Triple-negative breast cancer (TNBC) responds poorly to standard treatment protocols, recurring more frequently, more rapidly and with a higher mortality rate than other types of breast cancer. Photodynamic therapy (PDT) is an alternative treatment that uses a photosensitizing compound (PS) taken up by cells to produce reactive oxygen species (ROS) when exposed to specific wavelengths of light, leading to oxidative damage and cell death. We have synthesized and tested a series of novel porphyrin-derived PS for killing TNBC cells in vitro and have seen a wide range of potency. Most show little toxicity in the dark although at higher concentrations some show significant cell killing. We haven’t observed a significant correlation between the structures and properties of the side chains on the porphyrins and their toxicity in the light or in the dark. We also examined the mechanism of cell death induced by one of the most potent of these derivatives, PipOH, and by Foscan, a chlorin-based PS which has been in clinical trials. We began by testing cells on coverslips. Treatment of TNBC cells in vitro with PipOH alone caused a 0.6-fold increase in TUNEL-positive cells (indicating fragmentation of nuclear DNA, a step in cell death pathways), while treatment with PipOH + light gave a 3-fold increase. Treatment with PipOH and light significantly increased staining above background for both EndoG and activated caspase-3. Most of the cells that were treated with PipOH, with or without light, that were TUNEL-positive were also positive for activated caspase-3. This suggests that PipOH may make cells more likely to enter caspase-dependent apoptosis. In these experiments, it was apparent that a number of cells detached from the coverslips during the staining process, so we repeated some of these experiments using Foscan as the PS and analyzing the cells by flow cytometry. A significant fraction of the cells treated with Foscan and light showed activated caspase 3 and showed DNA fragmentation, suggesting that they are dying by apoptosis.

Light-induced cell death in response to a novel porphyrin derivative

2019 Spring National Meeting

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