Hypericin, the major component of St. John's Wort, absorbs light in the UV and visible ranges whereupon it becomes phototoxic through the production of
reactive oxygen species. Although photodynamic mechanisms (i.e. through endogenous
photosensitizers) play a role in UVA
phototherapy for the treatment of skin disorders such as
eczema and
psoriasis,
photodynamic therapy employing exogenous
photosensitizers are currently being used only for the treatment of certain forms of non-
melanoma skin cancers and
actinic keratoses. There are few reports however on its use in treating
melanomas. This in vitro study analyses the phototoxic effect of UVA (400-315 nm) - activated
hypericin in human pigmented and unpigmented
melanomas and immortalised keratinocytes and melanocytes. We show that neither
hypericin exposure nor UV irradiation alone reduces cell viability. We show that an exposure to 1 microM UVA-activated
hypericin does not bring about cell death, while 3 microM activated
hypericin induces a necrotic mode of cell death in pigmented
melanoma cells and melanocytes and an apoptotic mode of cell death in non-pigmented
melanoma cells and keratinocytes. We hypothesis that the necrotic mode of cell death in the pigmented cells is possibly related to the presence of
melanin-containing melanosomes in these cells and that the
hypericin-induced increase in
reactive oxygen species leads to an increase in permeability of melanosomes. This would result in toxic
melanin precursors (of an indolic and phenolic nature) leaking into the cytoplasm which in turn leads to cell death.
Hypericin localisation in the endoplasmic reticulum in these cells shown by fluorescent microscopy, further support a disruption in cellular processing and induction of cell death. In contrast, this study shows that cells that do not contain melanosomes (non-pigmented
melanoma cells and keratinocytes) die by apoptosis. Further, using a mitochondrial-specific
fluorescent dye, we show that intracellular accumulation of
hypericin induces a mitochondrial-associated
caspase-dependent apoptotic mode of cell death. This work suggests that UVA is effective in activating
hypericin and that this
phototoxicity may be considered as treatment option in some cases of
lentigo maligna or
lentigo maligna melanoma that are too large for surgical resection.