Verteporfin- and sodium porfimer-mediated photodynamic therapy enhances pancreatic cancer cell death without activating stromal cells in the microenvironment

Abstract

The goal of our study was to determine the susceptibility of different pancreatic cell lines to clinically applicable photodynamic therapy (PDT). The efficacy of PDT of two different commercially available photosensitizers, verteporfin and sodium porfimer, was compared using a panel of four different pancreatic cancer cell lines, PANC-1, BxPC-3, CAPAN-2, and MIA PaCa-2, and an immortalized non-neoplastic pancreatic ductal epithelium cell line, HPNE. The minimum effective concentrations and dose-dependent curves of verteporfin and sodium porfimer on PANC-1 were determined. Since pancreatic cancer is known to have significant stromal components, the effect of PDT on stromal cells was also assessed. To mimic tumor-stroma interaction, a coculture of primary human fibroblasts or human pancreatic stellate cell (HPSCs) line with PANC-1 was used to test verteporfin-PDT-mediated cell death of PANC-1. Two cytokines (TNF-α and IL-1β) were used for stimulation of primary fibroblasts (derived from human esophageal biopsies) or HPSCs. The increased expression of smooth muscle actin (α-SMA) confirmed the activation of fibroblasts or HPSC upon treatment with TNF-α and IL-1β. Cell death assays showed that both sodium porfimer-and verteporfin-mediated PDT-induced cell death in a dose-dependent manner. However, verteporfin-PDT treatment had a greater efficiency with 60× lower concentration than sodium porfimer-PDT in the PANC-1 incubated with stimulated fibroblasts or HPSC. Moreover, activation of stromal cells did not affect the treatment of the pancreatic cancer cell lines, suggesting that the effects of PDT are independent of the inflammatory microenvironment found in this two-dimensional culture model of cancers.

The Hippo Signaling Pathway in Drug Resistance in Cancer

“…Additionally, in vivo verteporfin treatment showed its ability to suppress hepatomegaly caused by YAP overexpression or activation of endogenous YAP. The anti-cancer effects of verteporfin were further documented in bladder cancer [ 137 ], pancreatic cancer [ 138 , 139 ], ovarian cancer [ 140 ], breast cancer [ 141 ] and melanoma [ 142 ]. The prospective anti-cancer use of verteporfin is also supported by its ability to synergically enhance the efficacy of other drugs.…”

Electron Transfer-Supported Photodynamic Therapy

“…Porphyrin derivatives have been used as clinical photosensitizer for PDT [8][9][10][11]. Porfimer sodium [12,13] and Talaporfin sodium [13] are famous examples of clinically used photosensitizers. The PDT mechanism of these porphyrins is 1 O 2 generation.…”

“…As the PDT photosensitizers, porphyrins have been extensively studied and used [8][9][10][11]. For example, porfimer sodium [12,13] and talaporfin sodium [13], an oligomer and a monomer of a free-base anionic porphyrin, respectively, are well-known photosensitizers in clinical use. In general, the porphyrin photosensitizer (e.g., almost 60 mg/body for talaporfin sodium) is given for the target tissue, followed by irradiation of the visible light (e.g., 664 nm, 150 mW cm −2 , and 10 J cm −2 ).…”

The Exploitation of Liposomes in the Inhibition of Autophagy to Defeat Drug Resistance

“…Melanoma is a very aggressive tumor, has a primary skin site and multiple metastases that explain the morbidity and mortality in the population. Recently, verteporfin, a benzoporphyrin derivative, has been shown to have an anti-tumor effect on melanoma cells in vitro, in a preclinical model of transgenic mouse (Lu et al, 2019) and in the clinical treatment of macular degeneration. Verteporfin action consists in inhibiting the formation of autophagosomes by depriving the cells of glucose and serum, by blocking the p62 oligomerization, a protein useful for the sequestration of ubiquinated targets into autophagosomes.…”