title: Dasatinib (BMS-35482) interacts synergistically with docetaxel, gemcitabine, topotecan, and doxorubicin in ovarian cancer cells with high SRC pathway activation and protein expression.
abstract: OBJECTIVE
  This study aimed to explore the activity of dasatinib in combination with docetaxel, gemcitabine, topotecan, and doxorubicin in ovarian cancer cells.
  
  
  METHODS
  Cells with previously determined SRC pathway and protein expression (SRC pathway/SRC protein IGROV1, both high; SKOV3, both low) were treated with dasatinib in combination with the cytotoxic agents. SRC and paxillin protein expression were determined pretreatment and posttreatment. Dose-response curves were constructed, and the combination index (CI) for drug interaction was calculated.
  
  
  RESULTS
  In the IGROV1 cells, dasatinib alone reduced phospho-SRC/total SRC 71% and p-paxillin/t-paxillin ratios 77%. Phospho-SRC (3%-33%; P = 0.002 to 0.04) and p-paxicillin (6%-19%; P = 0.01 to 0.05) levels were significantly reduced with dasatinib in combination with each cytotoxic agent. The combination of dasatinib and docetaxel, gemcitabine, or topotecan had a synergistic antiproliferative effect (CI, 0.49-0.68), whereas dasatinib combined with doxorubicin had an additive effect (CI, 1.08).In SKOV3 cells, dasatinib resulted in less pronounced reductions of phospho-SRC/total SRC (49%) and p-paxillin/t-paxillin (62%). Phospho-SRC (18%; P < 0.001) and p-paxillin levels (18%; P = 0.001; 9%; P = 0.007) were significantly decreased when dasatinib was combined with docetaxel and topotecan (p-paxillin only). Furthermore, dasatinib combined with the cytotoxics in the SKOV3 cells produced an antagonistic interaction on the proliferation of these cells (CI, 1.49-2.27).
  
  
  CONCLUSIONS
  Dasatinib in combination with relapse chemotherapeutic agents seems to interact in a synergistic or additive manner in cells with high SRC pathway activation and protein expression. Further evaluation of dasatinib in combination with chemotherapy in ovarian cancer animal models and exploration of the use of biomarkers to direct therapy are warranted.
authors.affiliation: *Division of Gynecologic Oncology, †Departments of Medicine, and ‡Medical Oncology, Duke Cancer Institute, Duke University Medical Center, Durham, NC.
authors.forename: Angeles Alvarez
authors.initials: AA
authors.lastname: Secord
authors.forename: Deanna
authors.initials: D
authors.lastname: Teoh
authors.forename: Jingquan
authors.initials: J
authors.lastname: Jia
authors.forename: Andrew B
authors.initials: AB
authors.lastname: Nixon
authors.forename: Lisa
authors.initials: L
authors.lastname: Grace
authors.forename: David J
authors.initials: DJ
authors.lastname: Adams
authors.forename: Susan K
authors.initials: SK
authors.lastname: Murphy
mesh_terms: D000970:Antineoplastic Agents / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000378:metabolism*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D000069439:Dasatinib; D003841:Deoxycytidine / Q000031:analogs & derivatives / Q000627:therapeutic use; D000077143:Docetaxel; D004317:Doxorubicin / Q000627:therapeutic use; D004354:Drug Screening Assays, Antitumor; D004357:Drug Synergism; D005260:Female; D006801:Humans; D051419:Paxillin / Q000378:metabolism; D011743:Pyrimidines / Q000494:pharmacology / Q000627:therapeutic use*; D015398:Signal Transduction / Q000235:genetics; D043823:Taxoids / Q000627:therapeutic use; D013844:Thiazoles / Q000494:pharmacology / Q000627:therapeutic use*; D019772:Topotecan / Q000627:therapeutic use; D019061:src-Family Kinases / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D000093542:Gemcitabine
chemical_list: D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D051419:Paxillin; D011743:Pyrimidines; D043823:Taxoids; D013844:Thiazoles; D003841:Deoxycytidine; D000077143:Docetaxel; D019772:Topotecan; D004317:Doxorubicin; D019061:src-Family Kinases; D000069439:Dasatinib; D000093542:Gemcitabine