iridoids and Neoplasms

Topics: Antineoplastic Agents; Apoptosis; Humans; Iridoids; Neoplasms; Reactive Oxygen Species; Uncoupling Protein 2

The Mediterranean diet (MD) is a combination of foods mainly rich in antioxidants and anti-inflammatory nutrients that have been shown to have many health-enhancing effects. Extra-virgin olive oil (EVOO) is an important component of the MD. The importance of EVOO can be attributed to phenolic compounds, represented by phenolic alcohols, hydroxytyrosol, and tyrosol, and to secoiridoids, which include oleocanthal, oleacein, oleuropein, and ligstroside (along with the aglycone and glycosidic derivatives of the latter two). Each secoiridoid has been studied and characterized, and their effects on human health have been documented by several studies. Secoiridoids have antioxidant, anti-inflammatory, and anti-proliferative properties and, therefore, exhibit anti-cancer activity. This review summarizes the most recent findings regarding the pharmacological properties, molecular targets, and action mechanisms of secoiridoids, focusing attention on their preventive and anti-cancer activities. It provides a critical analysis of preclinical, in vitro and in vivo, studies of these natural bioactive compounds used as agents against various human cancers. The prospects for their possible use in human cancer prevention and treatment is also discussed.

Topics: Aldehydes; Animals; Anti-Inflammatory Agents; Antineoplastic Agents; Antioxidants; Cyclopentane Monoterpenes; Diet, Mediterranean; Glucosides; Humans; Iridoid Glucosides; Iridoids; Neoplasms; Olive Oil; Phenols; Phenylethyl Alcohol; Pyrans

Phenolic secoiridoids from olive, including oleocanthal, oleuropein and related derivatives, are bioactive natural products with documented anticancer activities, that have mainly been attributed to their antioxidant, anti-inflammatory and antiproliferative effects. This review summarizes the results of the preclinical studies on the natural secoiridoids of olive used as single agents or in combination with other chemotherapeutics against cancer cells. The molecular targets of their action are described. A critical analysis of the importance of the experimental studies in view of the possible use in humans is also discussed.

Topics: Adjuvants, Pharmaceutic; Animals; Antineoplastic Agents; Humans; Iridoids; Neoplasms; Olea

Genipin, an aglycone derived from the iridoid glycoside, geniposide, is isolated and characterized from the extract of Gardenia jasminoides Ellis fruit (family Rubiaceae). It has long been used in traditional oriental medicine for the prevention and treatment of several inflammation driven diseases, including cancer. Genipin has been shown to have hepatoprotective activity acting as a potent antioxidant and inhibitor of mitochondrial uncoupling protein 2 (UCP2), and also reported to exert significant anticancer effects. It is an excellent crosslinking agent that helps to make novel sustained or delayed release nanoparticle formulations. In this review, we present the latest developments of genipin as an anticancer agent and briefly describe its diverse mechanism(s) of action. Several lines of evidence suggest that genipin is a potent inhibitor of UCP2, which functions as a tumor promoter in a variety of cancers, attenuates generation of reactive oxygen species and the expression of matrix metalloproteinase 2, as well as induces caspase-dependent apoptosis in vitro and in in vivo models. These finding suggests that genipin can serve as both a prominent anticancer agent as well as a potent crosslinking drug that may find useful application in several novel pharmaceutical formulations.

Topics: Animals; Antineoplastic Agents; Cross-Linking Reagents; Humans; Iridoids; Nanoparticles; Neoplasms

Olive fruit is a significant and promising source of potential bioactive compounds such as oleuropein and hydroxytyrosol. Oleuropein is the ester of elenolic acid and 3,4-dihydroxyphenyl ethanol (HT). It is the main glycoside in olives, the degradation of which results in the formation of hydroxytyrosol in olive oil. Both plays a significant role in the reduction of coronary heart diseases and a certain type of cancers. Both olive oil phenols have an effective role counter to cell proliferation, cell growth, migration, invasion, and angiogenesis. They down regulate the expression of BCL-2 and COX-2 proteins, and reduced DNA damage. Hydroxytyrosol and oleuropein inhibited the multiple stages in colon carcinogenesis; initiation, promotion, and metastasis. They also provide protection against various human cancers including colorectal, skin, breast, thyroid, digestive, lung, brain, blood, and cervical. This review article discusses the anticancer perspectives and mechanisms of oleuropein and hydroxytyrosol in cell cultures and animal and human studies.

