iridoids and Pancreatic-Neoplasms

Oleuropein is an ester of elenolic acid and hydroxytyrosol (3, 4-dihydroxyphenylethanol). It is a phenolic compound and the most luxuriant in olives. The detailed information related to the anticancer effects of oleuropein was collected from the internet database PubMed/Medline, ResearchGate, Web of Science, Wiley Online Library, and Cnki using appropriate keywords until the end of October 2021. Oleuropein has been shown to have antioxidant, anticancer, antiinflammatory, cardioprotective, neuroprotective, and hepatoprotective effects. Previous studies also revealed that oleuropein could effectively inhibit the malignant progression of esophageal cancer, gastric cancer, breast cancer, lung cancer, liver cancer, pancreatic cancer, ovarian cancer, prostate cancer, and cervical cancer. Recently, the role of oleuropein in inhibiting tumor cell proliferation, invasion, and migration and inducing tumor cell apoptosis has gained extensive attention. In this review, we have summarized the latest research progress related to the antioncogenic mechanisms and the potential role of oleuropein in targeting different human malignancies. Based on these findings, it can be concluded that oleuropein can function as a promising chemopreventive and chemotherapeutic agent against cancer, but its more detailed anticancer effects and underlying mechanisms need to be further validated in future preclinical as well as clinical studies.

Topics: Antineoplastic Agents; Humans; Iridoid Glucosides; Iridoids; Male; Pancreatic Neoplasms

Valtrate is a novel epoxy iridoid ester isolated from Chinese herbal medicine Valeriana jatamansi Jones with anti-proliferative activity against various human cancer cell lines. However, its efficacy and molecular mechanisms against pancreatic cancer (PC) cells are largely unclear.. To investigate the anti-cancer effects of valtrate on PC cell lines and its underlying mechanisms.. Valtrate significantly inhibited the growth of PC cells without affecting the growth of normal pancreatic epithelial cells HPDE, induced significant apoptosis and cell cycle arrest in G2/M phase. Moreover, valtrate inhibited the tumor growth of PC cell PANC-1 in xenograft mice by 61%. Further mechanism study demonstrated that valtrate could increase the expression level of Bax, suppress Bcl-2 as well as c-Myc and Cyclin B1, inhibit the transcriptional activity of Stat3, while valtrate decreased the expression level of Stat3 and phosphated-Stat3 (Tyr705) and induced the high molecular aggregation of Stat3. Molecular docking analysis predicted that valtrate might interact with Cys712 of Stat3 protein. Valtrate could also induce a transient depleted intracellular glutathione (GSH) level and increased reactive oxygen species (ROS). NAC (N-acetylcysteine), a reducer reversed valtrate-induced the depletion of Stat3, p-Stat3, c-Myc, and Cyclin B1.. Valtrate exerts anti-cancer activity against PC cells by directly targeting Stat3 through a covalent linkage to inhibit Stat3 activity, which causes apoptosis and cell cycle arrest.

Topics: Animals; Apoptosis; Cell Cycle Checkpoints; Cell Line, Tumor; Cell Proliferation; Cyclin B1; Female; Humans; Iridoids; Mice; Mice, Inbred BALB C; Molecular Docking Simulation; Pancreatic Neoplasms; Proto-Oncogene Proteins c-bcl-2; Proto-Oncogene Proteins c-myc; Reactive Oxygen Species; Signal Transduction; STAT3 Transcription Factor; Valerian; Xenograft Model Antitumor Assays

