St John's Wort (Hypericum perforatum L.) photomedicine: hypericin-photodynamic therapy induces metastatic melanoma cell death.

Abstract

Hypericin, an extract from St John's Wort (Hypericum perforatum L.), is a promising photosensitizer in the context of clinical photodynamic therapy due to its excellent photosensitizing properties and tumoritropic characteristics. Hypericin-PDT induced cytotoxicity elicits tumor cell death by various mechanisms including apoptosis, necrosis and autophagy-related cell death. However, limited reports on the efficacy of this photomedicine for the treatment of melanoma have been published. Melanoma is a highly aggressive tumor due to its metastasizing potential and resistance to conventional cancer therapies. The aim of this study was to investigate the response mechanisms of melanoma cells to hypericin-PDT in an in vitro tissue culture model. Hypericin was taken up by all melanoma cells and partially co-localized to the endoplasmic reticulum, mitochondria, lysosomes and melanosomes, but not the nucleus. Light activation of hypericin induced a rapid, extensive modification of the tubular mitochondrial network into a beaded appearance, loss of structural details of the endoplasmic reticulum and concomitant loss of hypericin co-localization. Surprisingly the opposite was found for lysosomal-related organelles, suggesting that the melanoma cells may be using these intracellular organelles for hypericin-PDT resistance. In line with this speculation we found an increase in cellular granularity, suggesting an increase in pigmentation levels in response to hypericin-PDT. Pigmentation in melanoma is related to a melanocyte-specific organelle, the melanosome, which has recently been implicated in drug trapping, chemotherapy and hypericin-PDT resistance. However, hypericin-PDT was effective in killing both unpigmented (A375 and 501mel) and pigmented (UCT Mel-1) melanoma cells by specific mechanisms involving the externalization of phosphatidylserines, cell shrinkage and loss of cell membrane integrity. In addition, this treatment resulted in extrinsic (A375) and intrinsic (UCT Mel-1) caspase-dependent apoptotic modes of cell death, as well as a caspase-independent apoptotic mode that did not involve apoptosis-inducing factor (501 mel). Further research is needed to shed more light on these mechanisms.

• Authors: Britta Kleemann, Benjamin Loos, Thomas J Scriba, Dirk Lang, Lester M Davids
• Journal: PloS one (PLoS One) Vol. 9 Issue 7 Pg. e103762 ( 2014) ISSN: 1932-6203 [Electronic] United States
• PMID: 25076130 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Anthracenes
• Apoptosis Regulatory Proteins
• Photosensitizing Agents
• Perylene
• hypericin

Topics

• Anthracenes
• Apoptosis (drug effects)
• Apoptosis Regulatory Proteins (genetics, metabolism)
• Cell Line, Tumor
• Cell Size (drug effects)
• Drug Screening Assays, Antitumor
• Endoplasmic Reticulum (drug effects, pathology)
• Female
• Humans
• Hypericum (chemistry)
• Melanoma (drug therapy, pathology)
• Middle Aged
• Perylene (analogs & derivatives, metabolism, pharmacology)
• Photochemotherapy
• Photosensitizing Agents (metabolism, pharmacology)
• Pigmentation (drug effects)
• Skin Neoplasms (drug therapy, pathology)
• Transcriptional Activation