Spotlight on ROS and β3-Adrenoreceptors Fighting in Cancer Cells.

The role of ROS and RNS is a long-standing debate in cancer. Increasing the concentration of ROS reaching the toxic threshold can be an effective strategy for the reduction of tumor cell viability. On the other hand, cancer cells, by maintaining intracellular ROS concentration at an intermediate level called "mild oxidative stress," promote the activation of signaling that favors tumor progression by increasing cell viability and dangerous tumor phenotype. Many chemotherapeutic treatments induce cell death by rising intracellular ROS concentration. The persistent drug stimulation leads tumor cells to simulate a process called hormesis by which cancer cells exhibit a biphasic response to exposure to drugs used. After a first strong response to a low dose of chemotherapeutic agent, cancer cells start to decrease the response even if high doses of drugs were used. In this framework, β3-adrenoreceptors (β3-ARs) fit with an emerging antioxidant role in cancer. β3-ARs are involved in tumor proliferation, angiogenesis, metastasis, and immune tolerance. Its inhibition, by the selective β3-ARs antagonist (SR59230A), leads cancer cells to increase ROS concentration thus inducing cell death and to decrease NO levels thus inhibiting angiogenesis. In this review, we report an overview on reactive oxygen biology in cancer cells focusing on β3-ARs as new players in the antioxidant pathway.