Exploring glutamate-gated chloride channels in cancer cells: A narrative review on a hypothetical mechanism underpinning the anticancer effects of antiparasitic drugs

Chloride channels play a fundamental role in cellular homeostasis, influencing ion balance, pH regulation, and apoptotic signaling. While glutamate-gated chloride channels (GluCl) are traditionally restricted to invertebrates, recent evidence suggests that functionally analogous chloride conductances may exist in cancer cells, contributing to tumor survival and metabolic adaptation. Notably, chloride intracellular channels (CLICs), particularly CLIC6, have emerged as strong candidates for chloride-mediated oncogenic signaling. CLIC6 is overexpressed in multiple malignancies, including breast, ovarian, lung, gastric, and pancreatic cancers, and is known to interact with dopamine D₂-like receptors. Patchclamp studies have confirmed its chloride-selective conductance, localization to the plasma membrane, and regulation by pH and redox potential. The unexpected anticancer effects of antiparasitic drugs such as ivermectin, which targets GluCl channels in parasites, suggest a possible chloride-mediated mechanism of cytotoxicity in tumors. Ivermectininduced chloride influx may disrupt ionic equilibrium, hyperpolarize the plasma membrane, and trigger mitochondrial dysfunction, leading to oxidative stress, cytochrome c release, and caspase activation. This ionic disruption may also interfere with key oncogenic pathways, including PI3K/AKT, Wnt/β-catenin, and NF-κB, impairing tumor proliferation and immune evasion. Given the structural and functional parallels between GluCl channels and CLIC6, ivermectin’s efficacy may be partially mediated through chloride channel dysregulation. This review synthesizes molecular, electrophysiological, and pharmacological evidence supporting the existence of GluCl-like chloride conductance in cancer cells and its therapeutic implications. Further research is needed to characterize chloride ion dynamics in tumors, validate CLIC6 as a potential GluCl channel analog, and explore chloride channel-targeting strategies for cancer treatment, opening new frontiers in oncology.

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