tranilast and Esophageal-Neoplasms

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.

Topics: Animals; Antineoplastic Agents; Cell Line, Tumor; Esophageal Neoplasms; Esophageal Squamous Cell Carcinoma; Humans; Ion Channels; Mice; Mice, Nude; Neoplastic Stem Cells

Transient receptor potential vanilloid 2 (TRPV2) was previously shown to play an important role in the maintenance of cancer stem cells, and its specific inhibitor, tranilast, also has potential as a targeted therapeutic agent for esophageal squamous cell carcinoma (ESCC). The present study is being conducted to confirm the safety and efficacy of the additional use of tranilast with conventional preoperative adjuvant chemotherapy for patients with advanced ESCC.. Between 56 and 59 patients aged between 20 and 74 years with clinically diagnosed Stage II or Stage III ESCC will be enrolled. Eligible patients will receive preoperative adjuvant chemotherapy, 2 cycles of combination therapy with cisplatin, 5-fluorouracil, and tranilast. Recruitment started in November 2019, with the final follow-up being planned for March 2029. One subject has been enrolled since October 21, 2020. The pathological therapeutic effect is the primary endpoint. The objective response rate, safety of preoperative adjuvant chemotherapy, recurrence-free survival (RFS), and overall survival (OS) are the secondary endpoints. RFS and OS will be calculated as the time from surgery to first recurrence and all-cause death, respectively.. This protocol has been approved by the Institutional Review Boards of Kyoto Prefectural University of Medicine and all participating hospitals in August 30, 2019 (Number: CRB5180001). Written informed consent will be obtained from all patients before their registration, which is in accordance with the Declaration of Helsinki. The results of the present study will be disseminated via publication in peer-reviewed journals.. Trial registration number jRCTs051190076.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Adjuvant; Cisplatin; Dose-Response Relationship, Drug; Esophageal Neoplasms; Esophageal Squamous Cell Carcinoma; Female; Fluorouracil; Humans; Male; Middle Aged; ortho-Aminobenzoates; Severity of Illness Index; Survival Analysis; Young Adult

The potential of membrane transporters activated in cancer stem cells (CSCs) as new therapeutic targets for cancer is attracting increasing interest. Therefore, the present study examined the expression profiles of ion transport-related molecules in the CSCs of esophageal adenocarcinoma (EAC).. Cells that highly expressed aldehyde dehydrogenase 1 family member A1 (ALDH1A1) were separated from OE33 cells, a human Barrett's EAC cell line, by fluorescence-activated cell sorting. CSCs were identified based on the formation of tumorspheres. Gene expression profiles in CSCs were examined by a microarray analysis.. Among OE33 cells, ALDH1A1 messenger RNA levels were higher in CSCs than in non-CSCs. Furthermore, CSCs exhibited resistance to cisplatin and had the capacity to redifferentiate. The results of the microarray analysis of CSCs showed the up-regulated expression of several genes related to ion channels/transporters, such as transient receptor potential vanilloid 2 (TRPV2) and solute carrier family 12 member 2 (SLC12A2). The cytotoxicities of the TRPV2 inhibitor tranilast and the SLC12A2 inhibitor furosemide were higher at lower concentrations in CSCs than in non-CSCs, and both markedly reduced the number of tumorspheres. The cell population among OE33 cells that highly expressed ALDH1A1 also was significantly decreased by these inhibitors.. Based on the present results, TRPV2 and SLC12A2 are involved in the maintenance of CSCs, and their specific inhibitors, tranilast and furosemide, respectively, have potential as targeted therapeutic agents for EAC.

