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Ailanthone inhibits cell growth and migration of cisplatin resistant bladder cancer cells through down-regulation of Nrf2, YAP, and c-Myc expression.
Phytomedicine 2019; 56:156-164P

Abstract

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 demonstrated 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 concentrations 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 effectiveness. 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 particular 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.

Authors+Show Affiliations

Department of Clinical and Biological Science, University of Turin, Corso Raffaello 30, 10125 Torino, Italy.Department of Clinical and Biological Science, University of Turin, Corso Raffaello 30, 10125 Torino, Italy. Electronic address: stefania.pizzimenti@unito.it.Department of Drug Science and Technology, University of Turin, Via Pietro Giuria 9, 10125 Turin, Italy.Department of Clinical and Biological Science, University of Turin, Corso Raffaello 30, 10125 Torino, Italy.Department of Drug Science and Technology, University of Turin, Via Pietro Giuria 9, 10125 Turin, Italy.Department of Clinical and Biological Science, University of Turin, Corso Raffaello 30, 10125 Torino, Italy.Department of Drug Science and Technology, University of Turin, Via Pietro Giuria 9, 10125 Turin, Italy.Department of Agricultural, Forest and Food Sciences, University of Turin, Largo Paolo Braccini 2, 10095 Grugliasco (TO), Italy.Department of Chemistry, University of Turin, Via Pietro Giuria 7, 10125 Turin, Italy.Department of Clinical and Biological Science, University of Turin, Corso Raffaello 30, 10125 Torino, Italy.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

30668336

Citation

Daga, Martina, et al. "Ailanthone Inhibits Cell Growth and Migration of Cisplatin Resistant Bladder Cancer Cells Through Down-regulation of Nrf2, YAP, and c-Myc Expression." Phytomedicine : International Journal of Phytotherapy and Phytopharmacology, vol. 56, 2019, pp. 156-164.
Daga M, Pizzimenti S, Dianzani C, et al. Ailanthone inhibits cell growth and migration of cisplatin resistant bladder cancer cells through down-regulation of Nrf2, YAP, and c-Myc expression. Phytomedicine. 2019;56:156-164.
Daga, M., Pizzimenti, S., Dianzani, C., Cucci, M. A., Cavalli, R., Grattarola, M., ... Barrera, G. (2019). Ailanthone inhibits cell growth and migration of cisplatin resistant bladder cancer cells through down-regulation of Nrf2, YAP, and c-Myc expression. Phytomedicine : International Journal of Phytotherapy and Phytopharmacology, 56, pp. 156-164. doi:10.1016/j.phymed.2018.10.034.
Daga M, et al. Ailanthone Inhibits Cell Growth and Migration of Cisplatin Resistant Bladder Cancer Cells Through Down-regulation of Nrf2, YAP, and c-Myc Expression. Phytomedicine. 2019 Mar 15;56:156-164. PubMed PMID: 30668336.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Ailanthone inhibits cell growth and migration of cisplatin resistant bladder cancer cells through down-regulation of Nrf2, YAP, and c-Myc expression. AU - Daga,Martina, AU - Pizzimenti,Stefania, AU - Dianzani,Chiara, AU - Cucci,Marie Angele, AU - Cavalli,Roberta, AU - Grattarola,Margherita, AU - Ferrara,Benedetta, AU - Scariot,Valentina, AU - Trotta,Francesco, AU - Barrera,Giuseppina, Y1 - 2018/10/29/ PY - 2018/07/18/received PY - 2018/10/22/revised PY - 2018/10/27/accepted PY - 2019/1/23/pubmed PY - 2019/5/21/medline PY - 2019/1/23/entrez KW - Ailanthone KW - Bladder cancer KW - C-Myc KW - CDDP-resistance KW - Nrf2 KW - Yap SP - 156 EP - 164 JF - Phytomedicine : international journal of phytotherapy and phytopharmacology JO - Phytomedicine VL - 56 N2 - 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 demonstrated 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 concentrations 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 effectiveness. 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 particular 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. SN - 1618-095X UR - https://www.unboundmedicine.com/medline/citation/30668336/Ailanthone_inhibits_cell_growth_and_migration_of_cisplatin_resistant_bladder_cancer_cells_through_down_regulation_of_Nrf2_YAP_and_c_Myc_expression_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0944-7113(18)30554-3 DB - PRIME DP - Unbound Medicine ER -