Ionophores: Potential Use as Anticancer Drugs and Chemosensitizers

Abstract

Ion homeostasis is extremely important for the survival of both normal as well as neoplastic cells. The altered ion homeostasis found in cancer cells prompted the investigation of several ionophores as potential anticancer agents. Few ionophores, such as Salinomycin, Nigericin and Obatoclax, have demonstrated potent anticancer activities against cancer stem-like cells that are considered highly resistant to chemotherapy and responsible for tumor relapse. The preclinical success of these compounds in in vitro and in vivo models have not been translated into clinical trials. At present, phase I/II clinical trials demonstrated limited benefit of Obatoclax alone or in combination with other anticancer drugs. However, future development in targeted drug delivery may be useful to improve the efficacy of these compounds. Alternatively, these compounds may be used as leading molecules for the development of less toxic derivatives.

Keywords: chemosensitization; combination chemotherapy; ionophores; nigericin; obatoclax; salinomycin; stem cells.

Figure 1

Ionophore mediated ion transport across the membrane. (A) Small ionophores “ion carriers” bind with ion, shield it from lipophilic interior of membrane, transport it across the membrane and release it other side of membrane. (B) Large ionophores form “ion channels” across the membrane and transport ions through these channels. These channels have a hydrophilic interior which assist in transport of ions while its lipophilic exterior shield ions from repulsive interior of membrane. (C) Polyether ionophores carry ions across membrane by electroneutral, electrogenic and biomimetic methods based on the microenvironmental conditions and structure of ionophore. Panel C was modified from [71].