Topics: Adenocarcinoma; Antineoplastic Agents; Cell Line, Tumor; Esophageal Neoplasms; Furosemide; Humans; Neoplastic Stem Cells; Solute Carrier Family 12, Member 2; TRPV Cation Channels

Recent evidence suggests that the targeting of membrane proteins specifically activated in cancer stem cells (CSCs) is an important strategy for cancer therapy. The objectives of the present study were to investigate the expression and activity of ion-transport-related molecules in the CSCs of esophageal squamous cell carcinoma.. Cells exhibiting strong aldehyde dehydrogenase 1 family member A1 (ALDH1A1) activity were isolated from TE8 cells by fluorescence-activated cell sorting, and CSCs were then generated with the sphere formation assay. The gene expression profiles of CSCs were examined by microarray analysis.. Among TE8 cells, ALDH1A1 messenger RNA and protein levels were higher in CSCs than in non-CSCs. The CSCs obtained were resistant to cisplatin and had the ability to redifferentiate. The results of the microarray analysis revealed that the expression of 50 genes encoding plasma membrane proteins was altered in CSCs, whereas that of several genes related to ion channels, including transient receptor potential vanilloid 2 (TRPV2), was upregulated. The TRPV2 inhibitor tranilast was more cytotoxic at a lower concentration in CSCs than in non-CSCs, and effectively decreased the number of tumorspheres. Furthermore, tranilast significantly decreased the cell population that strongly expressed ALDH1A1 among TE8 cells.. The results of the present study suggest that TRPV2 is involved in the maintenance of CSCs, and that its specific inhibitor, tranilast, has potential as a targeted therapeutic agent against esophageal squamous cell carcinoma.

Topics: Aldehyde Dehydrogenase; Aldehyde Dehydrogenase 1 Family; Antineoplastic Agents; Carcinoma, Squamous Cell; Cell Differentiation; Cell Line, Tumor; Cell Proliferation; Drug Screening Assays, Antitumor; Esophageal Neoplasms; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Gene Knockdown Techniques; Humans; Molecular Targeted Therapy; Neoplasm Proteins; Neoplastic Stem Cells; ortho-Aminobenzoates; Retinal Dehydrogenase; Reverse Transcriptase Polymerase Chain Reaction; RNA, Neoplasm; Spheroids, Cellular; TRPV Cation Channels

As circumferential or near-circumferential endoscopic submucosal dissection (ESD) for superficial esophageal neoplasms might evoke refractory strictures, multiple sessions of endoscopic balloon dilation (EBD) are required. We aimed to assess the effectiveness and safety of oral agent tranilast with EBD for improving the efficacy of stricture dilation after esophageal ESD.. In an open-label prospective study at a single institution, 31 asymptomatic consecutive patients with superficial esophageal squamous cell carcinomas were enrolled from April 2007 to October 2010. After ESD, we performed scheduled EBD (twice weekly for 4 wk) with or without administration of oral agent tranilast for 8 weeks. Thereafter, we added additional EBD on the basis of solid criteria-for example, patient's awareness of vomiting >1/wk and inability of passage of routine endoscope through the ESD site. We compared the rates of post-ESD strictures and the numbers of additional EBD sessions for 48 weeks after ESD and the Dysphagia score between tranilast (T)-group and none (N)-group, based on patients' subjective symptoms, at 16, 24, and 48 weeks after ESD.. The percentage of post-ESD strictures in T-group was significantly lower than that in N-group (P=0.04). The median numbers of additional EBD sessions and Dysphagia score at 16 and 24 weeks after ESD in T-group were significantly smaller than those in N-group (P=0.0138, 0.002, 0.005, respectively). No adverse events and no recurrence were observed.. We demonstrated for the first time that scheduled EBD combined with oral agent tranilast might be effective and safe for improving the efficacy of stricture dilation after esophageal ESD.

Topics: Administration, Oral; Aged; Carcinoma, Squamous Cell; Catheterization; Dissection; Endoscopy, Gastrointestinal; Esophageal Neoplasms; Esophageal Stenosis; Esophagus; Female; Humans; Male; Middle Aged; ortho-Aminobenzoates; Pilot Projects; Prospective Studies; Treatment Outcome