Reactive oxygen species: an Achilles’ heel of melanoma?

Abstract

The successful treatment of melanoma has been hampered by the unique biology of this cancer. Fortunately, research to further our understanding of how melanoma cells differ from normal tissues has led to the discovery of potential new avenues of attack. One promising strategy relates to targeting the excess free radicals produced by melanomas. Melanocyte transformation into cancer is associated with significant structural alterations in the melanosome. In addition to pigment production, melanosomes also protect the cell by scavenging free radicals generated by sunlight and cellular metabolism. In melanoma, the disrupted and disorganized melanosome structure reverses this process. Melanosomes found in melanoma produce free radicals, such as hydrogen peroxide, furthering DNA damage. Melanosome generation of reactive oxygen species (ROS), in tandem with those generated by cancer metabolism, activate cellular signal transduction pathways that prevent cell death. ROS activation of proto-oncogene pathways in melanoma contributes to their resistance to chemotherapy. Fortunately, it may be possible to target these free radicals, just as Paris was able to successfully target Achilles' heel. The use of agents that block ROS scavenging, such as ATN-224 and disulfiram, have been explored clinically. A recent randomized Phase II trial with elesclomol, an agent that generates ROS, in combination with paclitaxel led to improved patient survival, suggesting that this may be a viable approach to advance the treatment of melanoma.

Electrochemical Nanoprobes for Single-Cell Analysis

“…Melanosomes found in melanomas, instead of protecting the cell from oxidative stress, produce free radicals. 48 Figure 6b shows that upon penetration of the melanoma cells the anodic current quickly increases followed by equilibration to a level above the one measured in the cell media (Figure 6c). A cell can withstand multiple penetrations and the value of anodic current measured inside the cell is consistent even after repeated penetrations/retractions.…”

Genetic, Epigenetic and Molecular Changes in Melanoma: A New Paradigm for Biological Classification

“…Most of apoptosis regulators are known to be potentially mutated or functionally altered by ROS: BRAF (RAS, MEK, and ERK within the MAPK pathway), PTEN, Rb and AKT (Wittgen & van Kempen, 2007;Fruehauf & Trapp, 2008). Melanoma cells generate large intracellular amounts of ROS (Sander et al, 2003) and excrete them into the extra cellular space.…”

“…Melanosomes of malignant melanocytes produce excessive amounts of ROS (Gidanian et al, 2008;Josse et al, 2010) and in addition produce, instead of the regular eumelanin, pheomelanin, which is associated with more oxidative stress. In view of these unique melanoma properties, elevated production of ROS seems to be a melanoma-specific defect (Fruehauf and Trapp, 2008). Other factors may contribute to elevate ROS levels around the primary tumor: the skin is a hypoxic tissue, leading to ROS production (Wittgen & van Kempen, 2007) and exogenous attacks (e.g.…”

“…After acquiring ROS resistance to block apoptosis, MM cells can also use high ROS levels to further stimulate their metastatic potential (Nishikawa and Hashida, 2006) through an impressive variety of pathways; from induction of DNA changes and activation of cell proliferation, to destruction of surrounding tissue, induction of adhesion molecules, activation of metastatic processes and escaping immune surveillance. In summary, ROS act as pro-metastatic agents through a wide range of pathways (Josse et al, 2010), which in melanoma cells accumulates early in tumor progression due to the alteration of melanin produced by characteristically abnormal melanosomes (Fruehauf & Trapp, 2008;Meyskens, 2001;Gidanian et al, 2008). HIF-1 activity is highly regulated by hydroxyl radicals and other reactive oxygen species (ROS) (Kietzmann & Gorlach, 2005;Wittgen & van Kempen, 2007, Kuphal et al, 2010 HIF-1 molecular complex is the major transcriptional regulator of the cellular and systemic response to a hypoxic environment, and is involved in cancerogenesis, regulating the expression of factors fundamental for angiogenesis (VEGF) and tumour invasion (glycolytic enzymes) (Forsythe et al, 1996;Wenger, 2002;Wiesener & Maxwell, 2003;Erler et al, 2006).…”

Targeting Adenosine Receptors for the Treatment of Melanoma

“…The effectiveness of the agent elesclomol against melanoma has been attributed to its ability to promote intracellular ROS generation. When used in association with paclitaxel in a Phase 2 clinical trial, elesclomol increased the progression-free survival of patients to 3.7 months versus 1.8 months for the second group of patients treated with paclitaxel alone (Fruehauf and Trapp, 2008).…”