A Glutathione Activatable Ion Channel Induces Apoptosis in Cancer Cells by Depleting Intracellular Glutathione Levels

Abstract

Cancer cells use elevated glutathione (GSH) levels as an inner line of defense to evade apoptosis and develop drug resistance. In this study, we describe a novel 2,4‐nitrobenzenesulfonyl (DNS) protected 2‐hydroxyisophthalamide system that exploits GSH for its activation into free 2‐hydroxyisophthalamide forming supramolecular M+/Cl− channels. Better permeation of the DNS protected compound into MCF‐7 cells compared to the free 2‐hydroxyisophthalamide and GSH‐activatable ion transport resulted in higher cytotoxicity, which was associated with increased oxidative stress that further reduced the intracellular GSH levels and altered mitochondrial membrane permeability leading to the induction of the intrinsic apoptosis pathway. The GSH‐activatable transport‐mediated cell death was further validated in rat insulinoma cells (INS‐1E); wherein the intracellular GSH levels showed a direct correlation to the resulting cytotoxicity. Lastly, the active compound was found to restrict the growth and proliferation of 3D spheroids of MCF‐7 cells with efficiency similar to that of the anticancer drug doxorubicin.

Fluorescent probes for the detection of disease-associated biomarkers

“…Therefore, GSH depletion could be an effective approach for cancer therapy. Talukdar and co-workers [183] found that the T-DNS probe This was accompanied with an increase in blue fluorescence emission at 410 nm (Fig. 30).…”

Stimuli-Responsive Cycloaurated ‘OFF-ON’ Switchable Anion Transporters

“…[14][15] Talukdar has recently reported GSH switchable synthetic ion channels capable of achieving transmembrane M + /Clsymport in presence of elevated levels of GSH. [16] These systems induced caspase-dependant apoptosis in MCF-7 cells which was correlated with the resulting cytotoxicity in rat insulinoma cells (INS-1E), which have high levels of intracellular GSH. [16] Inspired by the high affinity of thiols, such as GSH, for gold as exemplified by Che's seminal work on switch-on fluorescent probes [17] and the reported anion transport activity of 1,3bis(benzimidazol-2-yl)benzenes [18] and similar motifs [19] , we adapted Che's systems and designed and synthesized new switchable cycloaurated putative anion transporters based on the structurally related 1,3-bis(benzimidazol-2-yl)pyrimidine (BisBzImPy).…”

Hypertoxic self-assembled peptide with dual functions of glutathione depletion and biosynthesis inhibition for selective tumor ferroptosis and pyroptosis

“…The level of GSH in many kinds of solid tumor tissues was much higher than that in normal tissues and can be over 1000-fold higher than in blood [1,2]. The elevated GSH level helps to prevent apoptosis of cancer cells by detoxifying reactive oxygen species (ROS) [3] and induce chemotherapeutic drugs resistance through GSH spontaneous reactions or xenobiotics reactions catalyzed by GSH S-transferase (GST) [4,5]. GSH regulation strategies mainly include the depletion of existing intracellular GSH and the inhibition of GSH biosynthesis.…”