Innovative Research on Oxidizing Agents and Melanoma Cells

Overview

Melanoma, recognized as the most aggressive type of skin cancer, poses severe health risks due to its ability to metastasize, despite being less common than other skin cancers. The primary risk factor for melanoma is prolonged exposure to ultraviolet (UV) radiation, which leads to oxidative stress and inflammation in skin cells through photo-oxidative reactions.

Both ultraviolet and visible light can activate naturally occurring photosensitizers within tissues, converting light energy into reactive chemical species that damage essential biomolecules, including lipids in cellular membranes. However, these oxidative reactions can also be harnessed for therapeutic applications, such as in photodynamic therapy, which targets tumor cells and pathogens.

At the Center for Research on Redox Processes in Biomedicine (Redoxoma) at the University of São Paulo (USP), researchers have been investigating several oxidizing agents in conjunction with photodynamic therapy to develop new treatment strategies against melanoma.

Under the leadership of Professor Sayuri Miyamoto from the Institute of Chemistry (IQ-USP), the research team has identified endoperoxides generated from the oxidation of ergosterol and 7-dehydrocholesterol (7-DHC), both of which are sterol lipids, as effective in inducing apoptosis in melanoma cells. These findings were published in the journal Photochemistry and Photobiology.

Photodynamic therapy is increasingly recognized as a promising alternative to traditional treatment methods like surgery, notably due to its minimally invasive nature. The focus of the study was to enhance the effectiveness of photodynamic therapy by gaining a deeper understanding of the cellular membrane dynamics involved.

The research is part of a broader effort to elucidate the mechanisms of light-induced oxidative damage to cell membranes. The team carefully examined the photo-oxidation effects of ergosterol types I and II, 7-DHC, and cholesterol on these structures, identifying and characterizing the primary products that arise from these oxidation processes.

One of the critical insights from this research is that the permeability of cellular membranes is influenced by the specific type of oxidative damage. Cellular membranes consist of a lipid bilayer interspersed with proteins, primarily made up of phospholipids that are vulnerable to oxidative stress. Such oxidative events can compromise membrane integrity, heightening permeability and potentially leading to cell death.

There are two main classifications of photo-oxidation reactions: Type I produces reactive radical species, while Type II generates singlet molecular oxygen, a highly reactive form of oxygen.

The study revealed that the sterols ergosterol and 7-DHC offered superior membrane protection compared to cholesterol in Type I radical oxidation scenarios. Conversely, cholesterol exhibited greater efficacy in Type II singlet oxygen-mediated oxidations, suggesting its role as an antioxidant that organizes the membrane to inhibit oxidative access to unsaturated lipids.

During the process of membrane protection, these sterols undergo oxidation, yielding various products, including stable endoperoxides. The research indicated that endoperoxides derived from 7-DHC and ergosterol are particularly stable within these processes.

Prior research had shown that 7-DHC functions as an antioxidant, shielding cells from death caused by ferroptosis during Type I oxidation. However, this protective role comes at the cost of generating several oxidation products.

7-DHC is a precursor to cholesterol, both of which are prevalent sterols in mammals, while ergosterol is a yeast sterol with a structure similar to 7-DHC. A comparative study was undertaken to clarify the protective and harmful effects of these sterols, as existing literature on ergosterol was conflicting.

The research group also assessed the viability of A375 melanoma cells treated with 7-DHC, ergosterol, and their endoperoxides produced through photodynamic therapy, which induces both Type I and Type II oxidation. Notably, the endoperoxides from ergosterol and 7-DHC generated via singlet oxygen demonstrated heightened efficacy in eliminating melanoma cells compared to their parent molecules.

Future research will explore the influence of varying concentrations of endoperoxides and different radiation doses on their effectiveness, opening new avenues for investigation.