digoxin and Esophageal-Neoplasms

A prospective, controlled, randomized study of 80 patients undergoing esophageal operations was undertaken, in which one group of patients was given digoxin and the other was not. The incidence of cardiac dysrhythmia was compared in each group. Twenty-six patients underwent operation for benign disease. Equal numbers were digitalized or not and no dysrhythmias occurred. Fifty-four patients underwent operation for malignant disease. Of 26 in the group digitalized, 12 suffered dysrhythmia (46%). Of 28 not digitalized, 9 suffered dysrhythmia (32%). Overall, 39% of patients with malignant disease suffered a dysrhythmia compared with none with benign disease (p < 0.002 by chi 2).

Topics: Aged; Arrhythmias, Cardiac; Digoxin; Electrocardiography; Esophageal Diseases; Esophageal Neoplasms; Female; Humans; Intraoperative Complications; Male; Postoperative Complications; Premedication; Thoracotomy

Drug repurposing with a better understanding of the underlying mechanism has provided new avenues to find treatment for malignancies. Esophageal adenocarcinoma (EAC) is a rapidly increasing cancer with a dismal 5-year survival rate of <15%. Lack of efficient treatment options contributes to the high mortality rate of EAC. To find new therapy against EAC we performed unbiased drug screening of an FDA-approved drug library and identified that the cardiac glycosides including Ouabain, Digoxin and Digitoxin efficiently inhibit the proliferation of EAC cell lines (OE33 and OE19) both in vitro and in vivo. RNA-Sequencing analysis combined with RNAi screening revealed that Ouabain suppresses the proliferation of EAC cells through downregulation of p38 MAP-Kinase 6 (MAP2K6, also known as MKK6). Consistently, shRNA-mediated knockdown of MKK6 reduced the proliferation of EAC cells and tumor growth. Further analysis demonstrated that MKK6 inhibition leads to the reduced levels of the transcription factor SOX9. In line with this finding, deletion of SOX9 with CRISPR/Cas9 resulted in decreased proliferation of EACs in 3D organoid culture and reduced tumor growth. Together these findings establish a druggable axis that can be harnessed for therapeutic gain against EAC.

Topics: Adenocarcinoma; Animals; Cell Line, Tumor; Cell Proliferation; Digitoxin; Digoxin; Esophageal Neoplasms; Gene Expression Regulation, Neoplastic; Gene Knockdown Techniques; HEK293 Cells; Humans; MAP Kinase Kinase 6; Mice, Inbred NOD; Ouabain; Protein Kinase Inhibitors; Signal Transduction; SOX9 Transcription Factor; Xenograft Model Antitumor Assays