We have investigated the potential cell death mechanism promoted by Coriolus versicolor fungus‐derived protein‐bound polysaccharides (PBPs) in melanoma cells. Knowing that melanogenesis has the potential to affect the tumor behavior and melanoma therapy outcome, the cytotoxic effects of PBPs were evaluated in human SKMel‐188 melanoma cell line, whose phenotype, amelanotic versus pigmented, depends on the concentration of melanin precursors in the culture medium. Our results showed that inhibitory effect of PBPs (100 and 200 μg/ml) towards melanoma cells is inversely associated with the pigmentation level. This cytotoxicity induced in nonpigmented melanoma cells by PBPs was caspase‐independent; however, it was accompanied by an increased intracellular reactive oxygen species (ROS) generation. The ROS production was controlled by c‐Jun N‐terminal kinase (JNK) because SP600125, a JNK inhibitor, significantly reduced ROS generation and protected cells against PBPs‐induced death. We also found that PBPs‐induced lactate dehydrogenase release in amelanotic melanoma cells was abolished by co‐treatment with receptor‐interacting serine/threonine‐protein kinase 1 inhibitor, implying engagement of this kinase in PBPs‐induced death pathway. The results suggest that PBPs induce an alternative programmed cell death, regulated by receptor‐interacting protein‐1 and ROS and that this process is modified by melanin content in melanoma cells. These findings are remarkable when considering the use of commercially available Coriolus versicolor by patients who suffer from melanoma cancer.

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Based on these data we conclude that exposure duration (dose-response) plays a significant role in the immune response, specifically at the cellular level. While single 24 h-lasting exposure provoked changes that indicate an immune alarm stimulation, under the conditions which are typical for therapeutic use of ELF-MFs (repeated short daily exposure) the immune potentially harmful response has not been observed.

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