Luteolin suppresses bladder cancer growth via regulation of mechanistic target of rapamycin pathway.
Animals
Apoptosis
/ drug effects
Butylhydroxybutylnitrosamine
/ toxicity
Cell Line, Tumor
Cell Proliferation
/ drug effects
Disease Models, Animal
Gene Expression Regulation, Neoplastic
/ drug effects
Humans
Ki-67 Antigen
/ genetics
Luteolin
/ metabolism
Male
Mice
Proto-Oncogene Proteins c-akt
/ genetics
Rats
Signal Transduction
/ drug effects
TOR Serine-Threonine Kinases
/ genetics
Thioredoxins
/ genetics
Urinary Bladder Neoplasms
/ chemically induced
Xenograft Model Antitumor Assays
rho GTP-Binding Proteins
/ genetics
animal model
bladder cancer
chemoprevention
mTOR
oxidative stress
Journal
Cancer science
ISSN: 1349-7006
Titre abrégé: Cancer Sci
Pays: England
ID NLM: 101168776
Informations de publication
Date de publication:
Apr 2020
Apr 2020
Historique:
received:
15
08
2019
revised:
10
01
2020
accepted:
14
01
2020
pubmed:
30
1
2020
medline:
23
4
2020
entrez:
30
1
2020
Statut:
ppublish
Résumé
Luteolin is a natural flavonoid with strong anti-oxidative properties that is reported to have an anti-cancer effect in several malignancies other than bladder cancer. In this study, we describe the effect of luteolin on a human bladder cancer cell line, T24, in the context of the regulation of p21, thioredoxin-1 (TRX1) and the mechanistic target of rapamycin (mTOR) pathway. Luteolin inhibited cell survival and induced G2/M cell-cycle arrest, p21 upregulation and downregulation of phospho(p)-S6, which is downstream of mTOR signaling. Luteolin also upregulated TRX1 and reduced intracellular reactive oxygen species production. In a subcutaneous xenograft mouse model using the rat bladder cancer cell line, BC31, tumor volumes were significantly decreased in mice orally administered luteolin compared to control. Immunohistochemical analysis revealed that increased p21 and decreased p-S6 expression were induced in the luteolin treatment group. Moreover, in another in vivo N-butyl-N-(4-hydroxybutyl) nitrosamine (BBN)-induced rat bladder cancer model, the oral administration of luteolin led to a trend of decreased bladder tumor dimension and significantly decreased the Ki67-labeling index and p-S6 expression. Furthermore, the major findings on the metabolism of luteolin suggest that both plasma and urine luteolin-3'-O-glucuronide concentrations are strongly associated with the inhibition of cell proliferation and mTOR signaling. Moreover, a significant decrease in the squamous differentiation of bladder cancer is attributed to plasma luteolin-3'-glucuronide concentration. In conclusion, luteolin, and in particular its metabolized product, may represent another natural product-derived therapeutic agent that acts against bladder cancer by upregulating p21 and inhibiting mTOR signaling.
Identifiants
pubmed: 31994822
doi: 10.1111/cas.14334
pmc: PMC7156788
doi:
Substances chimiques
Ki-67 Antigen
0
MKI67 protein, human
0
TXN protein, human
0
Txn1 protein, rat
0
Butylhydroxybutylnitrosamine
3817-11-6
Thioredoxins
52500-60-4
mTOR protein, rat
EC 2.7.1.1
Proto-Oncogene Proteins c-akt
EC 2.7.11.1
TOR Serine-Threonine Kinases
EC 2.7.11.1
rho GTP-Binding Proteins
EC 3.6.5.2
Luteolin
KUX1ZNC9J2
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
1165-1179Subventions
Organisme : TOBE MAKI Scholarship Foundation
ID : 18-JA-501
Organisme : Aichi Health Promotion Fundation
ID : 30127
Organisme : Ministry of Health, Labour and Welfare
ID : 18K16705
Informations de copyright
© 2020 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.
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