Koumine Promotes ROS Production to Suppress Hepatocellular Carcinoma Cell Proliferation Via NF-κB and ERK/p38 MAPK Signaling

Abstract

In the past decades, hepatocellular carcinoma (HCC) has been receiving increased attention due to rising morbidity and mortality in both developing and developed countries. Koumine, one of the significant alkaloidal constituents of Gelsemium elegans Benth., has been regarded as a promising anti-inflammation, anxiolytic, and analgesic agent, as well as an anti-tumor agent. In the present study, we attempted to provide a novel mechanism by which koumine suppresses HCC cell proliferation. We demonstrated that koumine might suppress the proliferation of HCC cells and promote apoptosis in HCC cells dose-dependently. Under koumine treatment, the mitochondria membrane potential was significantly decreased while reactive oxygen species (ROS) production was increased in HCC cells; in the meantime, the phosphorylation of ERK, p38, p65, and IκBα could all be inhibited by koumine treatment dose-dependently. More importantly, the effects of koumine upon mitochondria membrane potential, ROS production, and the phosphorylation of ERK, p38, p65, and IκBα could be significantly reversed by ROS inhibitor, indicating that koumine affects HCC cell fate and ERK/p38 MAPK and NF-κB signaling activity through producing excess ROS. In conclusion, koumine could inhibit the proliferation of HCC cells and promote apoptosis in HCC cells; NF-κB and ERK/p38 MAPK pathways could contribute to koumine functions in a ROS-dependent manner.

Koumine Suppresses IL-1β Secretion and Attenuates Inflammation Associated With Blocking ROS/NF-κB/NLRP3 Axis in Macrophages

“…Emerging evidence has demonstrated that NF-κB plays a pivotal role in the inflammatory response and NLRP3 inflammasome activation ( Liu et al, 2017a ; Mahmoud et al, 2019 ). Moreover, KM is reportedly effective in inhibiting NF-κB signaling ( Yuan et al, 2019a ; Wu et al, 2020 ). To investigate whether the KM-induced suppression of NLRP3 inflammasome activation depends on the NF-κB pathway and affects LPS-induced priming, we analyzed the protein levels and nuclear localization of molecules related to the NF-κB pathway.…”

“…Koumine (KM) is a type of alkaloid derived from Gelsemium elegans, which is used as a traditional medicinal plant in China and other Asian countries ( Jin et al, 2014 ). Recent studies have demonstrated that KM has diverse pharmacological activities, including anti-psoriatic, anti-inflammatory, anti-tumor, analgesic, antioxidant and anxiolytic activities ( Xu et al, 2012 ; Chen et al, 2017 ; Jin et al, 2018b ; Jin et al, 2019 ; Yuan et al, 2019a ; Yuan et al, 2019b ; Wu et al, 2020 ). Numerous studies have shown that KM exerts anti-inflammatory effects by inhibiting the production of reactive oxygen species (ROS), regulating the Nrf2/NF-κB signaling pathway and decreasing the production of IL-1β, IL-6, TNF-α and nitric oxide ( Yuan et al, 2016a ; Wu et al, 2020 ).…”

Orally Administered Koumine Persists Longer in the Plasma of Aged Rats Than That of Adult Rats as Assessed by Ultra-Performance Liquid Chromatography-Tandem Mass Spectrometry

“…Koumine (KM), the most abundant alkaloid in Gelsemium elegans Benth. ( G. elegans ) has various pharmacological properties and is known to be effective in the treatment of numerous age-associated conditions including postoperative pain ( Xiong et al., 2017 ; Shoaib et al., 2019 ), inflammation ( Yuan et al., 2016 ; Wu et al., 2020 ), rheumatoid arthritis ( Yang et al., 2016 ), malignant tumors ( Yuan et al., 2019a ), nonalcoholic fatty liver disease ( Yue et al., 2019 ), oxidative stress ( Yuan et al., 2019b ), and neuropathic pain ( Jin et al., 2018a ; Jin et al., 2018b ). However, the pharmacokinetic profile of KM in the elderly or aged animals remains to be fully evaluated.…”

Anti‑inflammatory mechanism of berberine on lipopolysaccharide‑induced IEC‑18 models based on comparative transcriptomics

“…Subsequent phosphorylation of a set of iκBs results in their degradation and ubiquitination, releasing nF-κB factor, which can then translocate to the nucleus. MaPKs are highly conserved protein threonine/serine kinases, and three major subfamilies, including extracellular signal-regulating kinases (erKs) 1 and 2, JnK and p38, have been found in mammalian cells (59)(60)(61). MaPKs have been demonstrated to be involved in pro-inflammatory signaling pathways, and abundant evidence has demonstrated that the activation of erK1/2, JnK and p38 is involved in the upregulation of TnF-α, inducible nitric oxide synthase, il-6 and coX-2 in lPS-activated macrophages.…”