Abstract 2624: Methadone hydrochloride blocks epinephrine-induced proliferation and enhances apoptotic effects of nab-paclitaxel in esophageal adenocarcinoma

Abstract

Introduction: Esophageal adenocarcinoma (EAC) is an aggressive form of cancer with 5-year survival rates under 20%. The low survival rate is due largely to advanced stage upon diagnosis. Improved treatment options remain essential in combating the disease and bolstering patient outcomes. Nanoparticle albumin-bound paclitaxel (nab-paclitaxel) is a chemotherapeutic receiving attention for its potential in EAC treatment. The taxane has exhibited greater specificity for targeting cancer cells while decreasing cytotoxic effects to adjacent healthy populations. Unfortunately, chemoresistance remains an issue surrounding adequate treatment regimes. Epinephrine and its receptor, β2 adrenergic, have been shown to dysregulate various oncogenic pathways and reduce chemotherapeutics efficacy. Typically associated with pain management and addiction treatment, Methadone hydrochloride has been investigated for its potential to block the oncogenic effects of epinephrine and strengthen the impact of chemotherapeutics. In this study, we evaluated the enhancement of apoptosis by combination of nab-paclitaxel and methadone, and we demonstrated the ability of methadone to block epinephrine-induced chemoresistance. Method: We utilized PCR to elucidate EAC cell lines with the greatest expression of Mu opioid and β2 adrenergic receptors. Next, we investigated adequate dosages of methadone and epinephrine for the EAC cell lines by WST-1 assay. WST-1 assays were also utilized to determine cell growth under co-administration of nab-paclitaxel and methadone as well as methadone and epinephrine. Propidium iodine cell viability flow cytometry assay was used to detect cell death. Annexin V staining was utilized to further distinguish between apoptotic and necroptotic cells. Result: OE19 and OE33 cell lines showed increased expression of Mu and β2 adrenergic receptors, ensuring the cells were capable of binding to methadone or epinephrine. WST-1 assays established 100 nM of epinephrine and 200 nM of methadone as optimal dosages for both cell lines. Our previous studies demonstrated that about 5.85 uM of nab-paclitaxel (5ug/mL) induces apoptosis in OE19 and OE33. Propidium iodide staining showed the enhancement of cell death under combination treatment of nab-paclitaxel and methadone. Annexin V staining confirmed that the effect was via apoptosis. Conclusion: The current study demonstrated methadone’s ability to block epinephrine-induced cell proliferation and showed an enhanced effect on apoptosis when combining nab-paclitaxel with methadone in EAC treatment. Citation Format: Nicholas Cwidak, Sazzad Hassan, Chloe Johnson, Saisantosh Ponna, Niranjan Awasthi, Urs von Holzen. Methadone hydrochloride blocks epinephrine-induced proliferation and enhances apoptotic effects of nab-paclitaxel in esophageal adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2624.