TY - JOUR T1 - Sequence of CX-4945 and Cisplatin Administration Determines the Effectiveness of Drug Combination and Cellular Response in Cholangiocarcinoma Cells <em>In Vitro</em> JF - Anticancer Research JO - Anticancer Res SP - 6155 LP - 6167 DO - 10.21873/anticanres.15435 VL - 41 IS - 12 AU - JOMNARONG LERTSUWAN AU - ANYAPORN SAWASDICHAI AU - NATHAPOL TASNAWIJITWONG AU - KEVIN GASTON AU - PADMA-SHEELA JAYARAMAN AU - JUTAMAAD SATAYAVIVAD Y1 - 2021/12/01 UR - http://ar.iiarjournals.org/content/41/12/6155.abstract N2 - Background: The incidence of cholangiocarcinoma (CCA) is increasing worldwide and current single chemotherapeutic drug treatments are ineffective. CX-4945 and cisplatin are currently in clinical trial for CCA treatment. Materials and Methods: We assessed the effects of the sequence of administration of CX-4945 and cisplatin applied in combination treatments on their efficacy in CCA cells in vitro. CCA cell viability was examined using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assays. Apoptosis was examined using flow cytometry. The percentage of cells positive for phosphorylated H2A histone family member X (γ-H2AX) were measured using both flow cytometry and immunofluorescence. Results: CCA cell viability was reduced to 50% after 24 h of treatments with CX-4945 and cisplatin as single agents. Interestingly, treatment with cisplatin 6 h prior to CX-4945 treatment induced significantly more DNA damage and apoptosis than CX-4945 treatment followed by cisplatin. Unexpectedly, CX-4945 treatment followed by cisplatin was less effective than single treatment in RMCCA-1 CCA cells. In addition, a 1:1 ratio of each drug was the most effective combination in these cells. Conclusion: These data demonstrate that the combination of CX-4945 and cis platin acts additively when cisplatin is applied first, at least in part due to increased DNA damage and apoptosis. Furthermore, treatment with CX-4945 prior to cisplatin treatment reduces the efficacy of this drug combination in CCA cells. ER -