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Luteoloside suppresses proliferation and metastasis of hepatocellular carcinoma cells by inhibition of NLRP3 inflammasome.

Fan SH, Wang YY, Lu J, Zheng YL, Wu DM, Li MQ, Hu B, Zhang ZF, Cheng W, Shan Q - PLoS ONE (2014)

Bottom Line: Further studies showed that luteoloside could significantly reduce the intracellular reactive oxygen species (ROS) accumulation.The decreased levels of ROS induced by luteoloside was accompanied by decrease in expression of NLRP3 inflammasome resulting in decrease in proteolytic cleavage of caspase-1.Inactivation of caspase-1 by luteoloside resulted in inhibition of IL-1β.

View Article: PubMed Central - PubMed

Affiliation: Key Laboratory for Biotechnology on Medicinal Plants of Jiangsu Province, School of Life Science, Jiangsu Normal University, Xuzhou, Jiangsu, China.

ABSTRACT
The inflammasome is a multi-protein complex which when activated regulates caspase-1 activation and IL-1β secretion. Inflammasome activation is mediated by NLR proteins that respond to stimuli. Among NLRs, NLRP3 senses the widest array of stimuli. NLRP3 inflammasome plays an important role in the development of many cancer types. However, Whether NLRP3 inflammasome plays an important role in the process of hepatocellular carcinoma (HCC) is still unknown. Here, the anticancer effect of luteoloside, a naturally occurring flavonoid isolated from the medicinal plant Gentiana macrophylla, against HCC cells and the underlying mechanisms were investigated. Luteoloside significantly inhibited the proliferation of HCC cells in vitro and in vivo. Live-cell imaging and transwell assays showed that the migration and invasive capacities of HCC cells, which were treated with luteoloside, were significantly inhibited compared with the control cells. The inhibitory effect of luteoloside on metastasis was also observed in vivo in male BALB/c-nu/nu mouse lung metastasis model. Further studies showed that luteoloside could significantly reduce the intracellular reactive oxygen species (ROS) accumulation. The decreased levels of ROS induced by luteoloside was accompanied by decrease in expression of NLRP3 inflammasome resulting in decrease in proteolytic cleavage of caspase-1. Inactivation of caspase-1 by luteoloside resulted in inhibition of IL-1β. Thus, luteoloside exerts its inhibitory effect on proliferation, invasion and metastasis of HCC cells through inhibition of NLRP3 inflammasome. Our results indicate that luteoloside can be a potential therapeutic agent not only as an adjuvant therapy for HCC, but also, in the control and prevention of metastatic HCC.

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Luteoloside inhibits proliferation of HCC cells.(A) HPLC analysis of the purity of luteoloside used in the present study. Insert: The chemical structure of luteoloside. (B)–(C), comparative dose- and time-dependent effect of luteoloside on the proliferation potential of HCC cells. The percentage of cell viability in different treatment groups was determined using Cell Counting Kit-8 assay. *, P<0.05; **, P<0.01; ***, P<0.001; NS, not significant (P>0.05), versus non-luteoloside-treated control group.
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pone-0089961-g001: Luteoloside inhibits proliferation of HCC cells.(A) HPLC analysis of the purity of luteoloside used in the present study. Insert: The chemical structure of luteoloside. (B)–(C), comparative dose- and time-dependent effect of luteoloside on the proliferation potential of HCC cells. The percentage of cell viability in different treatment groups was determined using Cell Counting Kit-8 assay. *, P<0.05; **, P<0.01; ***, P<0.001; NS, not significant (P>0.05), versus non-luteoloside-treated control group.

Mentions: Luteoloside (Fig. 1A, Batch Number: 025-120622, Purity = 99.7%, purchased from Chengdu Herbpurify Co., Ltd., Chengdu, China), a naturally occurring flavonoid isolated from the medicinal plant Gentiana macrophylla, was dissolved at a concentration of 20 mM in 100% DMSO as a stock solution, stored at −20°C, and diluted with medium before each experiment. The final DMSO concentration did not exceed 0.1% throughout the study.


