Pro-oxidant Actions of Carotenoids in Triggering Apoptosis of Cancer Cells: A Review of Emerging Evidence

Abstract

Carotenoids are well known for their potent antioxidant function in the cellular system. However, in cancer cells with an innately high level of intracellular reactive oxygen species (ROS), carotenoids may act as potent pro-oxidant molecules and trigger ROS-mediated apoptosis. In recent years, the pro-oxidant function of several common dietary carotenoids, including astaxanthin, β-carotene, fucoxanthin, and lycopene, has been investigated for their effective killing effects on various cancer cell lines. Besides, when carotenoids are delivered with ROS-inducing cytotoxic drugs (e.g., anthracyclines), they can minimize the adverse effects of these drugs on normal cells by acting as antioxidants without interfering with their cytotoxic effects on cancer cells as pro-oxidants. These dynamic actions of carotenoids can optimize oxidative stress in normal cells while enhancing oxidative stress in cancer cells. This review discusses possible mechanisms of carotenoid-triggered ROS production in cancer cells, the activation of pro-apoptotic signaling by ROS, and apoptotic cell death. Moreover, synergistic actions of carotenoids with ROS-inducing anti-cancer drugs are discussed, and research gaps are suggested.

Isoproterenol-Induced Permeability Transition Pore-Related Dysfunction of Heart Mitochondria Is Attenuated by Astaxanthin

“…Indeed, AST itself stimulated hydrogen peroxide and superoxide anion production and increased the concentration of oxidative-stress-responsive SOD2 (see Figure 4 and Figure 5 ). A similar effect of AST was shown for cancer [ 49 ]. Partial prevention of elimination of the components of the damaged respiratory chain complexes in ISO-injected rats ( Figure 2 ) may be related to the stimulation of mitochondrial biogenesis by AST [ 50 ].…”

Low Dose Astaxanthin Treatments Trigger the Hormesis of Human Astroglioma Cells by Up-Regulating the Cyclin-Dependent Kinase and Down-Regulated the Tumor Suppressor Protein P53

“…We further investigated if ROS levels are affected by AXT treatment, as the anti-cancer effects of AXT were correlated with an increase of intracellular ROS levels in previous studies [ 9 , 18 ]. We treated cells with AXT under the same conditions that we used to investigate SOD expression and performed the DCFH-DA assay to monitor intracellular ROS levels ( Figure 4 ).…”

“…AXT has been shown to have high antioxidant activity compared to other carotenoids [ 33 ]. In cancer cell lines, it showed an opposite effect, acting as a pro-oxidant that induced apoptosis [ 8 , 18 ], which is a known phenomenon for carotenoids, probably due to the different ROS status between healthy and cancer cells [ 9 ]. In this study, we assayed the response of astroglioma cell lines to AXT treatment at concentrations ranging from 0 to 40 µM.…”

“…However, in healthy cells, carotenoids usually exhibit a protective effect against oxidative stress, and therefore, induce p53 downregulation, as seen in the corneal epithelial cells [ 46 ]. In a previous review, we suggested that this discrepancy might be dependent on the cellular environment; particularly, on its redox status [ 9 ]. Here, we found an instance of a biphasic response that was dose-dependent, suggesting that diverse factors could be involved in defining the role of carotenoids in cells.…”

“…The discrepancy between the response of healthy and cancer cells to AXT administration is probably due to the fact that over-proliferative cancer cells maintain high reactive oxygen species (ROS) levels when compared to healthy cells. In an environment with high ROS levels such as cancer cells, high levels of carotenoids act as pro-oxidants rather than anti-oxidants, leading to an imbalance in ROS expression, and thereby triggering apoptosis [ 9 ].…”