Santamarine Inhibits NF-кB and STAT3 Activation and Induces Apoptosis in HepG2 Liver Cancer Cells via Oxidative Stress.

Abstract

Sesquiterpene lactones have long been used in traditional Chinese medicines to treat inflammatory diseases. Recently, sesquiterpene lactone family compounds have been recognized as potential anticancer agents. Thus, it is necessary to explore new sesquiterpene lactones and their antitumor mechanism for cancer treatments. In the present study, we have explored the potential anti-cancer activity of a novel sesquiterpene lactone compound “santamarine” (STM) in HepG2 cells. It inhibited proliferation and induced apoptosis dose-dependently with IC50 ~ 70 μM. Induction of apoptosis was found to be linked with increased reactive oxygen species (ROS) generation, decreased activity of thioredoxin reductase (TrxR), glutathione (GSH) depletion, mitochondrial membrane potential (ΔΨm) dissipation, Bcl-2 family proteins modulation, cytochrome c release, caspases-9, -8 and -3 activation and PARP cleavage. Further mechanistic study demonstrated that STM inhibited the constitutive and TNF-α-induced translocation of NF-кB into nucleus by decreasing phosphorylation of IkB-α. Moreover, STM inhibited STAT3 activation by decreasing phosphorylation at tyrosine705. NAC pretreatment reversed the effect of STM-mediated cell death, NF-кB inhibition and blockage of STAT3 activity, indicating the involvement of oxidative stress in STM-mediated anticancer activity. Further studies are needed to explore the exact molecular mechanism of STM-induced apoptosis to develop it into a lead for treatment of liver cancer in future.

SANTAMARINE: Mechanistic studies on multiple diseases

“…Studies identified STM as a novel ROS-based anticancer compound during screening process. STM induced ROS generation and reduced the GSH/ GSSG ratio and TrxR activity in HepG2 cells (Mehmood et al, 2017) and A549 cells (Wu et al, 2017) in dose-and time-dependent manners, which were reversed by NAC pretreatment ( Figure 2 and Table 1).…”

“…Natural products inhibit the functions of STAT3 through different mechanism in vitro and in vivo, such as 2‐methoxystypandrone and cryptotanshinone (Kuang et al, ; Liu et al, ). STM inhibited STAT3 activation at Y705 and Src phosphorylation, which was reversed by NAC pretreatment in HepG2 cells (Mehmood et al, ).…”

“…For the mechanisms, an induction of intrinsic apoptosis could be considered due to the upregulation of pro‐apoptotic proteins including BAX, BAD, the downregulation of anti‐apoptotic protein Bcl‐2, the release of cytochrome c, the activation of caspase‐9 and caspase‐3, and the cleavage of PARP. Furthermore, STM induces extrinsic apoptosis in HepG2 cells through caspase‐8 activation and Bid cleavage (Mehmood et al, ). Similar results were obtained in another study using A549 lung adenocarcinoma cells (Wu et al, ).…”

“…Furthermore, IкB kinase (IKK) inhibitor IKK‐16 showed similar effects as STM. Therefore, STM inhibits both constitutive and TNF‐α‐induced activation of NF‐κB through ROS generation (Mehmood et al, ; Wu et al, ) (Figure and Table ).…”

“…Siculum (Rosselli et al, ) , rhizomes of Costus speciosus (Al‐Attas, El‐Shaer, Mohamed, Ibrahim, & Esmat, ), aerial parts of Ambrosia confertiflora (Coronado‐Aceves et al, ), roots of I. helenium (Li et al, ), and roots of Saussurea lappa (Choi et al, ) (Figure ). Various studies reported the effects of STM, including anticancer (Ma, Chong, Li, Cheung, & Tattersall, ; Mehmood, Maryam, Tian, Khan, & Ma, ; Wu, Zhu, Yan, Khan, & Yu, ), anti‐inflammatory (Matsuda et al, ), antibacterial (Sun, Syu, Don, Lu, & Lee, ), and anti‐ethanol activities (Matsuda, Shimoda, Uemura, & Yoshikawa, ). In this review, we summarize the original sources of STM, and its mechanistic biological studies and medicinal uses to provide a reference for the application to diseases.…”