Glucotropaeolin Promotes Apoptosis by Calcium Dysregulation and Attenuates Cell Migration with FOXM1 Suppression in Pancreatic Cancer Cells

Pancreatic ductal adenocarcinoma (PDAC) has naturally aggressive characteristics including postoperative recurrence, resistance to conventional treatment, and metastasis. Surgical resection with chemotherapeutic agents has been conducted as the major treatment for PDAC. However, surgical treatment is ineffective in the case of advanced cancer, and conventional adjuvant chemotherapy, including gemcitabine and 5-fluorouracil, show low effectiveness due to the high drug resistance of PDAC to this type of treatment. Therefore, the development of innovative therapeutic drugs is crucial to solving the present limitation of conventional drugs. Glucotropaeolin (GT) is a glucosinolate that can be isolated from the Brassicaceae family. GT has exhibited a growth-inhibitory effect against liver and colon cancer cells; however, there is no study regarding the anticancer effect of GT on PDAC. In our study, we determined the antiproliferative effect of GT in PANC-1 and MIA PaCa-2, representative of PDAC. We revealed the intracellular mechanisms underlying the anticancer effect of GT with respect to cell viability, reactive oxygen species (ROS) accumulation, alteration of mitochondrial membrane potential (MMP), calcium dysregulation, cell migration, and the induction of apoptosis. Moreover, GT regulated the signaling pathways related to anticancer in PDAC cells. Finally, the silencing of the forkhead box protein M, a key factor regulating PDAC progression, contributes to the anticancer property of GT in terms of the induction of apoptosis and cell migration. Therefore, GT may be a potential therapeutic drug against PDAC

Suppressive Effect of Fraxetin on Adipogenesis and Reactive Oxygen Species Production in 3T3-L1 Cells by Regulating MAPK Signaling Pathways

Recent studies have identified obesity as one of the world’s most serious chronic disorders. Adipogenesis, in which preadipocytes are differentiated into mature adipocytes, has a decisive role in establishing the number of adipocytes and determining the lipid storage capacity of adipose tissue and fat mass in adults. Fat accumulation in obesity is implicated with elevated oxidative stress in adipocytes induced by reactive oxygen species (ROS). Adipogenesis regulation by inhibiting adipogenic differentiation and ROS production has been selected as the strategy to treat obesity. The conventional anti-obesity drugs allowed by the U.S. Food and Drug Administration have severe adverse effects. Therefore, various natural products have been developed as a solution for obesity, suppressing adipogenic differentiation. Fraxetin is a major component extracted from the stem barks of Fraxinus rhynchophylla, with various bioactivities, including anti-inflammatory, anticancer, antioxidant, and antibacterial functions. However, the effect of fraxetin on adipogenesis is still not clearly understood. We studied the pharmacological functions of fraxetin in suppressing lipid accumulation and its underlying molecular mechanisms involving 3T3-L1 preadipocytes. Moreover, increased ROS production induced by a mixture of insulin, dexamethasone, and 3-isobutylmethylxanthine (MDI) in 3T3-L1 was attenuated by fraxetin during adipogenesis. These effects were regulated by mitogen-activated protein kinase (MAPK) signaling pathways. Therefore, our findings imply that fraxetin possesses inhibitory roles in adipogenesis and can be a potential anti-obesity drug

Stigmasterol Causes Ovarian Cancer Cell Apoptosis by Inducing Endoplasmic Reticulum and Mitochondrial Dysfunction

Background: Phytosterols have physiological effects and are used as medicines or food supplements. Stigmasterol has shown anticancer effects against various cancers such as hepatoma, cholangiocarcinoma, gall bladder carcinoma, endometrial adenocarcinoma and skin, gastric, breast, prostate, and cervical cancer. However, there are no reports on stigmasterol’s effects on ovarian cancer. Methods: We investigated the effects of stigmasterol on proapoptotic signals, mitochondrial function, reactive oxygen species production, and the cytosolic and mitochondrial calcium levels in human ovarian cancer cells, to understand the mechanisms underlying the effects of stigmasterol on ovarian cancer cells. We also conducted migration assay to confirm whether that stigmasterol inhibits ovarian cancer cell migration. Results: Stigmasterol inhibited development of human ovarian cancer cells. However, it induced cell apoptosis, ROS production, and calcium overload in ES2 and OV90 cells. In addition, stigmasterol stimulated cell death by activating the ER-mitochondrial axis. We confirmed that stigmasterol suppressed cell migration and angiogenesis genes in human ovarian cancer cells. Conclusions: Our findings suggest that stigmasterol can be used as a new treatment for ovarian cancer

