title: Cytotoxic effects of chemokine receptor 4 inhibition by AMD3100 in biliary tract cancer cells: Potential drug synergism with gemcitabine.
abstract: Biliary tract cancer (BTC) remains one of the most life-threatening types of cancer due to the lack of efficient therapies. Advanced tumour stages at the point of diagnosis and high chemoresistance are two of the predominant reasons for a 5-year survival rate of only ~5%. The present study investigated the effect of the chemokine receptor 4 (CXCR4) inhibitor AMD3100 (Plerixafor), alone and in combination with standard gemcitabine chemotherapy, on the proliferation of BTC cells. The expression of CXCR4 was analysed by reverse transcription-quantitative polymerase chain reaction in eight heterogeneously differentiated BTC cell lines. The effects of treatment with the CXCR4 antagonist, AMD3100, on cell viability and anchorage-independent growth, and the possible synergistic cytotoxic effects of AMD3100 with standard chemotherapeutics were assessed. The expression of CXCR4 was observed to a variable extent in all eight BTC cell lines, with SkChA-1 cells exhibiting the highest expression levels. Treatment with AMD3100 led to a marginal decrease in cell viability in the cell lines, with the exception of the CCSW-1 cells, and a significant reduction in the GBC, MzChA-1, SkChA.-1 and TFK-1 cell lines. The combined treatment of the SkChA-1 cells with varying concentrations of AMD3100 and standard gemcitabine chemotherapy revealed a more marked overall cytotoxicity, indicating a potential synergistic effect. In addition, AMD3100 significantly reduced anchorage-independent growth in the SkChA-1 cells. Overall, the results of the present study suggest that the inhibition of CXCR4 by AMD3100, in combination with gemcitabine, may be a suitable strategy for the future therapy of BTC.
authors.affiliation: Department of Internal Medicine I, Paracelsus Medical University/Salzburger Landeskliniken, Salzburg A‑5020, Austria.
authors.forename: Christian
authors.initials: C
authors.lastname: Mayr
authors.affiliation: Institute of Pathology, Paracelsus Medical University/Salzburger Landeskliniken, Salzburg A‑5020, Austria.
authors.forename: Daniel
authors.initials: D
authors.lastname: Neureiter
authors.affiliation: Department of Experimental Therapeutics, UT MD Anderson Cancer Center, Houston, TX 77054, USA.
authors.forename: Martin
authors.initials: M
authors.lastname: Pichler
authors.affiliation: Department of Internal Medicine I, Paracelsus Medical University/Salzburger Landeskliniken, Salzburg A‑5020, Austria.
authors.forename: Frieder
authors.initials: F
authors.lastname: Berr
authors.affiliation: Department of Internal Medicine I, Paracelsus Medical University/Salzburger Landeskliniken, Salzburg A‑5020, Austria.
authors.forename: Andrej
authors.initials: A
authors.lastname: Wagner
authors.affiliation: Department of Internal Medicine I, Paracelsus Medical University/Salzburger Landeskliniken, Salzburg A‑5020, Austria.
authors.forename: Tobias
authors.initials: T
authors.lastname: Kiesslich
authors.affiliation: Department of Hematology and Oncology, Klinikum Braunschweig, Braunschweig D‑38118, Germany.
authors.forename: Konrad
authors.initials: K
authors.lastname: Namberger
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001596:Benzylamines; D001652:Bile Ducts / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D000080027:Cyclams; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000494:pharmacology; D004357:Drug Synergism; D004847:Epithelial Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D005704:Gallbladder / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D015972:Gene Expression Regulation, Neoplastic; D006571:Heterocyclic Compounds / Q000494:pharmacology*; D006801:Humans; D019718:Receptors, CXCR4 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D000093542:Gemcitabine
chemical_list: D000970:Antineoplastic Agents; D001596:Benzylamines; C527276:CXCR4 protein, human; D000080027:Cyclams; D006571:Heterocyclic Compounds; D019718:Receptors, CXCR4; D003841:Deoxycytidine; C088327:plerixafor; D000093542:Gemcitabine