Abstract
Background: Photodynamic therapy (PDT) induces tumor cell death by oxidative stress and hypoxia but also survival signaling through activation of hypoxia-inducible factor 1 (HIF-1). Since perihilar cholangiocarcinomas are relatively recalcitrant to PDT, the aims were to (1) determine the expression levels of HIF-1-associated proteins in human perihilar cholangiocarcinomas, (2) investigate the role of HIF-1 in PDT-treated human perihilar cholangiocarcinoma cells, and (3) determine whether HIF-1 inhibition reduces survival signaling and enhances PDT efficacy.Results: Increased expression of VEGF, CD105, CD31/Ki-67, and GLUT-1 was confirmed in human perihilar cholangiocarcinomas. PDT with liposome-delivered zinc phthalocyanine caused HIF-1α stabilization in SK-ChA-1 cells and increased transcription of HIF-1α downstream genes. Acriflavine was taken up by SK-ChA-1 cells and translocated to the nucleus under hypoxic conditions. Importantly, pretreatment of SK-ChA-1 cells with acriflavine enhanced PDT efficacy via inhibition of HIF-1 and topoisomerases I and II.Methods: The expression of VEGF, CD105, CD31/Ki-67, and GLUT-1 was determined by immunohistochemistry in human perihilar cholangiocarcinomas. In addition, the response of human perihilar cholangiocarcinoma (SK-ChA-1) cells to PDT with liposome-delivered zinc phthalocyanine was investigated under both normoxic and hypoxic conditions. Acriflavine, a HIF-1α/HIF-1β dimerization inhibitor and a potential dual topoisomerase I/II inhibitor, was evaluated for its adjuvant effect on PDT efficacy.Conclusions: HIF-1, which is activated in human hilar cholangiocarcinomas, contributes to tumor cell survival following PDT in vitro. Combining PDT with acriflavine pretreatment improves PDT efficacy in cultured cells and therefore warrants further preclinical validation for therapy-recalcitrant perihilar cholangiocarcinomas.
Highlights
Photodynamic therapy (PDT) is a non-to-minimally invasive treatment modality for a variety of solid cancers
The incidence of tumor hypoxia and the importance of hypoxiainducible factor 1 (HIF-1) expression in a large variety of tumors have been widely established, literature on this phenomenon www.impactjournals.com/oncotarget in perihilar cholangiocarcinomas is scarce. It was investigated whether hypoxia-related proteins (VEGF for angiogenic signaling, CD105 and CD31/Ki-67 for neovascularization, and glucose transporter 1 (GLUT-1) for glycolysis) were present in perihilar cholangiocarcinoma resection specimens
The hematoxylin and eosin staining (Figure 1A) revealed that perihilar cholangiocarcinomas were characterized by clusters of tumor cells surrounded by relatively large areas of desmoplastic tissue
Summary
Photodynamic therapy (PDT) is a non-to-minimally invasive treatment modality for a variety of solid cancers. PDT yields complete response rates of 50–90% in the majority of the abovementioned cancers, nasopharyngeal-, urothelial-, and perihilar cholangiocarcinomas are relatively refractory to PDT. This may be in part due to hypoxia-mediated survival signaling that is triggered by the stabilization of hypoxia inducible factor 1 (HIF-1) following PDT [10,11,12]. Photodynamic therapy (PDT) induces tumor cell death by oxidative stress and hypoxia and survival signaling through activation of hypoxiainducible factor 1 (HIF-1). Since perihilar cholangiocarcinomas are relatively recalcitrant to PDT, the aims were to (1) determine the expression levels of HIF1-associated proteins in human perihilar cholangiocarcinomas, (2) investigate the role of HIF-1 in PDT-treated human perihilar cholangiocarcinoma cells, and (3) determine whether HIF-1 inhibition reduces survival signaling and enhances PDT efficacy
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