Abstract
Cholangiocarcinoma (CCA), which is highly malignant, shows a relatively poor prognosis, due to the insensitivity of the tumour to chemotherapy and radiotherapy. Photodynamic therapy (PDT) has become a promising palliative therapeutic option for patients with unresectable cholangiocarcinoma (CCA), while the functional amount of ROS is limited by intracellular redox systemen. Sulfasalazine (SASP), a well-known anti-inflammatory agent, which also acts as an inhibitor of the amino acid transport system xc (xCT), decreases the intracellular glutathione (GSH) level, thus weakening the antioxidant defence of the cell by inhibition of the antiporter. However, the combination of SASP and PDT remains unexplored. We have reported that polyhematoporphyrin (PHP)-mediated PDT inhibits the cell viability of CCA cells and organoids. Furthermore, in PHP-enriched HCCC-9810 and TFK-1CCA cells, SASP enhances the sensitivity to PHP-mediated PDT through a GSH-dependent mechanism. We found that PHP-PDT can up-regulate xCT expression to promote cells against overloaded ROS, while SASP reduces GSH levels. After the combination of SASP and PHP-PDT, cell viability and GSH levels were significantly inhibited. xCT was also observed to be inhibited by SASP in human organoid samples. Our findings suggest that, in combination with PDT, SASP has potential as a promising approach against CCA.
Highlights
Cholangiocarcinoma (CCA) is an adenocarcinoma or papillary tumour arising from the bile duct epithelial cells, located along the intrahepatic and extrahepatic biliary tree (GERA et al, 2017; KENDALL et al, 2019)
We propose that SASP-induced cystine depletion resulted in a reduction in the intracellular GSH levels, inducing a rapid accumulation of reactive oxygen species (ROS), which become a steady resource for Photodynamic therapy (PDT)
immunohistochemical staining (IHC) was used to detect xCT expression in CCA organoids treated with SASP and PHP-PDT, and the results showed that the xCT expression of untreated CCA organoids (NC) was mild to moderate, and that of CCA organoids treated with PHP-PDT alone was strongly positive, while it was negative after SASP treatment alone
Summary
Cholangiocarcinoma (CCA) is an adenocarcinoma or papillary tumour arising from the bile duct epithelial cells, located along the intrahepatic and extrahepatic biliary tree (GERA et al, 2017; KENDALL et al, 2019). Epidemiology has shown that the morbidity and mortality of CCA have an uprising trend worldwide (BRIDGEWATER et al, 2016). CCA is more prevalent in Asia, with an incidence of up to 85 per 100,000 people in some areas (KHAN et al, 2019). CCA is insensitive to chemotherapy and radiotherapy, with surgical resection still being the first treatment option (DOHERTY et al, 2017). The early stage of CCA has no evident clinical symptoms, and patients usually lose the opportunity to undergo surgical operation after diagnosis (KRASINSKAS, 2018), contributing to a survival period of non-surgery patients lower than 1 year (RERKNIMITR et al, 2013). Research shows that patients with CCA with effective
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