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.

Manipulation of Transmembrane Transport by Synthetic K+ Ionophore Depsipeptides and Its Implications in Glucose‐Stimulated Insulin Secretion in β‐Cells

“…The different mechanism of transport activity triggers a divergent physiological response in the insulin secretion mechanism . Previous studies have related the effect of cereulide‐induced GSIS inhibition to impaired mitochondrial production of ATP, which is strongly dependent upon the membrane depolarization caused by specific carriers such as sCereulide …”

“…[33,34] The rest of the compounds have no acidic groups,a nd therefore the complexes JG100·K + , JG121·K + ,a nd JG115·K + are positivelyc harged speciesw ith electrogenic K + transporta ctivity across lipid bilayers. The different mechanism of transport activity [35,36] triggers a divergentp hysiological response in the insulins ecretionm echanism. [37,38] Previous studies have related the effect of cereulide-inducedG SIS inhibition to impaired mitochondrial production of ATP, whichi ss trongly dependent upon the membrane depolarization caused by specific carriers such as sCereulide.…”

Esterase‐Activatable Synthetic M+/Cl− Channel Induces Apoptosis and Disrupts Autophagy in Cancer Cells

“…that target autophagy have great applications in evading cancer‐related problems . Obatoclax is an analogue of prodigiosin, and its mechanism of action is linked to the alkalization of lysosomes, by which it disturbs the autophagy process . Synthetic ion transporters have apoptosis‐inducing activity in cancer cells; however, synthetic transporters that play a dual role in inducing apoptosis and disrupting autophagy are very rare …”

Multidrug Resistance in Hepatocellular Carcinoma

“…Extensive studies have been carried out during the last few decades to enhance the efficacy of chemotherapy by suppressing or evading the mechanisms of MDR. These approaches include the use of MDR modulators or chemosensitizers (79,80), improved drug delivery (81,82), RNAi therapy (83), and natural products (84).…”