J Cancer 2013; 4(7):585-596. doi:10.7150/jca.7030

Research Paper

The Autophagy Inhibitor Verteporfin Moderately Enhances the Antitumor Activity of Gemcitabine in a Pancreatic Ductal Adenocarcinoma Model

Elizabeth Donohue1, Anitha Thomas2, Norbert Maurer2, Irina Manisali2, Magali Zeisser-Labouebe2, Natalia Zisman2, Hilary J. Anderson1, Sylvia S. W. Ng3, Murray Webb2, Marcel Bally2,4, Michel Roberge1,2✉

1. Department of Biochemistry and Molecular Biology, University of British Columbia;
2. Centre for Drug Research and Development, University of British Columbia;
3. Department of Pharmaceutical Sciences, BC Cancer Agency;
4. Department of Experimental Therapeutics, BC Cancer Agency, Vancouver, British Columbia, Canada

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is highly resistant to chemotherapy. It has been described as requiring elevated autophagy for growth and inhibiting autophagy has been proposed as a treatment strategy. To date, all preclinical reports and clinical trials investigating pharmacological inhibition of autophagy have used chloroquine or hydroxychloroquine, which interfere with lysosomal function and block autophagy at a late stage. Verteporfin is a newly discovered autophagy inhibitor that blocks autophagy at an early stage by inhibiting autophagosome formation. Here we report that PDAC cell lines show variable sensitivity to verteporfin in vitro, suggesting cell-line specific autophagy dependence. Using image-based and molecular analyses, we show that verteporfin inhibits autophagy stimulated by gemcitabine, the current standard treatment for PDAC. Pharmacokinetic and efficacy studies in a BxPC-3 xenograft mouse model demonstrated that verteporfin accumulated in tumors at autophagy-inhibiting levels and inhibited autophagy in vivo, but did not reduce tumor volume or increase survival as a single agent. In combination with gemcitabine verteporfin moderately reduced tumor growth and enhanced survival compared to gemcitabine alone. While our results do not uphold the premise that autophagy inhibition might be widely effective against PDAC as a single-modality treatment, they do support autophagy inhibition as an approach to sensitize PDAC to gemcitabine.

Keywords: autophagy, pancreatic cancer, verteporfin, gemcitabine, chemosensitization

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How to cite this article:
Donohue E, Thomas A, Maurer N, Manisali I, Zeisser-Labouebe M, Zisman N, Anderson HJ, Ng SSW, Webb M, Bally M, Roberge M. The Autophagy Inhibitor Verteporfin Moderately Enhances the Antitumor Activity of Gemcitabine in a Pancreatic Ductal Adenocarcinoma Model. J Cancer 2013; 4(7):585-596. doi:10.7150/jca.7030. Available from http://www.jcancer.org/v04p0585.htm