Topics: Animals; Antineoplastic Agents; Cell Movement; Cell Proliferation; Coronary Disease; DNA Damage; Humans; Iridoid Glucosides; Iridoids; Neoplasm Invasiveness; Neoplasms; Neovascularization, Pathologic; Olea; Olive Oil; Phenylethyl Alcohol; Pyrans

Cancer comprises a collection of related diseases characterized by the existence of altered cellular pathways resulting in an abnormal tendency for uncontrolled growth. A broad spectrum, coordinated, and personalized approach focused on targeting diverse oncogenic pathways with low toxicity and economic natural compounds can provide a real benefit as a chemopreventive and/or treatment of this complex disease. Oleuropein, a bioactive phenolic compound mainly present in olive oil and other natural sources, has been reported to modulate several oncogenic signalling pathways. This review presents and critically discusses the available literature about the anticancer and onco-suppressive activity of oleuropein and the underlying molecular mechanisms implicated in the anticarcinogenic and therapeutic effects. The existence of limitations and the promising perspectives of research on this phenolic compound are also critically analyzed and discussed.

Topics: Animals; Anticarcinogenic Agents; Apoptosis; Chemoprevention; Humans; Iridoid Glucosides; Iridoids; MAP Kinase Signaling System; Neoplasms; Protein Kinase Inhibitors

Cancer is a multifaceted and genomically complex disease. Rapidly accumulating preclinical and clinical studies are emphasizing on wide ranging molecular mechanisms that underpin cancer development, progression and metastasis. Intratumor heterogeneity, loss of apoptosis, rapidly developing resistance against molecular therapeutics and off-target effects are some of the deeply studied resistance mechanisms. Data obtained through high-throughput technologies has considerably enhanced our understanding of the intracellular signaling cascades frequently dysregulated spatio-temporally. There is an ever-expanding list of synthetic and natural agents reported to activate tumor suppressor genes and inhibit oncogenes in cancer cells. Markedly reduced tumor growth has also been documented in xenografted mice administered with phytochemicals. Oleuropein is a bioactive ingredient isolated from various sources and there is evidence of complete regression of tumors in 9- 12 days in mice orally administered with Oleuropein. In this review we summarize recent developments in use of Oleuropein as an anticancer agent. Extraction and isolation of Oleuropein and how it modulates intracellular signaling network to induce apoptosis in cancer cells. Human epidermal growth factor receptor 2 (HER2) frequently overexpressed in breast cancer cells is inhibited by Oleuropein. Interestingly, trastuzumab efficacy was notably enhanced in Oleuropein treated breast cancer cells. There is still insufficient information related to Oleuropein mediated microRNA regulation in cancer cells. We still do not have information about regulation of different signaling cascades by Oleuropein which are deregulated in cancer. Future studies must converge on a deeper analysis of target molecular network of Oleuropein and its efficacy as a tumor growth inhibitor in xenografted mice.

Topics: Animals; Apoptosis; Humans; Iridoid Glucosides; Iridoids; Mice; Neoplasms; Proto-Oncogene Proteins c-akt; Reactive Oxygen Species; Signal Transduction

Iridoids represent a large group of cyclopenta[c]pyran monoterpenoids that occur wide-spread in nature, mainly in dicotyledonous plant families like Apocynaceae, Scrophulariaceae, Diervillaceae, Lamiaceae, Loganiaceae and Rubiaceae. Recently, more extensive studies revealed that iridoids exhibit a wide range of bioactivity, such as neuroprotective, antinflammatory and immunomodulator, hepatoprotective and cardioprotective effects. Anticancer, antioxidant, antimicrobic, hypoglycaemic, hypolipidemic, choleretic, antispasmodic and purgative properties were also reported. The aim of the present review is to discuss the recent developments on biological and pharmacological activities of iridoids, supporting the new therapeutic possibilities for the use of these compounds.

Topics: Anti-Infective Agents; Antineoplastic Agents; Antioxidants; Cardiotonic Agents; Drug Design; Humans; Immunologic Factors; Iridoids; Neoplasms; Neuroprotective Agents

