Abstract LB-013: Propranolol alters the intracellular accumulation of doxorubicin and sensitizes angiosarcoma cells to chemotherapy

Abstract

Abstract Introduction: We and others have found that propranolol, a beta adrenergic receptor antagonist used to treat heart disease, improved the overall survival of patients with angiosarcoma. While combination treatment with chemotherapies has further improved patient responses, identification of chemotherapy drugs that synergize with propranolol may refine treatment protocols. We previously showed that doxorubicin accumulates within the lysosomes of angiosarcoma cell lines, leading to drug resistance. Because propranolol is also lysosomotropic, we sought to determine whether propranolol could reduce the lysosomal accumulation of doxorubicin, increasing tumor cell chemosensitivity. Methods: We used angiosarcoma cell lines to evaluate the effects of doxorubicin in combination with propranolol on cell viability, doxorubicin retention, and drug efflux. The effects of the adrenergic agonist, epinephrine, on doxorubicin retention and efflux were also evaluated. Transmission electron microscopy and cell viability assays were used to assess the long-term effects of propranolol treatment on the lysosome system and doxorubicin resistance, respectively. Results: While propranolol sensitized cells to doxorubicin by reducing the lysosomal accumulation of the drug, it increased the cytosolic concentration of doxorubicin by inhibiting drug efflux. Epinephrine had the opposite effect, reducing the cytosolic accumulation of doxorubicin and activating drug efflux. Although long-term exposure to propranolol expanded both the size and number of cellular lysosomes, cells remained sensitive to doxorubicin treatment in the presence of propranolol; however, removal of propranolol increased drug resistance above previous levels. Conclusions: Angiosarcoma cells sequestered doxorubicin in cellular lysosomes and enhanced drug efflux to circumvent cytotoxicity. Propranolol countered these processes by altering the intracellular distribution of doxorubicin, allowing higher concentrations of drug to reach its nuclear target. Removal of propranolol allowed doxorubicin to re-accumulate in lysosomes, increasing drug resistance. While our results support the use of lysosomotropic chemotherapy drugs in combination with propranolol to increase cytotoxic effects, they also suggest concurrent administration with chemotherapy to reduce the development of resistant cell populations. These results may aid in the rational design of other lysosomotropic chemotherapies in combination with propranolol to treat angiosarcomas. Citation Format: Jhuma Saha, Jong-Hyuk Kim, Clarissa Amaya, Caleb Witcher, Derek M. Korpela, Ali Khammanivong, Josephine Taylor, Brad A. Bryan, Erin B. Dickerson. Propranolol alters the intracellular accumulation of doxorubicin and sensitizes angiosarcoma cells to chemotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr LB-013.