Cytotoxic effects of chemokine receptor 4 inhibition by AMD3100 in biliary tract cancer cells: Potential drug synergism with gemcitabine

Abstract

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.

Biliary tract cancer stem cells - translational options and challenges

“…Drug-based inhibition of CXCR4 using AMD3100 suppressed migration and invasion of BTC cells, and this effect was only observable in the CD24+ CSC subpopulation[50]. Interestingly, AMD3100 treatment also reduced sphere formation potential of BTC cells in another study, further connecting CXCR4 expression with stem cell characteristics[51]. RNA interference-mediated knockdown of CXCR4 in an IHC model inhibited proliferation and colony formation in vitro as well as tumorigenicity in vivo [52].…”

Cholangiocarcinoma therapy with nanoparticles that combine downregulation of MicroRNA-210 with inhibition of cancer cell invasiveness

“…Inhibition of the signaling pathway with CXCR4 antagonists decreases the motility and invasion of CCA cells 15 - 17 . Inhibition of CXCR4 can also reverse drug resistance and improve chemotherapy 18 , 19 , as documented by the chemosensitizing effect of a CXCR4 antagonist AMD3100 to GEM in human CCA cells 20 . Several studies reported that CXCR4 inhibition reduced the stemness of cancer cells to overcome drug resistance 21 , 22 .…”