Inchinkoto (ICKT) is a popular choleretic and hepatoprotective herbal medicine that is widely used in Japan. Geniposide, a major ingredient of ICKT, is metabolized to genipin by gut microbiota, which exerts a choleretic effect. This study investigates the relationship between stool genipin-producing activity and diversity of the clinical effect of ICKT in patients with malignant obstructive jaundice. Fifty-two patients with malignant obstructive jaundice who underwent external biliary drainage were included. ICKT was administered as three packets per day (7.5 g/day) for three days and 2.5 g on the morning of the fourth day. Stool samples were collected before ICKT administration and bile flow was monitored on a daily basis. The microbiome, genipin-producing activity, and organic acids in stools were analyzed. The Shannon-Wiener (SW) index was calculated to evaluate gut microbiome diversity. The stool genipin-producing activity showed a significant positive correlation with the SW index. Stool genipin-producing activity positively correlated with the order Clostridia (obligate anaerobes), but negatively correlated with the order Lactobacillales (facultative anaerobes). Moreover, stool genipin-producing activity was positively correlated to the concentration valeric acid, but negatively correlated to the concentration of lactic acid and succinic acid. The change of bile flow at 2 and 3 days after ICKT administration showed significant positive correlation with genipin-producing activity (correlation coefficient, 0.40 and 0.29, respectively, P < 0.05). An analysis of stool profile, including stool genipin-producing activity, may predict the efficacy of ICKT. Modification of the microbiome may be a target to enhance the therapeutic effect of ICKT.

Topics: Adult; Aged; Aged, 80 and over; Bile; Carboxylic Acids; Cholagogues and Choleretics; Clostridium; Drugs, Chinese Herbal; Feces; Female; Gastrointestinal Microbiome; Humans; Iridoids; Jaundice, Obstructive; Lactobacillales; Male; Middle Aged; Neoplasms; Treatment Outcome

The present study aims to assess the antioxidant and antiviral effectiveness of leaf extracts obtained from

Topics: Antioxidants; HeLa Cells; Humans; Iridoids; Neoplasms; Olea; Plant Extracts

Several individual olive oil phenols (OOPs) and their secoiridoid derivatives have been shown to exert anti-proliferative and pro-apoptotic activity in treatments of human cancer cell lines originating from several tissues. This study evaluated the synergistic anti-proliferative/cytotoxic effects of five olive secoiridoid derivatives (oleocanthal, oleacein, oleuropein aglycone, ligstroside aglycone and oleomissional) in all possible double combinations and of total phenolic extracts (TPEs) on eleven human cancer cell lines representing eight cell-culture-based cancer models. Individual OOPs were used to treat cells for 72 h in half of their EC

Topics: Antineoplastic Agents; Cell Line, Tumor; Humans; Iridoids; Neoplasms; Olea; Olive Oil; Phenols; Plant Extracts

Olive leaf extract is a valuable source of phenolic compounds; primarily, oleuropein (major component) and rutin. This natural olive leaf extract has potential use as a therapeutic agent for cancer treatment. However, its clinical application is hindered by poor pharmacokinetics and low stability. To overcome these limitations, this study aimed to enhance the anticancer activity and stability of oleuropein and rutin by loading them into PEGylated Nano-phytosomes. The developed PEGylated Nano-phytosomes exhibited favorable characteristics in terms of size, charge, and stability. Notably, the anticolonic cancer activity of the Pegylated Nano-phytosomes loaded with oleuropein (IC50=0.14 μM) and rutin (IC50=0.44 μM) surpassed that of pure oleuropein and rutin alone. This outcome highlights the advantageous impact of Nano-phytosomes to augment the anticancer potential of oleuropein and rutin. These results present a promising pathway for the future development of oleuropein and rutin Nano-phytosomes as effective options for passive tumor-targeted therapy, given their improved stability and efficacy.

Topics: Antioxidants; Iridoid Glucosides; Iridoids; Neoplasms; Olea; Plant Extracts; Plant Leaves; Polyethylene Glycols; Rutin

We isolated seven new iridoid glucosides (valerianairidoids I-VII;

Topics: Humans; Iridoid Glucosides; Iridoids; Neoplasms; Neoplastic Stem Cells; Plant Roots; Valerian

Olive oil phenols (OOPs) are associated with the prevention of many human cancers. Some of these have been shown to inhibit cell proliferation and induce apoptosis. However, no systematic comparative study exists for all the investigated compounds under the same conditions, due to difficulties in their isolation or synthesis. Herein are presented innovative methods for large-scale selective extraction of six major secoiridoids from olive oil or leaves enabling their detailed investigation. The cytotoxic/antiproliferative bioactivity of these six compounds was evaluated on sixteen human cancer cell lines originating from eight different tissues. Cell viability with half-maximal effective concentrations (EC50) was evaluated after 72 h treatments. Antiproliferative and pro-apoptotic effects were also assessed for the most bioactive compounds (EC50 ≤ 50 μM). Oleocanthal (1) showed the strongest antiproliferative/cytotoxic activity in most cancer cell lines (EC50: 9−20 μM). The relative effectiveness of the six OOPs was: oleocanthal (1) > oleuropein aglycone (3a,b) > ligstroside aglycone (4a,b) > oleacein (2) > oleomissional (6a,b,c) > oleocanthalic acid (7). This is the first detailed study comparing the bioactivity of six OOPs in such a wide array of cancer cell lines, providing a reference for their relative antiproliferative/cytotoxic effect in the investigated cancers.

