Rational development of synergistic combinations of chemotherapy and molecular targeted agents for colorectal cancer treatment.

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  • Additional Information
    • Source:
      Publisher: BioMed Central Country of Publication: England NLM ID: 100967800 Publication Model: Electronic Cited Medium: Internet ISSN: 1471-2407 (Electronic) Linking ISSN: 14712407 NLM ISO Abbreviation: BMC Cancer Subsets: MEDLINE
    • Publication Information:
      Original Publication: London : BioMed Central, [2001-
    • Subject Terms:
      Drug Synergism*; Colorectal Neoplasms/*drug therapy ; Drug Resistance, Neoplasm/*genetics ; Protein Kinase Inhibitors/*administration & dosage; Aminopyridines/administration & dosage ; Aminopyridines/adverse effects ; Animals ; Benzimidazoles/administration & dosage ; Benzimidazoles/adverse effects ; Camptothecin/administration & dosage ; Camptothecin/adverse effects ; Camptothecin/analogs & derivatives ; Cell Proliferation/drug effects ; Colorectal Neoplasms/genetics ; Colorectal Neoplasms/pathology ; HT29 Cells ; Humans ; Irinotecan ; MAP Kinase Kinase 1/antagonists & inhibitors ; Mice ; Molecular Targeted Therapy ; Morpholines/administration & dosage ; Morpholines/adverse effects ; Protein Kinase Inhibitors/adverse effects ; Signal Transduction/drug effects ; Xenograft Model Antitumor Assays
    • Abstract:
      Background: The irinotecan-induced phosphokinome changes in colorectal cancer (CRC) cells were used to guide the selection of targeted agents to be tested in combination with irinotecan.
      Methods: Phosphokinome profiling with peptide arrays of tumour samples from nude mice xenografted with HT29 cells and treated or not with an effective dose of irinotecan was used to identify signalling pathways activated by irinotecan treatment. Then, drugs targeting these pathways were combined in vitro with irinotecan to test potential synergistic effect. The interactions between these drug combinations were assessed by a dose matrix approach. Confirmation of the most potential combination has been confirmed in vivo in xenografted mice.
      Results: Irinotecan induced in vivo the activation of AKT and MEK1 phosphorylation. The dose matrix approach showed that BKM120 (PI3K inhibitor) and MEK162 (MEK inhibitor) are synergistic in vitro and in vivo with a cytostatic and cytotoxic effect, while combination of BKM120 and irinotecan or MEK162 and irinotecan are only additive or even antagonistic. However, the triple combination of SN38, BKM120 and MEK162 showed a better synergistic effect that BKM120 and MEK162, indicating that the cells need to inhibit both AKT and ERK pathways to become more sensitive to irinotecan-based chemotherapies.
      Conclusion: Analysis of chemotherapy-induced phosphokinome changes helps to elucidate the mechanisms of drug resistance and to guide the selection of targets for combination therapies with synergistic activity.
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    • Contributed Indexing:
      Keywords: Colorectal cancer; Drug combinations; Irinotecan; Phosphokinome; Synergistic effect
    • Accession Number:
      0 (Aminopyridines)
      0 (Benzimidazoles)
      0 (Morpholines)
      0 (NVP-BKM120)
      0 (Protein Kinase Inhibitors)
      181R97MR71 (binimetinib)
      7673326042 (Irinotecan)
      EC 2.7.12.2 (MAP Kinase Kinase 1)
      XT3Z54Z28A (Camptothecin)
    • Publication Date:
      Date Created: 20180815 Date Completed: 20181025 Latest Revision: 20191210
    • Publication Date:
      20231215
    • Accession Number:
      PMC6090616
    • Accession Number:
      10.1186/s12885-018-4712-z
    • Accession Number:
      30103709