Cranberry Proanthocyanidins Mitigate Reflux-Induced Transporter Dysregulation in an Esophageal Adenocarcinoma Model

• Main Authors: Yun Zhang (Author), Katherine M. Weh (Author), Bridget A. Tripp (Author), Jennifer L. Clarke (Author), Connor L. Howard (Author), Shruthi Sunilkumar (Author), Amy B. Howell (Author), Laura A. Kresty (Author)
• Format: Book
• Published: MDPI AG, 2023-12-01T00:00:00Z.
• Subjects: article
• Online Access: Connect to this object online.
• Notes: 10.3390/ph16121697; 1424-8247
• Keywords: cancer prevention; cranberry proanthocyanidins; plant polyphenols; reflux-induced esophageal adenocarcinoma; ATP-binding cassette transporters; solute carrier transporters; Medicine; R; Pharmacy and materia medica; RS1-441
• Source: Pharmaceuticals, Vol 16, Iss 12, p 1697 (2023)

We recently reported that cranberry proanthocyanidins (C-PACs) inhibit esophageal adenocarcinoma (EAC) by 83% through reversing reflux-induced bacterial, inflammatory and immune-implicated proteins and genes as well as reducing esophageal bile acids, which drive EAC progression. This study investigated whether C-PACs' mitigation of bile reflux-induced transporter dysregulation mechanistically contributes to EAC prevention. RNA was isolated from water-, C-PAC- and reflux-exposed rat esophagi with and without C-PAC treatment. Differential gene expression was determined by means of RNA sequencing and RT-PCR, followed by protein assessments. The literature, coupled with the publicly available Gene Expression Omnibus dataset GSE26886, was used to assess transporter expression levels in normal and EAC patient biopsies for translational relevance. Significant changes in ATP-binding cassette (ABC) transporters implicated in therapeutic resistance in humans (i.e., <i>Abcb1</i>, <i>Abcb4</i>, <i>Abcc1</i>, <i>Abcc3</i>, <i>Abcc4</i>, <i>Abcc6</i> and <i>Abcc10</i>) and the transport of drugs, xenobiotics, lipids, and bile were altered in the reflux model with C-PACs' mitigating changes. Additionally, C-PACs restored reflux-induced changes in solute carrier (SLC), aquaporin, proton and cation transporters (i.e., <i>Slc2a1</i>, <i>Slc7a11</i>, <i>Slc9a1</i>, <i>Slco2a1</i> and <i>Atp6v0c</i>). This research supports the suggestion that transporters merit investigation not only for their roles in metabolism and therapeutic resistance, but as targets for cancer prevention and targeting preventive agents in combination with chemotherapeutics.