The Autophagy Inhibitor Verteporfin Moderately Enhances the Antitumor Activity of Gemcitabine in a Pancreatic Ductal Adenocarcinoma Model
Autor: | Natalia Zisman, Marcel B. Bally, Magali Zeisser-Labouebe, Sylvia S. W. Ng, Hilary J. Anderson, Murray S. Webb, Anitha Thomas, Norbert Maurer, Michel Roberge, Irina Manisali, Elizabeth Donohue |
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Rok vydání: | 2013 |
Předmět: |
autophagy
Pathology medicine.medical_specialty endocrine system diseases medicine.medical_treatment pancreatic cancer 03 medical and health sciences 0302 clinical medicine In vivo Chloroquine Pancreatic cancer medicine 030304 developmental biology 0303 health sciences Chemotherapy verteporfin business.industry Autophagy gemcitabine medicine.disease chemosensitization Verteporfin In vitro Gemcitabine 3. Good health Oncology 030220 oncology & carcinogenesis Cancer research business Research Paper medicine.drug |
Zdroj: | Journal of Cancer |
ISSN: | 1837-9664 |
Popis: | 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. |
Databáze: | OpenAIRE |
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