title: Imatinib Inhibits the Renewal and Tumorigenicity of CT-26 Colon Cancer Cells after Cytoreductive Treatment with Doxorubicin.
abstract: Conventional anti-cancer drugs preferentially eliminate differentiated cancer cells but those cells that are spared (i.e. cancer stem cells: CSC), initiate recurrence. We tested whether drugs that target receptor tyrosine kinases (RTKs) involved in developmental signaling cascades and activated in CSC, could be used to silence and/or to eliminate colorectal cancer cells refractory to conventional treatment with cytoreductive drugs. A sequential treatment model was thereby developed with doxorubicin (DOX) and imatinib. CT-26 mouse colon carcinoma cells were pre-treated with DOX to select DOX-refractory cells with CSC properties, which were then subsequently treated with RTK inhibitor imatinib, where their regrowth was found to be inhibited. Under both normoxic and hypoxic conditions, imatinib potently inhibited clonogenicity of DOX-refractory CT-26 cells. Treatment with DOX did not eliminate tumorigenic CT-26 cells, since CT-26 cells pre-exposed to DOX in vitro, when inoculated subcutaneously, induced tumors in 90 % of mice, as opposed to a 100 % rate in the case of chemonaive CT-26 cells. In mice inoculated with chemonaive CT-26 cells, tumor formation was not prevented by imatinib. However, imatinib prevented tumor formation in 50 % of mice inoculated with CT-26 cells pre-exposed to DOX in vitro, with the remaining 50 % mice showing delayed tumor formation. These results suggest that the sequential use of the drug imatinib, as a drug targeting cancer cells expressing stem cell features after conventional cytoreductive treatment, is a promising future strategy for preventing tumor recurrence.
authors.affiliation: Department of Immunology, Maria Sklodowska-Curie Memorial Cancer Centre and Institute of Oncology, Roentgena 5, 02-781, Warsaw, Poland. magip@coi.waw.pl.
authors.forename: Małgorzata
authors.initials: M
authors.lastname: Przybyszewska
authors.affiliation: Department of Immunology, Maria Sklodowska-Curie Memorial Cancer Centre and Institute of Oncology, Roentgena 5, 02-781, Warsaw, Poland.
authors.forename: Joanna
authors.initials: J
authors.lastname: Miłoszewska
authors.affiliation: Department of Immunology, Maria Sklodowska-Curie Memorial Cancer Centre and Institute of Oncology, Roentgena 5, 02-781, Warsaw, Poland.
authors.forename: Agnieszka
authors.initials: A
authors.lastname: Kotlarz
authors.affiliation: Department of Immunology, Maria Sklodowska-Curie Memorial Cancer Centre and Institute of Oncology, Roentgena 5, 02-781, Warsaw, Poland.
authors.forename: Paweł
authors.initials: P
authors.lastname: Swoboda
authors.affiliation: Department of Genetics, Maria Sklodowska-Curie Memorial Cancer Centre and Institute of Oncology, ul. Roentgena 5, 02-781, Warsaw, Poland.
authors.forename: Kazimiera
authors.initials: K
authors.lastname: Pyśniak
authors.affiliation: Pharmaceutical Research Institute, Rydygiera 8, 01-793, Warsaw, Poland.
authors.forename: Wojciech
authors.initials: W
authors.lastname: Szczepek
authors.affiliation: Pharmaceutical Research Institute, Rydygiera 8, 01-793, Warsaw, Poland.
authors.forename: Łukasz
authors.initials: Ł
authors.lastname: Kaczmarek
authors.affiliation: Department of Immunology, Maria Sklodowska-Curie Memorial Cancer Centre and Institute of Oncology, Roentgena 5, 02-781, Warsaw, Poland.
authors.forename: Sergiusz
authors.initials: S
authors.lastname: Markowicz
mesh_terms: D000071916:AC133 Antigen / Q000737:chemistry; D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003110:Colonic Neoplasms / Q000188:drug therapy*; D004317:Doxorubicin / Q000627:therapeutic use*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D005434:Flow Cytometry; D000860:Hypoxia; D000068877:Imatinib Mesylate / Q000627:therapeutic use*; D051379:Mice; D008807:Mice, Inbred BALB C; D009364:Neoplasm Recurrence, Local; D014411:Neoplastic Stem Cells / Q000187:drug effects; D010100:Oxygen / Q000737:chemistry; D060888:Real-Time Polymerase Chain Reaction; D015398:Signal Transduction
chemical_list: D000071916:AC133 Antigen; D000970:Antineoplastic Agents; C000606024:Prom1 protein, mouse; D004317:Doxorubicin; D000068877:Imatinib Mesylate; D010100:Oxygen
keywords: Colorectal cancer; Doxorubicin; Drug resistance; Imatinib; PDGFRs; Sequential therapy; Stemness