APIM-peptide targeting PCNA improves the efficacy of docetaxel treatment in the TRAMP mouse model of prostate cancer
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Caroline K. Søgaard1,7, Siver A. Moestue2,3,4, Morten B. Rye1,7, Jana Kim2,5, Anala Nepal1, Nina-Beate Liabakk1, Siri Bachke1, Tone F. Bathen2,5, Marit Otterlei1,6,7 and Deborah K. Hill2,5
1Department of Cancer Research and Molecular Medicine, Norwegian University of Science and Technology (NTNU), Trondheim, Norway
2Department of Circulation and Medical Imaging, Norwegian University of Science and Technology (NTNU), Trondheim, Norway
3Department of Laboratory Medicine, Women’s and Children’s Health, Norwegian University of Science and Technology (NTNU), Trondheim, Norway
4Department of Pharmacy, Faculty of Health Sciences, Nord University, Namsos, Norway
5Department of Radiology, St. Olavs Hospital, Trondheim University Hospital, Trondheim, Norway
6APIM Therapeutics A/S, Trondheim, Norway
7Clinic of Surgery, St. Olavs Hospital, Trondheim University Hospital, Trondheim, Norway
Marit Otterlei, email: [email protected]
Deborah K. Hill, email: [email protected]
Keywords: magnetic resonance imaging; gene expression; apoptosis; MAPK; PI3K/AKT
Received: June 07, 2017 Accepted: November 06, 2017 Published: January 27, 2018
Docetaxel is the chemotherapeutic choice for metastatic hormone-refractory prostate cancer, however, it only marginally improves the survival rate. The purpose of the present study was to examine if a peptide targeting the cellular scaffold protein PCNA could improve docetaxel’s efficacy. We found that docetaxel given in combination with a cell penetrating peptide containing the AlkB homolog 2 PCNA interacting motif (APIM-peptide), reduced the prostate volume and limited prostate cancer regrowth in vivo in the immunocompetent transgenic adenocarcinoma model of prostate cancer (TRAMP). In accordance with this, we found that the APIM-peptide enhanced the efficacy of docetaxel in vitro. Gene expression analysis on prostate cancer cell lines indicated that the combination of docetaxel and APIM-peptide alters expression of genes involved in cellular signaling, apoptosis, and prostate cancer development. These changes were not detected in single agent treated cells. Our results suggest that targeting PCNA and thereby affecting multiple cellular pathways simultaneously has the potential to improve docetaxel therapy of advanced prostate cancer.
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