Laminarin Attenuates ROS-Mediated Cell Migration and Invasiveness through Mitochondrial Dysfunction in Pancreatic Cancer Cells

Pancreatic ductal adenocarcinoma (PDAC) is a notoriously aggressive type of cancer with a high metastasis rate. It is conventionally treated by surgical resection and neoadjuvant chemotherapy. However, continuous chemotherapy leads to relapse in most PDAC patients due to chemical resistance. Therefore, novel anticancer agents need to be identified and developed. The antitumor activities of laminarin extracted from brown algae against hepatocarcinoma, lung, and colon cancer have been established. However, its effects on pancreatic cancer have remained obscure. Our study identified the anticancer effects of laminarin on pancreatic cancer cells and tried to explain its intracellular mechanisms. We assessed the cell viability of PANC-1 and MIA PaCa-2 cells using MTT assay. Hanging drop method was used for the spheroid formation. Flow cytometry was conducted to evaluate the several intracellular alterations including apoptosis, ROS production, mitochondrial membrane potential (MMP), and calcium concentration induced by laminarin. An invasion test was performed to assess the inhibitory effect of laminarin on cell migration and the invasive genes were evaluated by RT-qPCR. Signaling pathway related with anticancer effects of laminarin was analyzed by western blot. We report that inhibiting laminarin increased the proliferation and viability of the representative pancreatic cancer cell lines, MIA PaCa-2 and PANC-1. Laminarin triggered apoptosis and mitochondrial impairment as evidenced by depolarized mitochondrial membranes, disrupted calcium, and suppressed cell migration caused by reactive oxygen species production and related intracellular signaling pathways. Moreover, laminarin showed synergistic effects when combined with 5-FU, a standard anticancer agent for PDAC. The present study is the first to report that laminarin exerts anticancer effect through ROS production in pancreatic cancer cells. Laminarin shows potential to serve as a new anticancer agent for treating PDAC

Fucosterol Suppresses the Progression of Human Ovarian Cancer by Inducing Mitochondrial Dysfunction and Endoplasmic Reticulum Stress

Ovarian cancer is difficult to diagnose early and has high rates of relapse and mortality. Therefore, the treatment of ovarian cancer needs to be improved. Recently, several studies have been conducted in an attempt to develop anticancer drugs from naturally derived ingredients. Compared to traditional chemotherapy, natural compounds can overcome drug resistance with lower side effects. Fucosterol, a phytosterol present in brown algae, reportedly possesses many bioactive effects, including anticancer properties. However, the anticancer effects of fucosterol in ovarian cancer remain unexplored. Therefore, we investigated the effects of fucosterol on progression in human ovarian cancer cells. Fucosterol inhibited cell proliferation and cell-cycle progression in ovarian cancer cells. Additionally, fucosterol regulated the proliferation-related signaling pathways, the production of reactive oxygen species, mitochondrial function, endoplasmic reticulum stress, angiogenesis, and calcium homeostasis. Moreover, it decreased tumor formation in a zebrafish xenograft model. These results indicate that fucosterol could be used as a potential therapeutic agent in ovarian cancer

Disruption of Endoplasmic Reticulum and ROS Production in Human Ovarian Cancer by Campesterol

Phytosterols, which are present in a variety of foods, exhibit various physiological functions and do not have any side effects. Here, we attempted to identify functional role of campesterol in regulation of oxidative stress by leading to cell death of ovarian cancer. We investigated the effects of campesterol on cancer cell aggregation using a three-dimensional (3D) culture of human ovarian cancer cells. The effects of campesterol on apoptosis, protein expression, proliferation, the cell cycle, and the migration of these cells were determined to unravel the underlying mechanism. We also investigated whether campesterol regulates mitochondrial function, the generation of reactive oxygen species (ROS), and calcium concentrations. Our results show that campesterol activates cell death signals and cell death in human ovarian cancer cells. Excessive calcium levels and ROS production were induced by campesterol in the two selected ovarian cancer cell lines. Moreover, campesterol suppressed cell proliferation, cell cycle progression, and cell aggregation in ovarian cancer cells. Campesterol also enhanced the anticancer effects of conventional anticancer agents. The present study shows that campesterol can be used as a novel anticancer drug for human ovarian cancer

