Abstract
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.
Highlights
The role of reactive oxygen species (ROS) and Reactive nitrogen species (RNS) is a long-standing debate in cancer
Intracellular ROS are mainly generated in the mitochondria through activation of redox reactions catalyzed by specialized enzymes of electron transporter chain (ETC) where small amounts of oxygen are univalent and reduced into free radicals [3, 4], to produce cellular energy [5] (Figure 1)
This phenomenon is similar to hormesis, a process in which exposure to a low dose of a chemical agent is damaging at higher doses, induces an adaptive beneficial effect on the cell following an initial disruption in homeostasis [98]
Summary
Reactive species or free radicals include reactive oxygen and nitrogen species collectively and are termed reactive oxygen nitrogen species (RONS). NOX catalyzes the production of a superoxide free radical by transferring one electron to oxygen from nicotinamide adenine dinucleotide phospate oxidase (NADPH). During this process, O2 is transported from the extracellular space to the cell interior and H+ is exported [10]. NO inhibits mitochondrial respiration by binding the binuclear center of cytochrome c oxidoreductase (Complex III), leading to the inhibition of the enzyme activity with consequent inhibition of electron transfer and increase in O2− production [73, 74]
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