Synergistic effect of Sorafenib and Sunitinib with Enzastaurin, a selective protein kinase C inhibitor in renal cell carcinoma cell lines.
Enzastaurin (LY317615.HCl) is an oral selective PKC-beta inhibitor with antiproliferative efficacy in various tumor models. This study was designed to investigate whether combination therapy with Enzastaurin and other targeted agents including Sorafenib and Sunitinib enhanced anti-tumor efficacy in renal cell carcinoma cell lines. Enzastaurin alone presented not active in renal cell carcinoma cell lines. Both Sorafenib and Sunitinib with Enzastaurin at concentrations feasible in vivo showed a synergistic reduction of viable RCC cells by inhibiting cell growth through inhibition of phospho-S6-kinase and GSK3-beta. The combination of Enzastaurin with Sorafenib and Sunitinib seems highly encouraging and warrants further investigation in vivo.
Vogl
Ursula Maria
UM
Clinical Division of Oncology, Department of Medicine I, Medical University Vienna, Waehringer Guertel 18-20, Vienna, Austria. ursula.vogl@meduniwien.ac.at
Berger
Walter
W
Micksche
Michael
M
Pirker
Christine
C
Lamm
Wolfgang
W
Pichelmeyer
Oskar
O
Zielinski
Christoph C
CC
Schmidinger
Manuela
M
D000970:Antineoplastic Agents / Q000494:pharmacology*; D001557:Benzenesulfonates / Q000494:pharmacology*; D002292:Carcinoma, Renal Cell; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D019008:Drug Resistance, Neoplasm; D004357:Drug Synergism; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D007211:Indoles / Q000494:pharmacology*; D009536:Niacinamide / Q000031:analogs & derivatives; D010671:Phenylurea Compounds; D011493:Protein Kinase C; D064546:Protein Kinase C beta; D011725:Pyridines / Q000494:pharmacology*; D011758:Pyrroles / Q000494:pharmacology*; D019893:Ribosomal Protein S6 Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D015398:Signal Transduction; D000077157:Sorafenib; D000077210:Sunitinib
D000970:Antineoplastic Agents; D001557:Benzenesulfonates; D007211:Indoles; D010671:Phenylurea Compounds; D011725:Pyridines; D011758:Pyrroles; D009536:Niacinamide; D000077157:Sorafenib; D000071679:Glycogen Synthase Kinase 3 beta; D019893:Ribosomal Protein S6 Kinases; D011493:Protein Kinase C; D064546:Protein Kinase C beta; D038362:Glycogen Synthase Kinase 3; C504878:enzastaurin; D000077210:Sunitinib