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Research ArticleExperimental Studies

Sequence of CX-4945 and Cisplatin Administration Determines the Effectiveness of Drug Combination and Cellular Response in Cholangiocarcinoma Cells In Vitro

JOMNARONG LERTSUWAN, ANYAPORN SAWASDICHAI, NATHAPOL TASNAWIJITWONG, KEVIN GASTON, PADMA-SHEELA JAYARAMAN and JUTAMAAD SATAYAVIVAD
Anticancer Research December 2021, 41 (12) 6155-6167; DOI: https://doi.org/10.21873/anticanres.15435
JOMNARONG LERTSUWAN
1Laboratory of Immunology, Chulabhorn Research Institute, Bangkok, Thailand;
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ANYAPORN SAWASDICHAI
2Laboratory of Chemical Carcinogenesis, Chulabhorn Research Institute, Bangkok, Thailand;
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NATHAPOL TASNAWIJITWONG
3Laboratory of Pharmacology, Chulabhorn Research Institute, Bangkok, Thailand;
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KEVIN GASTON
4Division of Translational Medical Sciences, School of Medicine, University of Nottingham, Nottingham, U.K.
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PADMA-SHEELA JAYARAMAN
4Division of Translational Medical Sciences, School of Medicine, University of Nottingham, Nottingham, U.K.
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JUTAMAAD SATAYAVIVAD
3Laboratory of Pharmacology, Chulabhorn Research Institute, Bangkok, Thailand;
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  • For correspondence: jutamaad@cri.or.th
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Abstract

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.

Key Words:
  • CX-4945
  • cisplatin
  • treatment sequence
  • cholangiocarcinoma
  • apoptosis
  • methuosis
  • Received October 8, 2021.
  • Revision received November 8, 2021.
  • Accepted November 10, 2021.
  • Copyright © 2021 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.
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Anticancer Research: 41 (12)
Anticancer Research
Vol. 41, Issue 12
December 2021
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Sequence of CX-4945 and Cisplatin Administration Determines the Effectiveness of Drug Combination and Cellular Response in Cholangiocarcinoma Cells In Vitro
JOMNARONG LERTSUWAN, ANYAPORN SAWASDICHAI, NATHAPOL TASNAWIJITWONG, KEVIN GASTON, PADMA-SHEELA JAYARAMAN, JUTAMAAD SATAYAVIVAD
Anticancer Research Dec 2021, 41 (12) 6155-6167; DOI: 10.21873/anticanres.15435

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Sequence of CX-4945 and Cisplatin Administration Determines the Effectiveness of Drug Combination and Cellular Response in Cholangiocarcinoma Cells In Vitro
JOMNARONG LERTSUWAN, ANYAPORN SAWASDICHAI, NATHAPOL TASNAWIJITWONG, KEVIN GASTON, PADMA-SHEELA JAYARAMAN, JUTAMAAD SATAYAVIVAD
Anticancer Research Dec 2021, 41 (12) 6155-6167; DOI: 10.21873/anticanres.15435
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Keywords

  • CX-4945
  • Cisplatin
  • treatment sequence
  • cholangiocarcinoma
  • apoptosis
  • methuosis
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