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    Ailanthone inhibits cell growth and migration of cisplatin resistant CORM-3 T cancer cells through down-regulation of Nrf2, YAP, and c-Myc expression.
    Martina Dagaa,1, Stefania Pizzimentia,1, , Chiara Dianzanib, Marie Angele Cuccia, Roberta Cavallib, Margherita Grattarolaa, Benedetta Ferrarab, Valentina Scariotd, Francesco Trottac,2, Giuseppina Barreraa,2
    a Department of Clinical and Biological Science, University of Turin, Corso Raffaello 30, 10125 Torino, Italy b Department of Drug Science and Technology, University of Turin, Via Pietro Giuria 9, 10125 Turin, Italy c Department of Chemistry, University of Turin, Via Pietro Giuria 7, 10125 Turin, Italy d Department of Agricultural, Forest and Food Sciences, University of Turin, Largo Paolo Braccini 2, 10095 Grugliasco (TO), Italy
    Bladder cancer
    Background: Ailanthone (Aila) is a natural active compound isolated from the Ailanthus altissima, which has been shown to possess an “in vitro” growth-inhibitory effect against several cancer cell lines. Advanced bladder cancer is a common disease characterized by a frequent onset of resistance to cisplatin-based therapy. The cisplatin (CDDP) resistance is accompanied by an increase in Nrf2 protein expression which contributes to conferring resistance. Recently, we demonstrated a cross-talk between Nrf2 and YAP. YAP has also been de-monstrated to play an important role in chemoresistance of bladder cancer.
    Purpose: We analyzed the antitumor effect of Aila in sensitive and CDDP-resistant bladder cancer cells and the molecular mechanisms involved in Aila activity.
    Study design: Sensitive and CDDP-resistant 253J B-V and 253J bladder cancer cells, intrinsically CDDP-resistant T24 bladder cancer cells and HK-2 human renal cortex cells were used. Cells were treated with diverse con-centrations of Aila and proliferation, cell cycle, apoptosis and gene expressions were determined. Methods: Aila toxicity and proliferation were determined by MTT and colony forming methods, respectively. Cell cycle was determined by cytofluorimetric analysis through PI staining method. Apoptosis was detected using Annexin V and PI double staining followed by quantitative flow cytometry. Expressions of Nrf2, Yap, c-Myc, and house-keeping genes were determined by western blot with specific antibodies. Cell migration was detected by wound healing and Boyden chamber analysis.
    Results: Aila inhibited the growth of sensitive and CDDP-resistant bladder cancer cells with the same effec-tiveness. On the contrary, the growth of HK-2 cells was only slightly reduced by Aila. Cell cycle analysis revealed an accumulation of Aila-treated bladder cancer cells in the G0/G1 phase. Interestingly, Aila strongly reduced Nrf2 expression in these cell lines. Moreover, Aila significantly reduced YAP, and c-Myc protein expression. The random and the oriented migration of bladder cancer cells were strongly inhibited by Aila treatment, in parti-cular in CDDP-resistant cells.
    Conclusion: Aila inhibited proliferation and invasiveness of bladder cancer cells. Its high effectiveness in CDDP resistant cells could be related to the inhibition of Nrf2, YAP, and c-Myc expressions. Aila could represent a new tool to treating CDDP-resistant bladder cancers.
    Abbreviation: Aila, ailanthone; CDDP, cisplatin; Nrf2, NF-E2-related factor 2; YAP, yes-associated protein; MTT, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenylte-trazolium bromide; Keap1, Kelch-like ECH-associated protein 1; ARE, antioxidant response element; EpRE, electrophile response element; RPMI 1640, Roswell Park Memorial Institute medium; FBS, fetal bovine serum; EDTA, ethylenediaminetetraacetic acid; SDS, sodium dodecyl sulfate; TBS, tris-buffered saline; GAPDH, gly-ceraldehyde 3 phosphate dehydrogenase; GSTA4, glutathione S-transferase A4; PI, propidium iodide; FITC, fluorescein isothiocyanate