Abstract 4772: β3-adrenoceptor minimize doxorubicin effect in Ewing sarcoma by UCP2 activation

Abstract

Abstract The phenomenon of “Oxygen Paradox” arises when reactive oxygen species (ROS) overcome the cellular anti-oxidant defense system through either an escalation in ROS levels or a reduced capability of the cells to increase an antioxidant response. The deregulated redox signaling that stimulate an uncontrolled ROS increase, could induce both tumor initiation and progression, and cell death after chemotherapy treatment. In recent decades, the therapeutic choice for Ewing Sarcomas (ES) consisting of a multi-drug chemotherapy regimen combined with radiotherapy and surgery, has significantly improved the survival up to 70% in localized diseases. ES patients, often show resistance to multi chemotherapeutic agents since ES cells exhibit a high sensitivity to rapid changes in intracellular redox environment. In this context, an antioxidant-inhibiting strategy was evaluated in vitro to test chemotherapeutic efficacy used in the standard treatment of ES such as the anthracycline doxorubicin (DOX) that increases ROS generation and oxidative stress (OS) in mitochondria. DOX is a strong exogenous ROS generator but lacks target specificity thereby it also affects normal cells resulting in several side-effects. Literature shows that DOX ability to reduce tumor progression is due to a DOX-induced ROS overproduction that occurs in mitochondria, known to be the main site of constant ROS production, and this effect is mediated by the mitochondrial NADPH oxidase (NADPHox) activity. To investigate why DOX causes resistance in ES patients, experiments in vitro were conducted with A673 ES cell line. A673 cells express a high level of the β3-adrenergic receptor (β3-AR) and are high susceptible to OS. Recently, β3-AR has become highly attractive in cancer biology for its ability to reduce tumor growth, metastasis, and its antioxidant properties as main regulator of the cellular response to OS. β3-AR working as ROS sensor control the redox state of the cells, driving them to life or death through mitochondria bioenergetics function. In our experimental setting DOX induced β3-AR expression which influenced the uncoupling protein 2 (UCP2) expression. β3-AR/UCP2 axis strongly decreased the mitochondrial activity by reducing ATP synthesis and mitochondrial ROS content and this effect was reverted by β3-AR antagonist, SR59230A. In summary, the DOX chemotherapy promotes β3-AR expression that decreases ROS levels through β3-AR/UCP2 axis. Decreased ROS levels allow ES cells to survive chemotherapy. Citation Format: Claudia Masi, Amada Pasha, Francesco Carrozzo, Martina Rosati, Alessandro Pini, Maura Calvani, Claudio Favre. β3-adrenoceptor minimize doxorubicin effect in Ewing sarcoma by UCP2 activation. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4772.