Natural compound valepotriate exhibits inhibitory activity against a number of cancers, but the effect of valepotriate against pancreatic cancer is unclear, and the structure-activity relationship of valepotriate has not been characterized. In this study, we performed a structure-based similarity search and found 16 hit compounds. Among the 16 hits, (1S,6S,7R)-6-(acetyloxy)-1-[(3-methylbutanoyl)oxy]-4a,5,6,7a-tetrahydro-1H-spiro[cyclopenta[c]pyran-7,2'-oxiran]-4-ylmethyl 3-methylbutanoate (denoted as Amcp) exhibited superior anticancer activity against human pancreatic cancer BxPC-3 and SW1990 cells. The anti-proliferation activity of Amcp was validated in human pancreatic cancer BxPC-3 and SW1990 cells in vitro. Amcp more effectively induced apoptosis in BxPC-3 and SW1990 cells than gemcitabine. At a concentration of 15 μM, Amcp significantly suppressed the PI3K/AKT pathway and disrupted the mitochondrial membrane equilibrium through modulation of Noxa and Mcl-1 balance in both cell lines. Meanwhile, knockdown of Noxa substantially attenuated Amcp-induced reduction of cell viability and anti-apoptotic protein Mcl-1 level in BxPC-3 cells. In addition, Amcp showed synergistic anticancer effects when combined with gemcitabine in BxPC-3 cells. To conclude, this work not only suggests that Amcp possesses a dual-inhibitory activity towards PI3K/AKT pathway and Mcl-1, but also enlightens further development of bioactive valepotriate derivatives.

Topics: Antineoplastic Agents; Apoptosis; Cell Proliferation; Cell Survival; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; Humans; Iridoids; Membrane Potential, Mitochondrial; Molecular Conformation; Pancreatic Neoplasms; Phosphatidylinositol 3-Kinases; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-akt; Proto-Oncogene Proteins c-bcl-2; RNA, Small Interfering; Structure-Activity Relationship; Tumor Cells, Cultured

Current chemotherapy drugs for pancreatic cancer only offer an increase in survival of up to six months. Additionally, they are highly toxic to normal tissues, drastically affecting the quality of life of patients. Therefore, the search for novel agents, which induce apoptosis in cancer cells while displaying limited toxicity towards normal cells, is paramount. The olive biophenols, oleuropein, hydroxytyrosol and tyrosol, have displayed cytotoxicity towards cancer cells without affecting non-tumorigenic cells in cancers of the breast and prostate. However, their activity in pancreatic cancer has not been investigated. Therefore, the aim of this study was to determine the anti-pancreatic cancer potential of oleuropein, hydroxytyrosol and tyrosol. Pancreatic cancer cells (MIA PaCa-2, BxPC-3, and CFPAC-1) and non-tumorigenic pancreas cells (HPDE) were treated with oleuropein, hydroxytyrosol and tyrosol to determine their effect on cell viability. Oleuropein displayed selective toxicity towards MIA PaCa-2 cells and hydroxytyrosol towards MIA PaCa-2 and HPDE cells. Subsequent analysis of Bcl-2 family proteins and caspase 3/7 activation determined that oleuropein and hydroxytyrosol induced apoptosis in MIA PaCa-2 cells, while oleuropein displayed a protective effect on HPDE cells. Gene expression analysis revealed putative mechanisms of action, which suggested that c-Jun and c-Fos are involved in oleuropein and hydroxytyrosol induced apoptosis of MIA PaCa-2 cells.

Topics: Apoptosis; Apoptosis Regulatory Proteins; Cell Cycle; Cell Line, Tumor; Humans; Iridoid Glucosides; Iridoids; Neoplasm Proteins; Olea; Pancreatic Neoplasms; Phenylethyl Alcohol

Several studies indicate that mitochondrial uncoupling protein 2 (UCP2) plays a pivotal role in cancer development by decreasing reactive oxygen species (ROS) produced by mitochondrial metabolism and by sustaining chemoresistance to a plethora of anticancer drugs. Here, we demonstrate that inhibition of UCP2 triggers Akt/mTOR pathway in a ROS-dependent mechanism in pancreatic adenocarcinoma cells. This event reduces the antiproliferative outcome of UCP2 inhibition by genipin, creating the conditions for the synergistic counteraction of cancer cell growth with the mTOR inhibitor everolimus. Inhibition of pancreatic adenocarcinoma cell growth and induction of apoptosis by genipin and everolimus treatment are functionally related to nuclear translocation of the cytosolic glycolytic enzyme glyceraldehyde 3-phosphate dehydrogenase (GAPDH). The synthetic compound (S)-benzyl-2-amino-2-(S)-3-bromo-4,5-dihydroisoxazol-5-yl-acetate (AXP3009), which binds GAPDH at its redox-sensitive Cys152, restores cell viability affected by the combined treatment with genipin and everolimus, suggesting a role for ROS production in the nuclear translocation of GAPDH. Caspase-mediated apoptosis by genipin and everolimus is further potentiated by the autophagy inhibitor 3-methyladenine revealing a protective role for Beclin1-mediated autophagy induced by the treatment. Mice xenograft of pancreatic adenocarcinoma further confirmed the antiproliferative outcome of drug combination without toxic effects for animals. Tumor masses from mice injected with UCP2 and mTOR inhibitors revealed a strong reduction in tumor volume and number of mitosis associated with a marked GAPDH nuclear positivity. Altogether, these results reveal novel mechanisms through which UCP2 promotes cancer cell proliferation and support the combined inhibition of UCP2 and of Akt/mTOR pathway as a novel therapeutic strategy in the treatment of pancreatic adenocarcinoma.