Topics: Antineoplastic Agents; Cell Line; Humans; Iridoids; Neoplasms; Olea; Olive Oil

Three-dimensional (3D) biomimetic cell culture platforms offer more realistic microenvironments that cells naturally experience in vivo. We developed a tunable hyaluronan-based hydrogels that could easily be modified to mimic healthy or malignant extracellular matrices (ECMs). For that, we pre-functionalized our hydrogels with an adhesive polypeptide (poly-l-lysine, PLL) or ECM proteins (type III and type IV collagens), naturally present in tumorous tissues, and next, we tuned their stiffness by crosslinking with gradual concentrations of genipin (GnP). Then, we thoroughly characterized our substrates before testing them with glioblastoma and breast cancer cells, and thereafter with endothelial cells. Overall, our hydrogels exhibited (a) increasing stiffness with GnP concentration for every pre-functionalization and (b) efficient enzyme resistance with PLL treatment, and also with type IV collagen but to a lesser extent. While PLL-treated hydrogels were not favorable to the culture of any glioblastoma cell lines, they enhanced the proliferation of breast cancer cells in a stiffness-dependent manner. Contrary to type III collagen, type IV collagen pre-treated hydrogels supported the proliferation of glioblastoma cells. The as-desired HA-based 3D tumor-like models we developed may provide a useful platform for the study of various cancer cells by simply tuning their biochemical composition and their mechanical properties.

Topics: Biomechanical Phenomena; Biomimetic Materials; Breast Neoplasms; Cell Line, Tumor; Cell Proliferation; Cross-Linking Reagents; Extracellular Matrix; Female; Glioblastoma; Humans; Hyaluronic Acid; Hydrogels; Iridoids; Neoplasms; Tumor Microenvironment

Photothermal nanodrugs based on biomolecules are critically important for advancing photothermal therapy (PTT). However, constructing photothermal nanodrugs from biomolecules is highly challenging because most biomolecules are inherently nonpigmented. Herein, we synthesize well-defined, uniform photothermal nanodrugs through a covalent assembly approach by using nonpigmented peptides and iridoids as building blocks. The resulting photothermal nanodrugs show broad absorption from the UV to the near-infrared region, high photothermal conversion efficiency along with robust photostability, and selective tumor accumulation, leading to highly efficient tumor ablation via PTT. This work represents the first example of photothermal nanodrugs that can be constructed by using nonpigmented biomolecules as building blocks and thus will conceivably promote the preclinical evaluation and clinical translation of PTT.

Topics: Animals; Antineoplastic Agents; Drug Delivery Systems; Humans; Iridoids; Mice; Nanoparticles; Neoplasms; Peptides; Photochemotherapy

Organic photothermal sensitizers, such as indocyanine green (ICG), have been widely explored in photothermal therapy as a good substitute for inorganic materials owing to their advantageous biosafety and strong absorption in the near-infrared region. However, their intrinsic low stability and rapid clearance from the body requires further modification for efficient therapeutic application. In this work, we employed a covalent assembly strategy by covalently cross-linking genipin and a functional bola-amino acid to fabricate stable and degradable nanoparticles capable of loading ICG. The covalent assembly introduced strong covalent interactions in the assembly system together with functional linkers, which led to both enhanced stability and extended functionalities. This is distinguished from the conventional supramolecular strategy that relies only on weak noncovalent interactions. The functional building unit, consisting of phenylalanine and the disulfide bond, enables both good assembly and controllable degradation owing to the disulfide bond that responds to glutathione. The assembled nanoparticles show high stability, negligible toxicity, and considerable biodegradability. After loading ICG, the ICG-loaded nanoparticles possessed high photothermal conversion efficiency, and showed an enhanced photothermal effect in the near-infrared region. This covalent assembly strategy could be extended to various biomolecules containing a primary amino group for the fabrication of efficient and multifunctional nanomaterials used in biomedical applications.

