Research Papers:

Inhibition of hypoxia inducible factor 1 and topoisomerase with acriflavine sensitizes perihilar cholangiocarcinomas to photodynamic therapy

Ruud Weijer, Mans Broekgaarden, Massis Krekorian, Lindy K. Alles, Albert C. van Wijk, Claire Mackaaij, Joanne Verheij, Allard C. van der Wal, Thomas M. van Gulik, Gert Storm and Michal Heger _

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Oncotarget. 2016; 7:3341-3356. https://doi.org/10.18632/oncotarget.6490

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Ruud Weijer1,2,*, Mans Broekgaarden1,*, Massis Krekorian1, Lindy K. Alles1, Albert C. van Wijk1, Claire Mackaaij3, Joanne Verheij3, Allard C. van der Wal3, Thomas M. van Gulik1, Gert Storm2,4, Michal Heger1,4

1Department of Experimental Surgery, Academic Medical Center, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands

2Department of Controlled Drug Delivery, MIRA Institute for Biomedical Technology and Technical Medicine, University of Twente, 7500 AE Enschede, The Netherlands

3Department of Pathology, Academic Medical Center, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands

4Department of Pharmaceutics, Utrecht Institute for Pharmaceutical Sciences, University of Utrecht, 3584 CG Utrecht, The Netherlands

*These authors have contributed equally to this work

Correspondence to:

Michal Heger, e-mail: [email protected]

Keywords: cancer therapy, drug delivery system, extrahepatic cholangiocarcinoma, hypoxia, tumor targeting

Received: August 03, 2015     Accepted: November 16, 2015     Published: November 27, 2015


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.

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