues have recently shown potent anticancer activity in a panel of cancer cell lines, including human melanoma, lung carcinoma, colorectal adenocarcinoma and mammary adenocarcinoma cells [19,20]. In this study, we extend the results obtained with those compounds bearing 4-alkoxy-2,2´-bipyrrole moieties [19] to several lung cancer cell lines and CSC, as well as characterize in deep for the first time the cellular and molecular events that are participating in the cell death induced by these potent compounds.…”

“…Moreover, tumorigenic properties of tumour spheres were assessed through subcutaneous transplantation in NOD.CB17-Prkdc scid /NcrCrl mice (Jackson Laboratories) and tumor growth curves were monitored. For detailed procedures and results see supplementary information in reference [20]. CSC were cultured as a cell suspension in RPMI media supplemented with 50 μg/mL EGF, 20 μg/mL bFGF, 1X ITS, 0.4% BSA and 2% B27 (Gibco, Paisley, UK).…”

“…We have recently synthesized novel synthetic tambjamine analogues bearing aromatic substituents in the enamine moiety, as well as explored different substitution patterns on characteristic alkoxy group of the central pyrrole ring. These compounds proved to be very efficient anion exchangers in liposome models, promoting both chloride and bicarbonate transport [18][19][20].…”

“…Moreover, a different type of tambjamine analogues, in which the characteristic 2,2`-bipyrrole unit is replaced by a 2-pyrrolylindole, have recently shown the ability to hyperpolarize the cellular membrane as well as differentiate and induce cell death in lung cancer stem cells [20], which are promising properties for their potential use in cancer therapy.…”