Imatinib Inhibits the Renewal and Tumorigenicity of CT-26 Colon Cancer Cells after Cytoreductive Treatment with Doxorubicin
| Autor: | Paweł Swoboda, Łukasz Kaczmarek, Joanna Miłoszewska, Agnieszka Kotlarz, Wojciech Szczepek, Sergiusz Markowicz, Małgorzata Przybyszewska, Kazimiera Pyśniak |
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| Rok vydání: | 2015 |
| Předmět: |
0301 basic medicine
Colorectal cancer Immunology Antineoplastic Agents Apoptosis Pharmacology Real-Time Polymerase Chain Reaction 03 medical and health sciences Mice 0302 clinical medicine Cancer stem cell Cell Line Tumor Carcinoma medicine Immunology and Allergy Animals Doxorubicin AC133 Antigen Hypoxia Cell Proliferation Mice Inbred BALB C business.industry Imatinib General Medicine medicine.disease Flow Cytometry In vitro Oxygen 030104 developmental biology Drug Resistance Neoplasm 030220 oncology & carcinogenesis Cancer cell Colonic Neoplasms Imatinib Mesylate Neoplastic Stem Cells Stem cell Neoplasm Recurrence Local business medicine.drug Signal Transduction |
| Zdroj: | Archivum immunologiae et therapiae experimentalis. 65(1) |
| ISSN: | 1661-4917 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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