β-Sitosterol and Gemcitabine Exhibit Synergistic Anti-pancreatic Cancer Activity by Modulating Apoptosis and Inhibiting Epithelial–Mesenchymal Transition by Deactivating Akt/GSK-3β Signaling

• Published in: Frontiers in pharmacology Vol. 9; p. 1525
• Main Authors: Cao, Zhang-qi, Wang, Xue-xi, Lu, Li, Xu, Jing-wen, Li, Xiao-bin, Zhang, Guang-ru, Ma, Zhan-jun, Shi, An-chen, Wang, Yan, Song, Yu-jun
• Format: Journal Article
• Language: English
• Published: Switzerland Frontiers Media S.A 08.01.2019
• Subjects: AKT; apoptosis; EMT; gemcitabine; pancreatic cancer; Pharmacology; β-sitosterol; GSK-3β; pancreatic cancer; β-sitosterol; apoptosis; AKT; gemcitabine; EMT
• ISSN: 1663-9812; 1663-9812
• DOI: 10.3389/fphar.2018.01525

β-sitosterol (BS), a major bioactive constituent present in plants, has shown potent anti-cancer activity against many human cancer cells, but its activity in pancreatic cancer (PC) cells has rarely been reported. Gemcitabine (GEM) is one of the first-line drugs for PC therapy, however, the treatment effect is not sustained due to prolonged drug resistance. In this study, we firstly studied the anti-PC activity and the mechanism of BS alone and in combination with GEM in vitro and in vivo . BS effectively inhibited the growth of PC cell lines by inhibiting proliferation, inducing G0/G1 phase arrest and apoptosis, suppressed the NF- kB activity, and increased expression of the protein Bax but decreased expression of the protein Bcl-2. Moreover, BS inhibited migration and invasion and downregulated epithelial–mesenchymal transition (EMT) markers and AKT/GSK-3β signaling pathways. Furthermore, the combination of BS and GEM exhibited a significant synergistic effect in MIAPaCa-2 and BXPC-3 cells. More importantly, the combined treatment with BS and GEM lead to significant growth inhibition of PC xenografts. Overall, our data revealed a promising treatment option for PC by the combination therapy of BS and GEM.