Abstract 1418: Proanthocyanidins enhance chemotherapy-induced esophageal adenocarcinoma cell death
Authors: Zhang Yun , Weh Katherine , Howard Connor , Lagisetty Kiran , McEwen Dyke , Lin Jules , Reddy Rishindra M. , Chang Andrew , Beer David G. , Howell Amy , Kresty Laura A. 
Published: July 2021

Abstract
Esophageal adenocarcinoma (EAC) is a devastating cancer characterized by rising incidence and poor prognosis. The five-year survival rate is 20% due to late stage diagnosis and ineffective treatment. It is estimated that only 15% of EAC patients have a complete histopathological response to standard chemotherapy. Thus, new strategies are urgently needed to improve therapeutic efficacy and patient survival. Our recent analysis of prechemotherapy endoscopic biopsies of EAC patients revealed differential response to neoadjuvant therapy. Differential response was reflected by two-year mortality of 9.1% in therapy responsive patients (Complete responders, no residual tumor), 22.2% in strong responders (improved TNM), 25.0% in intermediate responders (stable TNM), 42.9% in poor responders (worse TNM) and 77.8% in non-responders (worse TNM and metastasis). Transcriptomic analysis revealed differential response to therapy is linked to immune defense, inflammation (IL-4, IFNs), cell adhesion, signal transduction and angiogenesis regulation. Similar pathways were mitigated by cranberry proanthocyanidins (C-PAC) in a rat surgical model for EAC. Herein, we investigated C-PAC pretreatment alone or in combination with Paclitaxel and Carboplatin (chemo drug) on EAC cell viability (Calcein-AM), gene expression (RNA-seq) and select protein levels (Western blot). C-PAC pre-treatment and co-treatment enhance chemotherapy-induced EAC cell death, with the greatest synergistic effects in chemo-resistant OE33 cells. C-PAC pretreatment followed by chemo drugs decreased cell viability by an additional 50% and 17% compared to chemo drugs alone in OE33 cells and OE19 cells, respectively. Greater reductions were noted with pretreatment of C-PAC, followed by co-treatment with chemo drugs (64.9% in OE33 and 49.4% in OE19 cells). C-PAC enhanced chemo drug-induced EAC cell death via increased DNA damage, apoptosis and ECM degradation as evidenced by induction of phosphorylated H2AX and cleaved caspase-3, as well as inhibition of BCLXL and MMP9. C-PAC also mitigated elevated levels of P53, a gene with a well-documented role in EAC progression and therapeutic resistance. Transcriptome analysis of cells treated with C-PAC and chemo drugs is underway and will be compared to signaling networks differentially expressed in patients stratified by treatment responsiveness. Results suggest that C-PAC pretreatment may offer a non-toxic intervention strategy for enhancing chemotherapeutic efficacy.
Citation Format: Yun Zhang, Katherine Weh, Connor Howard, Kiran Lagisetty, Dyke McEwen, Jules Lin, Rishindra M. Reddy, Andrew Chang, David G. Beer, Amy Howell, Laura A. Kresty. Proanthocyanidins enhance chemotherapy-induced esophageal adenocarcinoma cell death [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1418.