Sorafenib overcomes irinotecan resistance in colorectal cancer by inhibiting the ABCG2 drug-efflux pump.: Sorafenib inhibits ABCG2 and overcome irinotecan resistance
| Autor: | Mazard, Thibault, Causse, Annick, Simony, Joelle, Leconet, Wilhem, Vezzio-Vie, Nadia, Torro, Adeline, Jarlier, Marta, Evrard, Alexandre, Del Rio, Maguy, Assenat, Eric, Martineau, Pierre, Ychou, Marc, Robert, Bruno, Gongora, Celine |
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| Přispěvatelé: | Unité d'Oncologie Médicale [St-Eloi], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-CHU Saint-Eloi, Institut de recherche en cancérologie de Montpellier (IRCM - U896 Inserm - UM1), Université Montpellier 1 (UM1)-CRLCC Val d'Aurelle - Paul Lamarque-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Service de Biochimie, Centre Hospitalier Universitaire de Nîmes (CHU Nîmes), Funding for this work has been supported by INSERM and CRCL ICM-Val D'Aurelle |
| Jazyk: | angličtina |
| Rok vydání: | 2013 |
| Předmět: |
MESH: Neoplasm Proteins
MESH: Xenograft Model Antitumor Assays MESH: HCT116 Cells ABCG2 colorectal cancer [SDV.CAN]Life Sciences [q-bio]/Cancer MESH: Receptor Epidermal Growth Factor MESH: Drug Synergism MESH: Phenylurea Compounds heterocyclic compounds MESH: Animals [SDV.BBM]Life Sciences [q-bio]/Biochemistry Molecular Biology neoplasms MESH: Mice irinotecan MESH: Humans MESH: Gene Expression Regulation Neoplastic [SDV.SP]Life Sciences [q-bio]/Pharmaceutical sciences digestive system diseases MESH: Drug Resistance Neoplasm MESH: Proto-Oncogene Proteins MESH: ATP-Binding Cassette Transporters MESH: Camptothecin sorafenib MESH: Niacinamide MESH: ras Proteins MESH: Colorectal Neoplasms |
| Zdroj: | Molecular Cancer Therapeutics Molecular Cancer Therapeutics, American Association for Cancer Research, 2013, 12 (10), pp.2121-34. ⟨10.1158/1535-7163.MCT-12-0966⟩ |
| ISSN: | 1535-7163 1538-8514 |
| DOI: | 10.1158/1535-7163.MCT-12-0966⟩ |
| Popis: | International audience; Despite recent advances in the treatment of colorectal cancer (CRC), tumor resistance is a frequent cause of chemotherapy failure. Therefore, new treatment options are needed to improve survival of patients with irinotecan-refractory CRCs, particularly those bearing KRAS mutations that preclude the use of anti-EGFR therapies. In this study, we investigated whether sorafenib could reverse irinotecan resistance, thereby enhancing the therapeutic efficacy of routinely used irinotecan-based chemotherapy. We used both in vitro (the HCT116, SW48, SW620, and HT29 colon adenocarcinoma cell lines and four SN-38-resistant HCT-116 and SW48 clones) and in vivo models (nude mice xenografted with SN-38-resistant HCT116 cells) to test the efficacy of sorafenib alone or in combination with irinotecan or its active metabolite, SN-38. We have shown that sorafenib improved the antitumoral activity of irinotecan in vitro, in both parental and SN-38-resistant colon adenocarcinoma cell lines independently of their KRAS status, as well as in vivo, in xenografted mice. By inhibiting the drug-efflux pump ABCG2, sorafenib favors irinotecan intracellular accumulation and enhances its toxicity. Moreover, we found that sorafenib improved the efficacy of irinotecan by inhibiting the irinotecan-mediated p38 and ERK activation. In conclusion, our results show that sorafenib can suppress resistance to irinotecan and suggest that sorafenib could be used to overcome resistance to irinotecan-based chemotherapies in CRC, particularly in KRAS-mutated tumors. |
| Databáze: | OpenAIRE |
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