Luteoloside suppresses proliferation and metastasis of hepatocellular carcinoma cells by inhibition of NLRP3 inflammasome.

Fan SH, Wang YY, Lu J, Zheng YL, Wu DM, Li MQ, Hu B, Zhang ZF, Cheng W, Shan Q - PLoS ONE (2014)

Luteoloside inhibits proliferation of HCC cells.(A) HPLC analysis of the purity of luteoloside used in the present study. Insert: The chemical structure of luteoloside. (B)–(C), comparative dose- and time-dependent effect of luteoloside on the proliferation potential of HCC cells. The percentage of cell viability in different treatment groups was determined using Cell Counting Kit-8 assay. *, P<0.05; **, P<0.01; ***, P<0.001; NS, not significant (P>0.05), versus non-luteoloside-treated control group.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3935965&req=5

pone-0089961-g001: Luteoloside inhibits proliferation of HCC cells.(A) HPLC analysis of the purity of luteoloside used in the present study. Insert: The chemical structure of luteoloside. (B)–(C), comparative dose- and time-dependent effect of luteoloside on the proliferation potential of HCC cells. The percentage of cell viability in different treatment groups was determined using Cell Counting Kit-8 assay. *, P<0.05; **, P<0.01; ***, P<0.001; NS, not significant (P>0.05), versus non-luteoloside-treated control group.
Mentions: Luteoloside (Fig. 1A, Batch Number: 025-120622, Purity = 99.7%, purchased from Chengdu Herbpurify Co., Ltd., Chengdu, China), a naturally occurring flavonoid isolated from the medicinal plant Gentiana macrophylla, was dissolved at a concentration of 20 mM in 100% DMSO as a stock solution, stored at −20°C, and diluted with medium before each experiment. The final DMSO concentration did not exceed 0.1% throughout the study.

Bottom Line: Further studies showed that luteoloside could significantly reduce the intracellular reactive oxygen species (ROS) accumulation.The decreased levels of ROS induced by luteoloside was accompanied by decrease in expression of NLRP3 inflammasome resulting in decrease in proteolytic cleavage of caspase-1.Inactivation of caspase-1 by luteoloside resulted in inhibition of IL-1β.

View Article: PubMed Central - PubMed

Affiliation: Key Laboratory for Biotechnology on Medicinal Plants of Jiangsu Province, School of Life Science, Jiangsu Normal University, Xuzhou, Jiangsu, China.

ABSTRACT
The inflammasome is a multi-protein complex which when activated regulates caspase-1 activation and IL-1β secretion. Inflammasome activation is mediated by NLR proteins that respond to stimuli. Among NLRs, NLRP3 senses the widest array of stimuli. NLRP3 inflammasome plays an important role in the development of many cancer types. However, Whether NLRP3 inflammasome plays an important role in the process of hepatocellular carcinoma (HCC) is still unknown. Here, the anticancer effect of luteoloside, a naturally occurring flavonoid isolated from the medicinal plant Gentiana macrophylla, against HCC cells and the underlying mechanisms were investigated. Luteoloside significantly inhibited the proliferation of HCC cells in vitro and in vivo. Live-cell imaging and transwell assays showed that the migration and invasive capacities of HCC cells, which were treated with luteoloside, were significantly inhibited compared with the control cells. The inhibitory effect of luteoloside on metastasis was also observed in vivo in male BALB/c-nu/nu mouse lung metastasis model. Further studies showed that luteoloside could significantly reduce the intracellular reactive oxygen species (ROS) accumulation. The decreased levels of ROS induced by luteoloside was accompanied by decrease in expression of NLRP3 inflammasome resulting in decrease in proteolytic cleavage of caspase-1. Inactivation of caspase-1 by luteoloside resulted in inhibition of IL-1β. Thus, luteoloside exerts its inhibitory effect on proliferation, invasion and metastasis of HCC cells through inhibition of NLRP3 inflammasome. Our results indicate that luteoloside can be a potential therapeutic agent not only as an adjuvant therapy for HCC, but also, in the control and prevention of metastatic HCC.

Show MeSH
Related in: MedlinePlus