sibmedСибирский научный медицинский журналСибирский научный медицинский журнал2410-25122410-2520ИЦиГ СО РАН10.18699/SSMJ20250401sibmed-2328Research ArticleОБЗОРЫREVIEWSИзучение глутамат-регулируемых хлоридных каналов в раковых клетках: нарративный обзор гипотетического механизма, лежащего в основе противоопухолевого эффекта антипаразитарных препаратовExploring glutamate-gated chloride channels in cancer cells: A narrative review on a hypothetical mechanism underpinning the anticancer effects of antiparasitic drugshttps://orcid.org/0000-0001-5480-1688АкльМ. М.AklM. M.

35516, г. Эль-Мансура, ул. Эль-Гумхурия, 25

35516, Mansoura, Elgomhouria st., 25

maherakl555@gmail.comhttps://orcid.org/0000-0003-3477-236XАхмедА.AhmedA.

13524, г. Эр-Рияд, ш. короля Фахда, 4499

13524, Riyadh, King Fahd Rd., 4499

drmedahmed@gmail.comУниверситет Эль-МансураЕгипетMansoura UniversityEgyptДепартамент общественного здравоохранения Первого медицинского объединения Эр-РиядаСаудовская АравияThe Public Health Department, Riyadh First Health ClusterSaudi Arabia202505092025454618Copyright © Акль М.М., Ахмед А., 20252025Акль М.М., Ахмед А.Akl M.M., Ahmed A.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://sibmed.elpub.ru/jour/article/view/2328

Хлоридные каналы играют фундаментальную роль в поддержании клеточного гомеостаза, влияя на ионный баланс, регуляцию pH и апоптотические сигнальные пути. Хотя глутамат-регулируемые хлоридные каналы (GluCl) традиционно ограничены беспозвоночными, последние данные свидетельствуют о том, что функционально-аналогичные проводимости хлоридов могут присутствовать в раковых клетках, способствуя выживанию опухоли и метаболической адаптации. Особенно выделяются внутриклеточные хлоридные каналы (CLIC), в частности CLIC6, как потенциальные участники онкогенной хлорид-зависимой сигнализации. CLIC6 сверхэкспрессируется при различных злокачественных новообразованиях, включая рак молочной железы, яичников, легких, желудка и поджелудочной железы, и взаимодействует с дофаминовыми рецепторами D2-подтипа. Электрофизиологические исследования методом патч-кламп подтвердили хлорид-селективную проводимость CLIC6, его локализацию в плазматической мембране и регуляцию pH и редокс-потенциалом. Неожиданные противораковые эффекты антипаразитарных препаратов, таких как ивермектин, который воздействует на каналы GluCl у паразитов, предполагают возможный механизм цитотоксичности в опухолях, опосредованный нарушением хлоридного обмена. Индуцированный ивермектином приток хлоридов может нарушить ионное равновесие, гиперполяризовать плазматическую мембрану и вызвать митохондриальную дисфункцию, что ведет к окислительному стрессу, выходу цитохрома с и активации каспаз. Это нарушение ионного обмена также может вмешиваться в ключевые онкогенные пути, включая PI3K/AKT, Wnt/β-катенин и NF-κB, нарушая пролиферацию опухоли и избегание иммунного ответа. Учитывая структурные и функциональные параллели между каналами GluCl и CLIC6, эффективность ивермектина может быть частично обусловлена дисрегуляцией хлоридных каналов. Данный обзор объединяет молекулярные, электрофизиологические и фармакологические данные, подтверждающие существование проводимости хлоридов, аналогичной опосредуемой каналами GluCl, в раковых клетках и ее терапевтические перспективы. Необходимы дальнейшие исследования для характеристики динамики хлоридных ионов в опухолях, подтверждения роли CLIC6 как потенциального аналога каналов GluCl и разработки стратегий, направленных на хлоридные каналы для лечения рака, что открывает новые горизонты в онкологии.

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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The authors declare that there are no conflicts of interest present.