Topics: Antineoplastic Agents; Apoptosis; Carcinoma, Pancreatic Ductal; Cell Line, Tumor; Cell Proliferation; Everolimus; Female; Glyceraldehyde-3-Phosphate Dehydrogenases; Humans; Iridoids; Male; Pancreatic Neoplasms; Protein Transport; Proto-Oncogene Proteins c-akt; Reactive Oxygen Species; Signal Transduction; TOR Serine-Threonine Kinases; Uncoupling Protein 2; Xenograft Model Antitumor Assays

To analyze the role of geniposide in the protein degradation of Txnip and to determine the impact of Txnip on geniposide-regulated GSIS in pancreatic INS-1 cells.. The content of Txnip protein was measured by western blot; insulin content and glucose uptake were determined by ELISA; and knockdown of Txnip was the method of RNA interference.. Glucose induces a rapid increase in Txnip protein, and geniposide accelerates the degradation of Txnip via proteasome pathway in the presence of high glucose (25 mM) in INS-1 pancreatic β-cells. And MG132, a proteasomal inhibitor, potentiates glucose uptake, metabolism (ATP production) and glucose-stimulated insulin secretion (GSIS) in high-glucose (25 mM)-treated INS-1 cells, but geniposide significantly prevents these effects. Furthermore, the combination of geniposide and Txnip knockdown shows substantial synergistic effects to reduce glucose uptake, metabolism and GSIS in high-glucose (25 mM)-treated INS-1 cells.. Txnip protein played an essential role in glucose uptake, metabolism and GSIS, and geniposide could accelerate the degradation via proteasome pathway in high-glucose-treated pancreatic INS-1 cells.

Topics: Animals; Carrier Proteins; Cell Cycle Proteins; Gene Expression Regulation; Glucose; Insulin; Insulin Secretion; Insulin-Secreting Cells; Insulinoma; Iridoids; Pancreatic Neoplasms; Proteasome Endopeptidase Complex; Proteolysis; Rats; Tumor Cells, Cultured

Olea europaea L. leaves are an agricultural waste product with a high concentration of phenolic compounds; especially oleuropein. Oleuropein has been shown to exhibit anti-proliferative activity against a number of cancer types. However, they have not been tested against pancreatic cancer, the fifth leading cause of cancer related death in Western countries. Therefore, water, 50% ethanol and 50% methanol extracts of Corregiola and Frantoio variety Olea europaea L. leaves were investigated for their total phenolic compounds, total flavonoids and oleuropein content, antioxidant capacity and anti-proliferative activity against MiaPaCa-2 pancreatic cancer cells. The extracts only had slight differences in their phytochemical properties, and at 100 and 200 μg/mL, all decreased the viability of the pancreatic cancer cells relative to controls. At 50 μg/mL, the water extract from the Corregiola leaves exhibited the highest anti-proliferative activity with the effect possibly due to early eluting HPLC peaks. For this reason, olive leaf extracts warrant further investigation into their potential anti-pancreatic cancer benefits.

