Artemisia annua L. Polyphenol-Induced Cell Death Is ROS-Independently Enhanced by Inhibition of JNK in HCT116 Colorectal Cancer Cells

Abstract

c-Jun N-terminal kinase (JNK) is activated by chemotherapeutic reagents including natural plant polyphenols, and cell fate is determined by activated phospho-JNK as survival or death depending on stimuli and cell types. The purpose of this study was to elucidate the role of JNK on the anticancer effects of the Korean plant Artemisia annua L. (pKAL) polyphenols in p53 wild-type HCT116 human colorectal cancer cells. Cell morphology, protein expression levels, apoptosis/necrosis, reactive oxygen species (ROS), acidic vesicles, and granularity/DNA content were analyzed by phase-contrast microscopy; Western blot; and flow cytometry of annexin V/propidium iodide (PI)-, dichlorofluorescein (DCF)-, acridine orange (AO)-, and side scatter pulse height (SSC-H)/DNA content (PI)-stained cells. The results showed that pKAL induced morphological changes and necrosis or late apoptosis, which were associated with loss of plasma membrane/Golgi integrity, increased acidic vesicles and intracellular granularity, and decreased DNA content through downregulation of protein kinase B (Akt)/β-catenin/cyclophilin A/Golgi matrix protein 130 (GM130) and upregulation of phosphorylation of H2AX at Ser-139 (γ-H2AX)/p53/p21/Bak cleavage/phospho-JNK/p62/microtubule-associated protein 1 light chain 3B (LC3B)-I. Moreover, JNK inhibition by SP600125 enhanced ROS-independently pKAL-induced cell death through downregulation of p62 and upregulation of p53/p21/Bak cleavage despite a reduced state of DNA damage marker γ-H2AX. These findings indicate that phospho-JNK activated by pKAL inhibits p53-dependent cell death signaling and enhances DNA damage signaling, but cell fate is determined by phospho-JNK as survival rather than death in p53 wild-type HCT116 cells.

Phytochemical Analysis and Anti-Inflammatory Activity of Different Ethanolic Phyto-Extracts of Artemisia annua L.

“…Studies have shown that AA phyto-extracts, particularly ART and its analogues, have therapeutic effects on a variety of tumors and immune-related disorders. The mitogenactivated protein kinase (MAPK) pathway could be involved in these beneficial properties by regulating inflammatory response, cell cycle development, and apoptosis processes [47,53]. Cells are able to recognize the specific patterns of conserved molecular motifs associated with microbial pathogens (e.g., LPS) through the toll-like receptor (TLR) family, whose members are highly conserved glycoprotein receptors.…”

Effects of Fermented Artemisia annua L. and Salicornia herbacea L. on Inhibition of Obesity In Vitro and In Mice

“…AW (Artemisia annua L.) is a common type of wormwood native to temperate Asia but naturalized worldwide and belonging to the family Asteraceae [15]. Its bioactive derivatives control ROS, DNA damage, DNA repair, cell cycle arrest, apoptosis, inflammatory response, angiogenesis, and multiple signaling pathways, showing an anti-cancer effect [38]. In addition, it has an anti-hyperglycemic effect and reduces insulin resistance by increasing adiponectin secretion in adipocytes [35].…”

“…Some metabolites showed different patterns for each fermented group. Unlike the GF group, the AF group showed a decrease in casticin (37) and an increase in pyroglutamyl-valine (1), pyroglutamyl-leucine (2), lactotyl-tryptophan (3), hydroxyglutaric acid (5), dihydrocaffeic acid (13), scopoletin (17), phloretic acid (19), 3-caffeoylquinic acid (21), 3,4-dicaffeoylquinic acid (23), 3-feruloyl-4-caffeoylquinic acid (24), hydroxybenzoic acid (30), syringic aldehyde (33), 4-ethylcatechol (32), 4-vinylcatechol (31), shikimic acid (38), and two non-identified metabolites (40,42) (Figure 2C). Relatedly, 9-DiHODE (8), 9,10-DiHOME (9), and N.I 2 (41) increased only in SF (Figure 2D).…”

The Synergistic Anticancer Effect of Some Plant Extracts in Combination against Human Liver Cancer Cell Line

“…Breast, liver, colon Prostate, Lung, Gastric (Tian et al, 2017); (Shati et al, 2020) Teucrium polium Glioblastoma, colon, melanoma, lung, breast (Khazaei et al, 2018) Linum usitatissimum Prostate, breast, colon, skin (Sharma et al, 2014); (Calado et al, 2018); (DeLuca et al, 2018); (Zhou et al, 2020) Artemisia annua Breast, colon, lung (Rassias and Weathers, 2019); (Ko et al, 2020); (Jung et al, 2021) Commiphora molmol Liver, cervix (Ramadan et al, 2017); (Anwar et al, 2021) Zingiber officinale Leukemia, prostate, breast, skin, ovarian, (Semwal et al, 2015); (Salehi et al, 2019) lung, pancreatic, colorectal…”