Ursolic acid enhances gemcitabine - induced apoptosis in bladder cancer via the PI3K/AKT and JNK signaling pathways

Abstract Background Gemcitabine (GEM) plays an important role in the chemotherapy of bladder cancer（BCa）. However, the chemoresistance and adverse effects of gemcitabine limit its effectiveness. Ursolic acid (UA) is a natural compound that exists in many natural medicinal plants and fruits, and has been demonstrated to enhance the efficacy of chemotherapy in multiple cancers. The present study aimed to observe the antitumor effects of a combination of GEM and UA in human bladder cancer cell lines, and to investigate the possible underlying mechanisms. Methods The human bladder cancer cell lines T24 and 5637 were treated with GEM and/or UA in vitro. Cell viability was measured by the Cell Counting Kit-8 assay. Apoptosis was detected by Hoechst 33258 staining, western blot and flow cytometry. Protein expression of signaling pathways was detected by western blot. Results UA synergistically inhibited proliferation with GEM in human bladder cancer cells. Compared with GEM treatment alone in T24 and 5637 cells, the combination of GEM and UA can enhance the antitumor effect. The PI3K/AKT and JNK signaling pathways are involved in human bladder cancer cells treated with GEM and UA. Both the Akt activator SC79 and the JNK inhibitor SP600125 reduced the expression of cleaved-PARP and cleaved-caspase3. Conclusions our present data demonstrated that UA enhanced GEM-induced apoptosis by inactivating the PI3K/AKT signaling pathway and activating the JNK signaling pathway. The combinational treatment strategy of GEM and UA may provide a potential rational basis for the clinical treatment of BCa.