Topics: Antineoplastic Agents; Antioxidants; Cell Line, Tumor; Cell Proliferation; Dose-Response Relationship, Drug; Flavonoids; Humans; Iridoid Glucosides; Iridoids; Olea; Pancreatic Neoplasms; Phenols; Plant Extracts; Plant Leaves

Uncoupling protein-2 (UCP2) may regulate glucose-stimulated insulin secretion. The current study investigated the effects of berberine, an alkaloid found in many medicinal plants, on oxidative stress and insulin secretion through restoration of UCP2 expression in high glucose (HG)-treated INS-1E cells and rat islets or in db/db mouse islets.. Mouse and rat pancreatic islets were isolated. Nitrotyrosine, superoxide dismutase (SOD)-1 and UCP2 expression and AMPK phosphorylation were examined by Western blotting. Insulin secretion was measured by ELISA. Mitochondrial reactive oxygen species (ROS) production was detected by confocal microscopy.. Incubation of INS-1E cells and rat islets with HG (30 mmol·L(-1); 8 h) elevated nitrotyrosine level, reduced SOD-1 and UCP2 expression and AMPK phosphorylation, and inhibited glucose-stimulated insulin secretion. HG also increased mitochondrial ROS in INS-1E cells. Co-treatment with berberine inhibited such effects. The AMPK inhibitor compound C, the UCP2 inhibitor genipin and adenovirus ucp2 shRNA inhibited these protective effects of berberine. Furthermore, compound C normalized berberine-stimulated UCP2 expression but genipin did not affect AMPK phosphorylation. Islets from db/db mice exhibited elevated nitrotyrosine levels, reduced expression of SOD-1 and UCP2 and AMPK phosphorylation, and decreased insulin secretion compared with those from db/m(+) mice. Berberine also improved these defects in diabetic islets and genipin blocked the effects of berberine.. Berberine inhibited oxidative stress and restored insulin secretion in HG-treated INS-IE cells and diabetic mouse islets by activating AMPK and UCP2. UCP2 is an important signalling molecule in mediating anti-diabetic effects of berberine.

Topics: AMP-Activated Protein Kinases; Animals; Berberine; Diabetes Mellitus, Experimental; Glucose; Insulin; Insulin Secretion; Insulinoma; Ion Channels; Iridoids; Islets of Langerhans; Male; Mice; Microscopy, Confocal; Mitochondria; Mitochondrial Proteins; Oxidative Stress; Pancreatic Neoplasms; Phosphorylation; Rats; Rats, Sprague-Dawley; Reactive Oxygen Species; Uncoupling Protein 2

Mitochondrial uncoupling protein 2 (UCP2) can moderate oxidative stress by favoring the influx of protons into the mitochondrial matrix, thus reducing electron leakage from respiratory chain and mitochondrial superoxide production. Here, we demonstrate that UCP2 inhibition by genipin or UCP2 siRNA strongly increases reactive oxygen species (ROS) production inhibiting pancreatic adenocarcinoma cell growth. We also show that UCP2 inhibition triggers ROS-dependent nuclear translocation of the glycolytic enzyme glyceraldehyde 3-phosphate dehydrogenase (GAPDH), formation of autophagosomes, and the expression of the autophagy marker LC3-II. Consistently, UCP2 over-expression significantly reduces basal autophagy confirming the anti-autophagic role of UCP2. Furthermore, we demonstrate that autophagy induced by UCP2 inhibition determines a ROS-dependent cell death, as indicated by the apoptosis decrease in the presence of the autophagy inhibitors chloroquine (CQ) or 3-methyladenine (3-MA), or the radical scavenger NAC. Intriguingly, the autophagy induced by genipin is able to potentiate the autophagic cell death triggered by gemcitabine, the standard chemotherapeutic drug for pancreatic adenocarcinoma, supporting the development of an anti-cancer therapy based on UCP2 inhibition associated to standard chemotherapy. Our results demonstrate for the first time that UCP2 plays a role in autophagy regulation bringing new insights into mitochondrial uncoupling protein field.

Topics: Adenocarcinoma; Apoptosis; Autophagy; Blotting, Western; Cell Line, Tumor; Cell Proliferation; Cholagogues and Choleretics; Fluorescent Antibody Technique; Glyceraldehyde-3-Phosphate Dehydrogenases; Humans; Ion Channels; Iridoids; Mitochondrial Proteins; Oxidative Stress; Pancreatic Neoplasms; Protein Transport; Reactive Oxygen Species; Real-Time Polymerase Chain Reaction; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; RNA, Small Interfering; Uncoupling Protein 2