PURPOSE: 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.
PURPOSE: 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: Louis J Lombardo; Francis Y Lee; Ping Chen; Derek Norris; Joel C Barrish; Kamelia Behnia; Stephen Castaneda; Lyndon A M Cornelius; Jagabandhu Das; Arthur M Doweyko; Craig Fairchild; John T Hunt; Ivan Inigo; Kathy Johnston; Amrita Kamath; David Kan; Herbert Klei; Punit Marathe; Suhong Pang; Russell Peterson; Sidney Pitt; Gary L Schieven; Robert J Schmidt; John Tokarski; Mei-Li Wen; John Wityak; Robert M Borzilleri Journal: J Med Chem Date: 2004-12-30 Impact factor: 7.446
Authors: Yoon-La Choi; Melanie Bocanegra; Mi Jeong Kwon; Young Kee Shin; Seok Jin Nam; Jung-Hyun Yang; Jessica Kao; Andrew K Godwin; Jonathan R Pollack Journal: Cancer Res Date: 2010-03-09 Impact factor: 12.701
Authors: Liz Y Han; Charles N Landen; Jose G Trevino; Jyotsnabaran Halder; Yvonne G Lin; Aparna A Kamat; Tae-Jin Kim; William M Merritt; Robert L Coleman; David M Gershenson; William C Shakespeare; Yihan Wang; Raji Sundaramoorth; Chester A Metcalf; David C Dalgarno; Tomi K Sawyer; Gary E Gallick; Anil K Sood Journal: Cancer Res Date: 2006-09-01 Impact factor: 12.701
Authors: Feng Roger Luo; Yu Chen Barrett; Zheng Yang; Amy Camuso; Kelly McGlinchey; Mei-Li Wen; Richard Smykla; Krista Fager; Robert Wild; Holly Palme; Susan Galbraith; Anne Blackwood-Chirchir; Francis Y Lee Journal: Cancer Chemother Pharmacol Date: 2008-02-27 Impact factor: 3.333
Authors: Jon R Wiener; T Christopher Windham; Veronica C Estrella; Nila U Parikh; Peter F Thall; Michael T Deavers; Robert C Bast; Gordon B Mills; Gary E Gallick Journal: Gynecol Oncol Date: 2003-01 Impact factor: 5.482
Authors: A P Algazi; J S Weber; S C Andrews; P Urbas; P N Munster; R C DeConti; J Hwang; V K Sondak; J L Messina; T McCalmont; A I Daud Journal: Br J Cancer Date: 2011-11-29 Impact factor: 7.640
Authors: I A McNeish; J A Ledermann; L Webber; L James; S B Kaye; M Hall; G Hall; A Clamp; H Earl; S Banerjee; R Kristeleit; F Raja; A Feeney; C Lawrence; L Dawson-Athey; M Persic; I Khan Journal: Ann Oncol Date: 2014-07-28 Impact factor: 32.976
Authors: Niharika B Mettu; Donna Niedzwiecki; Christel Rushing; Andrew B Nixon; Jingquan Jia; Sherri Haley; Wanda Honeycutt; Herbert Hurwitz; Johanna C Bendell; Hope Uronis Journal: Cancer Chemother Pharmacol Date: 2019-03-20 Impact factor: 3.333
Authors: R Manek; E Pakzamir; P Mhawech-Fauceglia; T Pejovic; H Sowter; S A Gayther; K Lawrenson Journal: Oncogenesis Date: 2016-08-15 Impact factor: 7.485
Authors: Samia Mohammed; Achraf A Shamseddine; Benjamin Newcomb; Ronald S Chavez; Tyler D Panzner; Allen H Lee; Daniel Canals; Chioma M Okeoma; Christopher J Clarke; Yusuf A Hannun Journal: Breast Cancer Res Date: 2021-07-27 Impact factor: 6.466