The Polysaccharide Extracted from <i>Umbilicaria esculenta</i> Inhibits Proliferation of Melanoma Cells through ROS-Activated Mitochondrial Apoptosis Pathway

Abstract

Melanoma is one of the most aggressive skin cancers with an increasing rate of morbidity. Umbilicaria esculenta is an edible lichen and its main component of extracts-polysaccharide (PUE) has shown significant antitumor effects in a variety of cancer types such as stomach adenocarcinoma. However, whether it has an anti-melanoma effect and the underlying mechanism has not been revealed. In this article, we showed that PUE extracted from Umbilicaria esculenta could inhibit the growth of A875 and A375 melanoma cells but without obvious toxicity to normal vascular endothelial cells. The generation of reactive oxygen species (ROS) in A875 cells was significantly elevated when treated with PUE for 24h. In addition, the expression of caspase-3 and -9 also increased as compared to the controlled group which resulted in the apoptosis of A875 melanoma cells. In the meantime, when pre-treated with N-acetylcysteine (NAC), the ROS scavenger, PUE induced apoptosis and cell death could be reversed via suppression of elevated generation of ROS and ROSmediated caspase-9 expression. In summary, our study demonstrated that PUE extracts from Umbilicaria esculenta have a potent anti-melanoma effect through the induction of ROS and caspases-3 and -9. It could provide a promising strategy of melanoma therapy with the components from the extracts of natural and edible plants such as lichen Umbilicaria esculenta. Key words Umbilicaria esculenta; extract; melanoma; reactive oxygen species; caspaseMelanoma is a malignancy notorious for its tendency of rapid metastasis and high mortality. It has been reported that over 76000 newly diagnosed cases of melanoma and nearly 9710 melanoma-related deaths were estimated in the United States in 2014.1) The incidence worldwide of melanoma is 15-25 per 100000 individuals. Although the proportion of melanoma in skin tumors is less than 5%, melanoma accounts for up to 75% of the deaths caused by all skin cancers.2) Chemotherapeutics such as Dacarbazine (DTIC) and immunotherapy (high-dose interleukin-2 and interferon-α) have been approved by the Food and Drug Administration (FDA) for melanoma treatment. Unfortunately, low response rates (ca. 15%), severe adverse effects as well as no improvement on overall survival (OS) limited their clinical application.3,4) The emergence of targeted therapy such as BRAF and mitogen-activated protein extracellular kinase (MEK) inhibitors, and immune checkpoint blockade such as anti-CTLA-4 and anti-PD-1 monoclonal antibodies marked great breakthrough in the management of patients with advanced melanoma.5,6) However, it is also not satisfied that, although these small targeted molecules have been proved to improve patients' QOL to some extent, adverse events such as pyrexia, photosensitivity and secondary cutaneous squamous-cell carcinomas and drug resistance which developed in about half of patients within several months treatment limited their effects. [7][8][9] Due to the characteristics of good efficacy, safety, and less toxicity to normal body tissues and organs, th...

Anti-tumor macrophages activated by ferumoxytol combined or surface-functionalized with the TLR3 agonist poly (I : C) promote melanoma regression

“…Therefore, NOX2-derived ROS was predicted to boost phagocytosis. An abnormal level of ROS is known to induce tumor cell apoptosis and damage tumor cell proliferation 56, 57. Consistently, suppression of cell growth was partly recovered by injection with NAC in the co-stimulation group (Figure 2G), which indicated that ROS was as well involved in macrophage activation-mediated tumor cell growth inhibition.…”

Quercetin induced NUPR1-dependent autophagic cell death by disturbing reactive oxygen species homeostasis in osteosarcoma cells

“…Recently, Monti et al (32) reported that NAC as a single agent reduced MCT4 stromal expression, which is a marker of glycolysis in breast cancer with reduced carcinoma cell proliferation in a clinical trial. However, other previous studies confirmed NAC inhibited anti-tumor effect of some chemical agents isolated from the plant, such as britannin, (33) Umbilicaria esculenta, (34) and cryptotanshinone. (35) Consistent with those previous studies, NAC also abolished quercetin-induced NUPR1-depended autophagic cell death in OS cells both in vitro and in vivo.…”

Anti‐Inflammatory Effects of Antarctic Lichen Umbilicaria antarctica Methanol Extract in Lipopolysaccharide‐Stimulated RAW 264.7 Macrophage Cells and Zebrafish Model

“…Extracts of Umbilicaria sp. contain several bioactive compounds with antioxidant, antimicrobial, anticancer, and antithrombotic activities, along with inhibitory effects on melanogenesis [10][11][12][13][14][15][16]. However, no studies have been reported on the anti-inflammatory effects of Umbilicaria sp.…”