Ailanthone inhibits cell growth and migration of cisplatin resistant bladder cancer cells through down-regulation of Nrf2, YAP, and c-Myc expression.
Adaptor Proteins, Signal Transducing
/ metabolism
Antineoplastic Agents
/ pharmacology
Apoptosis
/ drug effects
Cell Cycle
/ drug effects
Cell Line, Tumor
Cell Movement
/ drug effects
Cell Proliferation
/ drug effects
Cisplatin
/ pharmacology
Down-Regulation
/ drug effects
Drug Resistance, Neoplasm
/ drug effects
Humans
NF-E2-Related Factor 2
/ metabolism
Phosphoproteins
/ metabolism
Proto-Oncogene Proteins c-myc
/ metabolism
Quassins
/ pharmacology
Transcription Factors
Urinary Bladder Neoplasms
/ drug therapy
YAP-Signaling Proteins
Ailanthone
Bladder cancer
C-Myc
CDDP-resistance
Nrf2
Yap
Journal
Phytomedicine : international journal of phytotherapy and phytopharmacology
ISSN: 1618-095X
Titre abrégé: Phytomedicine
Pays: Germany
ID NLM: 9438794
Informations de publication
Date de publication:
15 Mar 2019
15 Mar 2019
Historique:
received:
18
07
2018
revised:
22
10
2018
accepted:
27
10
2018
pubmed:
23
1
2019
medline:
21
5
2019
entrez:
23
1
2019
Statut:
ppublish
Résumé
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. We analyzed the antitumor effect of Aila in sensitive and CDDP-resistant bladder cancer cells and the molecular mechanisms involved in Aila activity. 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. 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. 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. 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.
Sections du résumé
BACKGROUND
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
OBJECTIVE
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
METHODS
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
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
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
CONCLUSIONS
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.
Identifiants
pubmed: 30668336
pii: S0944-7113(18)30554-3
doi: 10.1016/j.phymed.2018.10.034
pii:
doi:
Substances chimiques
Adaptor Proteins, Signal Transducing
0
Antineoplastic Agents
0
MYC protein, human
0
NF-E2-Related Factor 2
0
NFE2L2 protein, human
0
Phosphoproteins
0
Proto-Oncogene Proteins c-myc
0
Quassins
0
Transcription Factors
0
YAP-Signaling Proteins
0
YAP1 protein, human
0
ailanthone
981-15-7
Cisplatin
Q20Q21Q62J
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
156-164Informations de copyright
Copyright © 2018. Published by Elsevier GmbH.