Luteolin and gemcitabine protect against pancreatic cancer in an orthotopic mouse model

Objective: This study aimed to evaluate the ability of luteolin (Lut), gemcitabine (Gem), and their combination (Lut + Gem) to prevent the growth of pancreatic tumors in vivo. Methods: The antitumor effect of intraperitoneally administered Lut, Gem, and Lut + Gem was evaluated using an orthotopic mouse model for 6 weeks. Tumor growth after injection of human pancreatic cancer cells was assessed by measuring pancreatic tumor mass. The mechanism of action of antitumor effect was assessed by immunohistochemistry and Western blot procedures. Results: Luteolin + Gem significantly lowered (P = 0.048) the pancreatic tumor mass compared with control. Luteolin, Gem, and Lut + Gem significantly reduced the proliferating cell nuclear antigen expression (25%, 37%, and 37%, respectively). Luteolin + Gemtreatment led to a significant reduction in the expressions of K-ras (46%, P = 0.0006), GSK-3β (34%, P = 0.014), P(Tyr216)GSK-3β (16%, P = 0.033), P(Ser311)NF-κB p65 (27%, P = 0.036), and bcl-2/bax ratio (68%, P = 0.006) while significantly increasing the expressions of cytochrome c (44%, P = 0.035) and caspase 3 (417%, P = 0.003). Conclusions: Luteolin + Gem promoted apoptotic cell death in pancreatic tumor cells in vivo through inhibition of the K-ras/GSK-3β/NF-κB signaling pathway, leading to a reduction in the Bcl-2/Bax ratio, release of cytochrome c, and activation of caspase 3.