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Title: PAK inhibition by PF-3758309 enhanced the sensitivity of multiple chemotherapeutic reagents in patient-derived pancreatic cancer cell lines.
Austin Authors: Wang, Kai;Huynh, Nhi;Wang, Xiao;Pajic, Marina;Parkin, Ashleigh;Man, Jennifer;Baldwin, Graham S;Nikfarjam, Mehrdad ;He, Hong 
Affiliation: St Vincent's Clinical School, Faculty of Medicine, University of NSW Australia
The Kinghorn Cancer Centre, The Garvan Institute of Medical Research 384 Victoria St, Darlinghurst, Sydney, NSW 2010, Australia
Department of Surgery, Austin Health, The University of Melbourne, Heidelberg, Victoria, Australia
Issue Date: 2019
Date: 2019-06-15
Publication information: American journal of translational research 2019; 11(6): 3353-3364
Abstract: Pancreatic ductal adenocarcinoma (PDA) remains the most lethal malignancy due to lack of an effective treatment. P21-activated kinases (PAKs) play a key role not only in cell proliferation and migration, but also in mediating chemo-resistance in PDA. The aim of this study was to investigate the combined effect of a PAK inhibitor PF-3758309 with multiple chemotherapeutic reagents on a panel of patient-derived PDA cell lines, and potential mechanisms involved. Cells were treated with PF-3758309 plus or minus gemcitabine, 5-fluorouracil (5-FU) or abraxane, and cell growth was determined using a cell proliferation assay kit. Protein expression profiles were measured by Western blot. PDA cells were subcutaneously injected into the flanks of SCID mice which were then treated with saline, gemcitabine, PF-3758309, gemcitabine plus PF-3758309 or abraxane. Tumour growth was measured by volume and weight. PAK1 was correlated with CK19 expression, and PAK4 with α-SMA and palladin expression. Combination of PF-3758309 with 5-FU, gemcitabine or abraxane further suppressed cell growth of patient-derived PDA cell lines in vitro. The combination of PF-3758309 with gemcitabine maximally inhibited tumour growth in vivo by suppressing cell proliferation. PF-3758309 inhibited the expression of HIF-1α, palladin and α-SMA both in vitro and in vivo. PAK inhibitor PF-3758309 can enhance anti-tumour effects of multiple chemotherapeutic reagents on a panel of patient-derived PDA cell lines. Combination of PF-3758309 with gemcitabine achieves comparable efficacy to combination of gemcitabine with abraxane, and thus provides a potential targeted therapy in the management of PDA.
ORCID: 0000-0002-0944-8747
Journal: American journal of translational research
PubMed URL: 31312349
ISSN: 1943-8141
Type: Journal Article
Subjects: PF-3758309
p21-activated kinase
pancreatic cancer
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