Molecular mechanism underlying the synergistic interaction between trifluorothymidine and the epidermal growth factor receptor inhibitor erlotinib in human colorectal cancer cell lines

Irene V. Bijnsdorp, Frank A. E. Kruyt, Masakazu Fukushima, Kees Smid, Shanti Gokoel, Godefridus J. Peters*

*Corresponding author for this work

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    Abstract

    The pyrimidine trifluorothymidine (TFT) inhibits thymidylate synthase (TS) and can be incorporated into the DNA. TFT, as part of TAS-102, is clinically evaluated in phase II studies as an oral chemotherapeutic agent. Erlotinib is a tyrosine kinase inhibitor of the epidermal growth factor receptor (EGFR) that is often deregulated in colorectal cancer. This study investigated molecular mechanisms underlying the cytotoxic actions of the combination of an EGFR-tyrosine kinase inhibitor with TFT in colorectal cancer cells Caco2, WiDR, Lovo92, and Colo320. Drug interactions were examined by the sulforhodamine B assay and subsequent combination index (CI) analyses, cell cycle effects by FACS analysis of propidium iodide stained cells, Akt, MAPK and EGFR phosphorylation and expression levels by Western blotting and TS activity by the TS in situ assay. All combination schedules were synergistic in wt-EGFR expressing (but with mutated downstream pathways) WiDR and Lovo92 (CI 0.4-0.8) and very synergistic in Caco2 cells (with wt-EGFR and functional downstream pathways; CI 0.1-0.3), but in EGFR-lacking Colo320 cells, no additional activity was found (CI 1.0-1.2). Synergism was mostly related to the induction of cell cycle arrest and an erlotinib-mediated inhibition of the pro-survival signaling through Akt and MAPK that was activated (phosphorylated) by TFT. Erlotinib inhibited TS activity in EGFR-expressing cell lines, probably due to cell cycle arrest in the G(1) phase. TS activity was slightly lower in the combinations, probably due to cell cycle interference. Taken together, the combination of erlotinib with TFT seems to present a potential strategy in the field of molecular therapeutics. (Cancer Sci 2010; 101: 440-447)

    Original languageEnglish
    Pages (from-to)440-447
    Number of pages8
    JournalCancer science
    Volume101
    Issue number2
    DOIs
    Publication statusPublished - Feb-2010

    Keywords

    • TYROSINE KINASE INHIBITOR
    • PHASE-II
    • INDUCED CYTOTOXICITY
    • MYELOID-LEUKEMIA
    • BREAST-CANCER
    • THERAPY
    • GEFITINIB
    • CAPECITABINE
    • COMBINATION
    • IRINOTECAN

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