Metalloporphyrin Pd(T4) Exhibits Oncolytic Activity and Cumulative Effects with 5-ALA Photodynamic Treatment against C918 Cells

Abstract

Photodynamic therapy is a non-invasive method where light activates a photosensitizer bound to cancer cells, generating reactive oxygen species and resulting in cell death. This study assessed the oncolytic potential of photodynamic therapy, comparing European Medicines Agency and United States Food and Drug Administration-approved 5-aminolevulinic acid (5-ALA) to a metalloporphyrin, Pd(T4), against a highly invasive uveal melanoma cell line (C918) in two- and three-dimensional models in vitro. Epithelial monolayer studies displayed strong oncolytic effects (>70%) when utilizing Pd(T4) at a fraction of the concentration, and reduced pre-illumination time compared to 5-ALA post-405 nm irradiance. When analyzed at sub-optimal concentrations, application of Pd(T4) and 5-ALA with 405 nm displayed cumulative effects. Lethality from Pd(T4)-photodynamic therapy was maintained within a three-dimensional model, including the more resilient vasculogenic mimicry-forming cells, though at lower rates. At high concentrations, modality of cell death exhibited necrosis partially dependent on reactive oxygen species. However, sub-optimal concentrations of photosensitizer exhibited an apoptotic protein expression profile characterized by increased Bax/Bcl-2 ratio and endoplasmic stress-related proteins, along with downregulation of apoptotic inhibitors CIAP-1 and -2. Together, our results indicate Pd(T4) as a strong photosensitizer alone and in combination with 5-ALA against C918 cells.

A Comparison of Porphyrin Photosensitizers in Photodynamic Inactivation of RNA and DNA Bacteriophages

“…At a low PdT4:virus ratio (~2 µM PdT4: ~10 10 PFU/mL), a noticeable shift was observed in the PdT4 Soret peak after 5 min incubation ( Figure 1 ). This red shift is caused by porphyrin binding, most likely to bacteriophage capsid proteins, though the shift is evident with nucleic acid and lipids as well [ 18 ]. No further shift was observed between 5- and 15-min incubation periods ( Figure S5 ).…”

“…Singlet oxygen acts over short distances (~150 nm) in aqueous solutions and therefore reacts with targets close to the site of formation [ 11 ]. Due to porphyrin interactions with nucleic acid, proteins, and lipids [ 18 ], viral inactivation can be mediated through disrupting multiple viral targets—i.e., envelope lipids, capsid and core proteins [ 19 ], and nucleic acids [ 20 , 21 ].…”

New Perspectives for Eye-Sparing Treatment Strategies in Primary Uveal Melanoma

“…Photodynamic therapy (PDT) action is based on the selective destruction of cancer cells or pathological vessels. The PDT mechanism uses light to activate photosensitizers, generating reactive oxygen species that kill cells [ 62 , 63 , 64 ]. Due to its specific mechanism of action, photodynamic therapy minimizes damage to normal cells [ 62 ].…”

New Perspectives for Eye-Sparing Treatment Strategies in Primary Uveal Melanoma

“…Photodynamic therapy (PDT) action is based on the selective destruction of cancer cells or pathological vessels. The PDT mechanism uses light to activate photosensitizers, generating reactive oxygen species that kill cells [53][54][55]. This reaction activates immune factors such as histamine, thromboxane, and TNF-α cytokines.…”

“…Another group of compounds commonly used in PDT is porphyrins and their derivatives. Studies carried out by Leviskas B et al have shown that Metalloporphyrin Pd (T4) is used alone or in combination with 5-aminolevulinic acid (the porphyrin synthesis precursor) is effective in PDT against highly invasive uveal melanoma cell line C918 in vitro [54].…”