Luteoloside Suppresses Proliferation and Metastasis of Hepatocellular Carcinoma Cells by Inhibition of NLRP3 Inflammasome

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.

Comparison of Lipoxygenase, Cyclooxygenase, Xanthine Oxidase Inhibitory Effects and Cytotoxic Activities of Selected Flavonoids

“…It was noted that catechin, epicatechin, puerarin and all the selected flavonoid glycosides at concentration up to 50 µM caused no more than 50% growth inhibition of MCF7, PC3, MGC803 and VERO cells. It were quite similar with previous report: compared to quercetin and luteolin, their glycosides rutin and luteoloside, respectively showed no significant growth inhibitory effects on cancer cells at concentration up to 50 µM [16,17] showing that the sugar moiety strongly affects the bioactivity of flavonoids. Meanwhile, apigenin, diosmetin, quercetin and luteolin in our study showed relatively good toxic effect in a dose-dependent manner, and the IC50 values were presented in Table 4.…”

Long Non-Coding RNA KCNQ1OT1 Promotes Cataractogenesis via miR-214 and Activation of the Caspase-1 Pathway

“…Apoptosis of lens epithelial cells is a common cellular mechanism of initiation and progression for noncongenital cataracts [25]. Apoptosis is the most widely recognized programme of cell death [26], but other cell death programmes, such as autophagy, oncosis and pyroptosis, are also involved in occurrence and development of diseases [27,28]. Our previous studies indicate that pyroptosis is implicated in the regulation of cataract formation.…”

Luteoloside Inhibits Proliferation of Human Chronic Myeloid Leukemia K562 Cells by Inducing G2/M Phase Cell Cycle Arrest and Apoptosis

“…In addition, toxicity evaluation on the normal cell HUVEC12 revealed only minor decrease in cell viability at the tested concentrations with an IC 50 of 91.8 μM for 72 h treatment. In contrast, luteoloside suppressed proliferation of several hepatocellular carcinoma cells [10], colon carcinoma cell COLO 320 DM and normal cell VERO [5] also in a dose-and time-dependent manner with IC 50 of about 75, 112.4 and 724 μM, respectively, for 72 h incubation. Therefore, the cytotoxic effects of luteoloside on K562 are in high efficiency and specific to some extent.…”

“…In this study, it is revealed that luteoloside can induce cell cycle arrest and apoptosis concomitantly with growth suppression of K562 cells. Thus, luteoloside has exhibited its anti-cancer effects not only on solid tumors [5,9,10] but also on blood malignancy.…”

“…Luteoloside, a natural flavone subclass derived from plants, has exhibited a series of biological activities, such as potential antibacterial and antifungal [4], free radical scavenging [5], anti-oxidative capabilities [6,7], protection effects against doxorubicininduced cardiotoxicity [8], and anticarcinogenic potential against colon carcinogenesis [5] and hepatocellular carcinoma [9,10], etc. However, the effects of luteoloside on blood malignancy have not been reported.…”