The Double-Edged Sword of Oxidative Stress in Skin Damage and Melanoma: From Physiopathology to Therapeutical Approaches

Abstract

The skin is constantly exposed to exogenous and endogenous sources of reactive oxygen species (ROS). An adequate balance between ROS levels and antioxidant defenses is necessary for the optimal cell and tissue functions, especially for the skin, since it must face additional ROS sources that do not affect other tissues, including UV radiation. Melanocytes are more exposed to oxidative stress than other cells, also due to the melanin production process, which itself contributes to generating ROS. There is an increasing amount of evidence that oxidative stress may play a role in many skin diseases, including melanoma, being the primary cause or being a cofactor that aggravates the primary condition. Indeed, oxidative stress is emerging as another major force involved in all the phases of melanoma development, not only in the arising of the malignancy but also in the progression toward the metastatic phenotype. Furthermore, oxidative stress seems to play a role also in chemoresistance and thus has become a target for therapy. In this review, we discuss the existing knowledge on oxidative stress in the skin, examining sources and defenses, giving particular consideration to melanocytes. Therefore, we focus on the significance of oxidative stress in melanoma, thus analyzing the possibility to exploit the induction of oxidative stress as a therapeutic strategy to improve the effectiveness of therapeutic management of melanoma.

Disruption of Redox Homeostasis by Alterations in Nitric Oxide Synthase Activity and Tetrahydrobiopterin along with Melanoma Progression

“…Under physiological conditions, there is a balance between the production and elimination of ROS [ 43 ]. Disruption of the redox homeostasis can promote several cancer types, including melanoma, which is in agreement with the literature [ 44 , 45 ]. ROS participate in the pathways related to proliferation, survival, invasion and metastasis [ 46 , 47 , 48 , 49 ].…”

“…On the other hand, ROS at high levels can have negative consequences, such as DNA damage and cell death, conferring an antitumor profile to these molecules. Many studies have reported ROS as a therapeutic strategy in the fight against cancer [ 44 , 50 , 51 , 52 , 53 ]. The treatment of molecules such disulfiram, brusatol and Buthionine sulfoximine render melanoma cells more sensitive to chemo- and radiotherapy through the modulation of redox homeostasis [ 54 , 55 ].…”

HO-1 Limits the Efficacy of Vemurafenib/PLX4032 in BRAFV600E Mutated Melanoma Cells Adapted to Physiological Normoxia or Hypoxia

“…Furthermore, the reduction of antioxidant defenses has been proposed as anticancer, sensitizer therapy in the treatment of melanoma, as recently reviewed [ 25 ]. However, also to be considered is the role played by NRF2-dependent antioxidant responses in limiting the side effect of chemotherapeutic drugs on normal tissues, as demonstrated for other tumors [ 26 ].…”

Antioxidant Therapy in Cancer: Rationale and Progress

“…Besides, the ACOX1-induction of ROS production was demonstrated to be involved in oxidative DNA damage and the progression of hepatocellular carcinoma (HCC) [ 50 ]. Ultraviolet (UV) radiation is also an important factor that contributes to ROS generation and subsequent carcinogenesis [ 51 ]. Cells exhibit an increased production of ROS when exposed to UV radiation.…”