Potential of the Akt inhibitor LY294005 to antagonize the efficacy of Cisplatin against HCT116 tumor cells in a DNA mismatch repair-dependent manner.
Human colorectal adenocarcinoma sublines either deficient (HCT116+ch2) or proficient (HCT116+ch3) in the function of MLH1, one of five proteins crucial to DNA mismatch repair (MMR), were used to investigate whether the Akt-specific inhibitor LY294005 could not only increase the efficacy of platinum drugs in HCT116 cells in general but also increase the efficacy of the cisplatinum compounds Cisplatin and Lipoplatin specifically in MLH1-deficient, Cisplatin- and Lipoplatin-resistant HCT116 cells. We report that, under the conditions it increased the efficacy of Docetaxel and did not affect that of 6-thioguanine, LY294005 decreased the sensitivity of both sublines to Cisplatin, Lipoplatin, Oxaliplatin, and Lipoxal. Notably, the LY294005-imposed decrease was significantly higher in the MLH1-proficient than in the MLH1-deficient subline with Cisplatin and Lipoplatin, whereas it was nearly the same in both sublines with Oxaliplatin and Lipoxal. These LY294005-imposed changes in drug sensitivity, i.e. increase with Docetaxel and decreases with platinum compounds, were not associated with the concomitant abrogation in the levels of phospho-Aktser473. Analogous changes in drug sensitivity were also observed with the PI3-kinase inhibitor LY294002, but these changes were associated with complete abrogation of phospho-Aktser473. These observations suggest a possible relationship between MMR-mediated cisplatinum DNA damage signaling and the Akt signaling pathway, e.g. a common target for both pathways. A possibly novel property of Akt in aggravating drug sensitivity may also be proposed.
Fedier
Andre
A
Department of Gynecology, University Hospital of Zurich, CH-8091 Zurich, Switzerland. andre.fedier@usz.ch
Erdmann
Ruediger
R
Boulikas
Teni
T
Fink
Daniel
D
D048868:Adaptor Proteins, Signal Transducing; D000230:Adenocarcinoma / Q000188:drug therapy* / Q000235:genetics; D000970:Antineoplastic Agents / Q000037:antagonists & inhibitors* / Q000627:therapeutic use; D020137:Base Pair Mismatch / Q000187:drug effects; D002352:Carrier Proteins / Q000235:genetics; D002867:Chromones / Q000494:pharmacology; D002945:Cisplatin / Q000037:antagonists & inhibitors* / Q000627:therapeutic use; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000235:genetics; D004260:DNA Repair / Q000187:drug effects; D000077143:Docetaxel; D019008:Drug Resistance, Neoplasm / Q000187:drug effects / Q000235:genetics; D006801:Humans; D007294:Inositol / Q000031:analogs & derivatives* / Q000494:pharmacology; D009025:Morpholines / Q000494:pharmacology; D000070957:MutL Protein Homolog 1; D009687:Nuclear Proteins / Q000235:genetics; D009944:Organoplatinum Compounds / Q000037:antagonists & inhibitors / Q000627:therapeutic use; D000077150:Oxaliplatin; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors*; D043823:Taxoids / Q000627:therapeutic use; D014407:Tumor Cells, Cultured
C477931:1L-6-hydroxymethyl-chiro-inositol 2(R)-2-O-methyl-3-O-octadecylcarbonate; D048868:Adaptor Proteins, Signal Transducing; D000970:Antineoplastic Agents; D002352:Carrier Proteins; D002867:Chromones; C501486:MLH1 protein, human; D009025:Morpholines; D009687:Nuclear Proteins; D009944:Organoplatinum Compounds; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors; D043823:Taxoids; D000077150:Oxaliplatin; D000077143:Docetaxel; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; D007294:Inositol; D051057:Proto-Oncogene Proteins c-akt; D000070957:MutL Protein Homolog 1; D002945:Cisplatin