title: Dasatinib and Doxorubicin Treatment of Sarcoma Initiating Cells: A Possible New Treatment Strategy.
abstract: Background. One of the major challenges affecting sarcoma treatment outcome, particularly that of metastatic disease, is resistance to chemotherapy. Cancer-initiating cells are considered a major contributor to this resistance. Methods. An immortalised nontransformed human stromal (mesenchymal) stem cell line hMSC-TERT4 and a transformed cell line hMSC-TERT20-CE8, known to form sarcoma-like tumours when implanted in immune-deficient mice, were used as models. Receptor tyrosine kinase (RTK) activation was analysed by RTK arrays and cellular viability after tyrosine kinases inhibitor (TKI) treatment with or without doxorubicin was assessed by MTS assay. Results. Initial results showed that the hMSC-TERT4 was more doxorubicin-sensitive while hMSC-TERT20-CE8 was less doxorubicin-sensitive evidenced by monitoring cell viability in the presence of doxorubicin at different doses. The epidermal growth factor receptor (EGFR) was activated in both cell lines. However hMSC-TERT20-CE8 exhibited significantly higher expression of the EGFR ligands. EGFR inhibitors such as erlotinib and afatinib alone or in combination with doxorubicin failed to further decrease cell viability of hMSC-TERT20-CE8. However, inhibition with the TKI dasatinib in combination with doxorubicin decreased cell viability of the hMSC-TERT20-CE8 cell line. Conclusion. Our results demonstrate that dasatinib, but not EGFR-directed treatment, can decrease cell viability of stromal cancer stem cells less sensitive to doxorubicin.
authors.affiliation: Department of Oncology, Aarhus University Hospital, 8000 Aarhus C, Denmark.
authors.forename: Ninna
authors.initials: N
authors.lastname: Aggerholm-Pedersen
authors.affiliation: Department of Clinical Biochemistry, Aarhus University Hospital, 8000 Aarhus C, Denmark.
authors.forename: Christina
authors.initials: C
authors.lastname: Demuth
authors.affiliation: Department of Oncology, Aarhus University Hospital, 8000 Aarhus C, Denmark.
authors.forename: Akmal
authors.identifier: 0000-0002-6020-2320
authors.initials: A
authors.lastname: Safwat
authors.affiliation: Department of Oncology, Aarhus University Hospital, 8000 Aarhus C, Denmark.
authors.forename: Peter
authors.initials: P
authors.lastname: Meldgaard
authors.affiliation: Laboratory for Molecular Endocrinology (KMEB), Department of Endocrinology, Odense University Hospital, 5000 Odense, Denmark; Danish Stem Cell Center (DanStem), Panum Institute, University of Copenhagen, 2200 Copenhagen, Denmark.
authors.forename: Moustapha
authors.initials: M
authors.lastname: Kassem
authors.affiliation: Department of Clinical Biochemistry, Aarhus University Hospital, 8000 Aarhus C, Denmark.
authors.forename: Boe
authors.initials: B
authors.lastname: Sandahl Sorensen