Pholidonone, an active stilbene derivative from Pholidota cantonensis, exhibits pro-apoptotic effect via induction of endoplasmic reticulum stress in human gastric cancer

Abstract

BackgroundGastric cancer (GC) is the second leading cause of cancer death worldwide. Current chemotherapeutic drugs exert therapeutic effects accompanied by severe side effects. Therefore, it is imperative to urgently find new drugs with low toxicity and high efficacy for the treatment of GC. Natural products as well as functional foods have always been rich sources of potential antitumor agents. Pholidota cantonensis Rolfe, a well-known functional food and a traditional Chinese medicine, has been used for a long time in China for inflammatory diseases. Previously, we have evaluated its possible antitumor potentials by screening different solvent extracts, and found that the ethyl acetate (EtOAc) extract showed potent cytotoxicity on human GC cell line AGS with an IC50 value of 33.68 ± 1.68 μg/mL. In view of the poor knowledge concerning the phytochemical and pharmacological study of P. cantonensis, it is essential to characterize the active compounds from EtOAc extract and the mechanisms of action underlying the antitumor effect of the herb.ObjectiveThis study aimed to identify the primary compounds in EtOAc extract of P. cantonensis involved in the antitumor activity of the plant by evaluating the cytotoxicity in two human GC cell lines, including AGS and BGC-823 cells. Since endoplasmic reticulum (ER) stress-induced cell apoptosis represents attractive targets for cancer therapy recently, we focused on the underlying mechanisms associated with ER stress-induced cell apoptosis and related signaling pathways.MethodsVarious chromatographic techniques, including silica gel, Sephadex LH-20, and octadecylsilyl silica gel (ODS) C18, were used to separate the main active compound from EtOAc extract of P. cantonensis. The cell viability of AGS and BGC-823 cells upon purified compound treatment was determined by a 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) assay. The alteration of cell morphology was observed using an inverted microscope. Cell apoptosis was determined by fluorescein isothiocyanate (FITC)-labeled annexin-V/propidium iodide (PI) double-staining and flow cytometry analysis. Western blot analyses were performed to examine the levels of intracellular signaling molecules involved in ER stress-induced apoptosis.ResultsA rare stilbene derivative pholidonone was isolated and identified. The results showed that pholidonone displayed potent cytotoxicity on human GC cells. The IC50 values for 24 and 48 h in AGS cells were 26.54 ± 0.32 and 25.20 ± 3.67 μM, and the IC50 values for 24 and 48 h in BGC-823 cells were 32.41 ± 3.83 and 17.28 ± 2.30 μM, respectively. In addition, pholidonone had pro-apoptotic effect on AGS and BGC-823 cells, and it upregulated the levels of proteins involved in ER stress, including BiP, PDI, Calnexin, Ero1-Lα, IRE1α, PERK, CHOP, and cleaved-caspase-3 in AGS and BGC-823 cells.ConclusionPholidonone can trigger ER stress-induced apoptosis through PERK and IRE1α signaling pathways. Pholidonone might be a potential naturally occurring antitumor agent.

Ursolic Acid Derivative UA232 Promotes Tumor Cell Apoptosis by Inducing Endoplasmic Reticulum Stress and Lysosomal Dysfunction

“…Increasing evidence suggests that ER stress may play a role in the cytotoxicity of many natural compounds 27 - 29 . ER stress was originally a protective response to different types of cellular damage.…”

1,5,6-Trimethoxy-2,7-dihydroxyphenanthrene from Dendrobium officinale Exhibited Antitumor Activities for HeLa Cells

“…bletilols [21] and pholidonone [22] were cytotoxic to cancer cells. Dendrobine and its derivatives have been deeply studied for their apoptotic capacities and signaling pathway [23,24].…”

“…Dendrobium officinale Kimura et Migo, a Chinese endemic herb plant, is a member of the Dendrobium plants (Orchidaceae), which are mainly distributed in eastern and southeastern China [20]. Among phenanthrene compounds from the Dendrobium plants, bletilols [21] and pholidonone [22] were cytotoxic to cancer cells. Dendrobine and its derivatives have been deeply studied for their apoptotic capacities and signaling pathway [23,24].…”

Orchidaceae-Derived Anticancer Agents: A Review

“…Various stilbene-based derivatives from orchids, e.g., pholidonone [158], bletilols [159] are cytotoxic against cancer cell lines. The former compound triggers apoptotic cell death in human gastric cancer cells, by inducing ER stress, probably via PERK and IRE1α signalling pathways [158].…”