Search

Recent evidence suggests that the targeting of membrane transporters specifically activated in cancer stem cells (CSCs) is an important strategy for cancer therapy. The objectives of the present study were to investigate the ion channel expression profiles in digestive CSCs. Cells strongly expressing CSC markers, such as ALDH1A1 and CD44, were separated from the human esophageal squamous cell carcinoma, gastric cancer, and pancreatic cancer cell lines using fluorescence-activated cell sorting, and CSCs were identified based on tumorsphere formation. Messenger RNA levels of CSC markers were higher in CSCs than in non-CSCs. These CSCs also exhibited resistance to anticancer agents. The microarray analysis revealed that the expression of transient receptor potential vanilloid 2 (TRPV2), voltage-gated calcium channels (VGCCs), and voltage-gated potassium channels (VGKCs) were upregulated in esophageal, gastric, and pancreatic CSCs, respectively, compared with non-CSCs. The TRPV2 inhibitor tranilast, VGCCs inhibitors amlodipine and verapamil, and VGKC inhibitor 4-aminopyridine exhibited greater cytotoxicity in CSCs compared with non-CSCs, and their inhibitory effects were also confirmed in a xenograft model in nude mice. Taking these results, phase I/II study to investigate clinical safety and efficacy of neoadjuvant combination chemotherapy of tranilast in advanced esophageal squamous cell carcinoma (TNAC study) is ongoing. These researches identified a role of ion channels in the persistence of CSCs and suggested that their inhibitors may have potential as a therapeutic agent for digestive cancers.

TACAN (Tmem120A), a mechanotransducing ion channel highly expressed in a subset of nociceptors, has recently been shown to contribute to detection of noxious mechanical stimulation. In the present study we evaluated its role in sensitization to mechanical stimuli associated with preclinical models of inflammatory and chemotherapy-induced neuropathic pain (CIPN). Intrathecal administration of an oligodeoxynucleotide antisense (AS-ODN) to TACAN mRNA attenuated TACAN protein expression in rat dorsal root ganglia (DRG). While TACAN AS-ODN produced only a modest increase in mechanical nociceptive threshold, it markedly reduced mechanical hyperalgesia produced by intradermal administration of prostaglandin E 2 , tumor necrosis factor alpha, and low molecular weight hyaluronan, and systemic administration of lipopolysaccharide, compatible with a prominent role of TACAN in mechanical hyperalgesia produced by inflammation. In contrast, TACAN AS-ODN had no effect on mechanical hyperalgesia associated with CIPN produced by oxaliplatin or paclitaxel. Our results provide evidence that TACAN plays a role in mechanical hyperalgesia induced by pronociceptive inflammatory mediators, but not CIPN, compatible with multiple mechanisms mediating mechanical nociception, and sensitization to mechanical stimuli in preclinical models of inflammatory versus CIPN. PERSPECTIVE: We evaluated the role of TACAN, a mechanotransducing ion channel in nociceptors, in preclinical models of inflammatory and CIPN. Attenuation of TACAN expression reduced hyperalgesia produced by inflammatory mediators but had not chemotherapeutic agents. Our findings support the presence of multiple mechanotransducers in nociceptors., (Copyright © 2020 United States Association for the Study of Pain, Inc. Published by Elsevier Inc. All rights reserved.)

We report herein the design, total synthesis, and functional analysis of a novel artificial ion channel molecule, designated as dansylated polytheonamide mimic (3). The channel 3 was designed based on an exceptionally potent cytotoxin, polytheonamide B (1). Our strategy for the development of synthetic ion channels, which could be easily derivatized for various functions, involved two key features. First, the structure of 1 was simplified by replacing many of nonproteinogenic amino acid residues which required multistep synthesis by commercially available amino acids while retaining those residues necessary for folding. It significantly reduced the number of synthetic steps and facilitated a practical chemical construction of 3. Second, the introduction of propargyl glycine at residue 44 enabled facile installation of dansyl group as a reporter of the membrane localization of 3. Application of a newly designed protective group strategy provided efficient construction of the 37 amino acid sequence of residues 12-48 through one automatic solid-phase peptide synthesis. After peptide cleavage from the resin, 3 was synthesized via dansyl group introduction and one fragment-coupling reaction with residues 1-11, followed by the global deprotection. The simplified mimic 3 exhibited potent cytotoxicity toward p388 mouse leukemia cells (IC(50) = 12 nM), effectively induced ion transport across the lipid bilayers of liposomes, and displayed H(+) and Na(+) ion channel activities. Because of its simplified yet functional scaffold structure with a potential for diversification, our rationally designed ion channel molecule should be useful as a novel platform for developing various cytotoxic channel molecules with additional desired functions.