Disruption of Endoplasmic Reticulum and ROS Production in Human Ovarian Cancer by Campesterol

Phytosterols, which are present in a variety of foods, exhibit various physiological functions and do not have any side effects. Here, we attempted to identify functional role of campesterol in regulation of oxidative stress by leading to cell death of ovarian cancer. We investigated the effects of campesterol on cancer cell aggregation using a three-dimensional (3D) culture of human ovarian cancer cells. The effects of campesterol on apoptosis, protein expression, proliferation, the cell cycle, and the migration of these cells were determined to unravel the underlying mechanism. We also investigated whether campesterol regulates mitochondrial function, the generation of reactive oxygen species (ROS), and calcium concentrations. Our results show that campesterol activates cell death signals and cell death in human ovarian cancer cells. Excessive calcium levels and ROS production were induced by campesterol in the two selected ovarian cancer cell lines. Moreover, campesterol suppressed cell proliferation, cell cycle progression, and cell aggregation in ovarian cancer cells. Campesterol also enhanced the anticancer effects of conventional anticancer agents. The present study shows that campesterol can be used as a novel anticancer drug for human ovarian cancer

Fucoidan Derived from Fucus vesiculosus Inhibits the Development of Human Ovarian Cancer via the Disturbance of Calcium Homeostasis, Endoplasmic Reticulum Stress, and Angiogenesis

Marine organisms are sources of several natural compounds with potential clinical use. However, only a few marine-based pharmaceuticals have been approved for use due to limited knowledge on their biological activities. Here, we identified the functional role of fucoidan extracted from Fucus vesiculosus on ovarian cancer. Fucoidan increased the death of ES-2 and OV-90 cells, through a reduction in proliferation, cell cycle arrest, releases of cytochrome c, reactive oxygen species (ROS) generation, and endoplasmic reticulum (ER) stress. Additionally, fucoidan increased the concentration of cytosolic and mitochondrial calcium in both cells. The decrease of cell proliferation was controlled by the inactivation of PI3K and MAPK signaling cascades in ES-2 and OV-90 cells. In a toxicity assay with normal zebrafish larvae, fucoidan did not induce toxicity, cardiotoxicity, development, kinesis, and apoptosis at different concentrations. However, it disrupted tumor formation and vascular development in a zebrafish xenograft model and angiogenesis transgenic (Tg, fli1-eGFP) model, respectively. Collectively, the results indicate that fucoidan may be a novel pharmaceutical for the management of human ovarian cancer

Laminarin-Derived from Brown Algae Suppresses the Growth of Ovarian Cancer Cells via Mitochondrial Dysfunction and ER Stress

Ovarian cancer (OC) is difficult to diagnose at an early stage and leads to the high mortality rate reported in the United States. Standard treatment for OC includes maximal cytoreductive surgery followed by platinum-based chemotherapy. However, relapse due to chemoresistance is common in advanced OC patients. Therefore, it is necessary to develop new anticancer drugs to suppress OC progression. Recently, the anticancer effects of laminarin, a beta-1,3-glucan derived from brown algae, have been reported in hepatocellular carcinoma, colon cancer, leukemia, and melanoma. However, its effects in OC are not reported. We confirmed that laminarin decreases cell growth and cell cycle progression of OC cells through the regulation of intracellular signaling. Moreover, laminarin induced cell death through DNA fragmentation, reactive oxygen species generation, induction of apoptotic signals and endoplasmic reticulum (ER) stress, regulation of calcium levels, and alteration of the ER-mitochondria axis. Laminarin was not cytotoxic in a zebrafish model, while in a zebrafish xenograft model, it inhibited OC cell growth. These results suggest that laminarin may be successfully used as a novel OC suppressor