Luteolin suppresses bladder cancer growth via regulation of mechanistic target of rapamycin pathway

Abstract

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 cellcycle 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-3ʹ-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-3ʹ-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. K E Y W O R D Sanimal model, bladder cancer, chemoprevention, mTOR, oxidative stress

Anti-Cancer Potential of Cannabinoids, Terpenes, and Flavonoids Present in Cannabis

“…Caused cell cycle arrest [362,[374][375][376][377]. Decreased cell viability and proliferation [378][379][380][381][382][383].…”

“…Bladder cancer cell survival was inhibited by luteolin by inducing G2/M cell cycle arrest, p21 upregulation and inhibition of mTOR signalling. In xenograft models, tumor volumes and dimensions were decreased after oral administration of luteolin [377]. When combined with the anticancer agent oxaliplatin, luteolin inhibited gastric cancer cell proliferation and induced apoptosis through the cytochrome-c and caspase pathways and by altering the cell cycle [391].…”

The Hallmarks of Flavonoids in Cancer

“…Decreased PI3K, AKT, and mTOR phosphorylation were also observed in human breast cancer cells at 50 µM for 48 h [ 210 ]. Remarkably, Myricetin [ 241 , 242 ], Apigenin [ 243 , 244 ] and its derivative Vitexin [ 206 , 207 ], Luteolin [ 226 , 228 , 245 ], Eriotyctiol [ 62 , 209 ], Taxifolin [ 216 , 246 , 247 ], Naringenin [ 248 , 249 ], EGCG [ 215 , 250 , 251 ], and Cyanidin [ 252 , 253 , 254 ] also decreased AKT phosphorylation and mTOR effectors in several cancer models, avoiding this feedback activation loop.…”

Natural compound rhein suppresses colorectal cancer cells growth through mTOR/p70S6 kinase pathway in vitro and in vivo

“…The Akt/mTOR signaling is essential for the proliferation, metabolism and angiogenesis [31]. Studies have reported that inhibition of mTOR effectively suppressed tumor growth in several cancers, including bladder [32], breast [33], pancreatic [34,35], and colon [6,9] cancers. mTORC1 and mTORC2 are the two different complexes of mTOR.…”