Topics: Amino Acids; Apoptosis; Drug Carriers; Glutathione; Humans; Indocyanine Green; Iridoids; Light; MCF-7 Cells; Microscopy, Electron, Transmission; Nanoparticles; Neoplasms; Photosensitizing Agents; Phototherapy; Spectrometry, Fluorescence; Temperature

Here, we have reported the influence of MMT and genipin in releasing curcumin from the Genipin crosslinked Chitosan/MMT nanoparticles, prepared by ionic gelation method. The nanoparticles were characterised using Fourier Transform Infrared Spectroscopy (FTIR), X-Ray Diffractometry (XRD), Scanning Electron Microscopy (SEM), and Transmission Electron Microscopy (TEM). Zeta potential and average diameter of the nanoparticles were found in the range 32-47 mV and 430-560 nm. Swelling and release of curcumin from the nanoparticles increased with the decrease in pH of the medium, MMT, and genipin content. Curcumin released from the nanoparticles reduced the viability of MCF-7 and Hep G2 cells as compared to untreated cells. The nanoparticles increased the level of reduced glutathione (GSH), superoxide dismutase (SOD), and catalase level in human PBMCs and decreased the level of Lipid peroxidation suggesting an enhanced protection against cellular damage. Lower pH and higher MMT concentration in the nanoparticles improved the mucoadhesive properties.

Topics: Antineoplastic Agents; Bentonite; Cell Survival; Chitosan; Cross-Linking Reagents; Curcumin; Delayed-Action Preparations; Drug Liberation; Hep G2 Cells; Humans; Iridoids; MCF-7 Cells; Neoplasms

Nyctanthes arbortristis Linn (Oleaceae) is widely distributed in sub-Himalayan regions and southwards to Godavari, India commonly known as Harsingar and Night Jasmine. In continuation of our drug discovery programme on Indian medicinal plants, we isolated arbortristoside-A (1) and 7-O-trans-cinnamoyl 6β-hydroxyloganin (2) from the seeds of N. Arbortristis, which exhibited moderate in vitro anticancer activity. Chemical transformation of 2 led to significant improvement in the activity in derivative 8 and 15 against HepG2 (human hepatocellular carcinoma), MCF-7 (breast adenocarcinoma) cell lines. The compounds 8 and 15 were also capable of cell cycle arrest and caspase dependent apoptosis in HepG2 cell lines. These iridoid derivatives hold promise for developing safer alternatives to the marketed drugs.

Topics: Antineoplastic Agents, Phytogenic; Apoptosis; Breast Neoplasms; Carcinoma, Hepatocellular; Caspases; Cell Cycle Checkpoints; Cinnamates; Hep G2 Cells; Humans; India; Iridoid Glucosides; Iridoids; Liver Neoplasms; MCF-7 Cells; Neoplasms; Oleaceae; Phytotherapy; Plant Extracts; Seeds

Stachys alopecuros subsp. divulsa (Lamiaceae), a perennial herb endemic to central Italy growing on mountain pastures, was investigated for the first time for the content of secondary metabolites, for the micromorphology and histochemistry of glandular trichomes, and for the biological activity of the volatile oil, namely cytotoxic, antioxidant and antimicrobial. The plant showed the molecular pattern of iridoids, among which a new iridoid diglycoside (4'-O-β-D-galactopyranosyl-teuhircoside) was detected, together with a sterol glucoside and a phenylethanoid glycoside. The essential oil from the flowering aerial parts was characterized by a high proportion of sesquiterpene hydrocarbons (65.1%), with (E)-caryophyllene (33.2%) as the most abundant, while other main components were germacrene D (7.6%), α-humulene (6.4%) and the oxygenated cis-sesquisabinene hydrate (10.2%). Taken together, polar and apolar chemical profiles support the classification of the species within the section Betonica of the genus Stachys. Micromorphological study revealed three types of glandular hairs secreting different classes of compounds, with type A peltate hairs producing the bulk of the essential oil. MTT assay revealed the potential of the volatile oil in inhibiting A375, HCT116 and MDA-MB 231 tumor cells (IC₅₀ values below 20 μg/ml).

Topics: Antineoplastic Agents, Phytogenic; Antioxidants; Bacteria; Cell Line, Tumor; Classification; Flowering Tops; Humans; Iridoids; Italy; Neoplasms; Oils, Volatile; Phytotherapy; Plant Extracts; Sesquiterpenes; Stachys; Trichomes

Investigation of the crude extract obtained from the aerial parts of Canthium multiflorum led to the isolation of a new iridoid (1) together with twelve known compounds. The structures of these compounds were elucidated by interpretation of 1D and 2D NMR spectroscopic data, accurate mass measurements and comparison with analytical data of previously known analogues. Most of the isolated compounds have been reported for the first time from C. multiflorium. The antimicrobial activities of the isolated compounds were evaluated on five different bacterial strains using agar diffusion technique. The Gram-positive bacterium Staphylococcus aureus subsp. aureus (DSM 799), and the Gram-negative bacteria Actinobacter calco-aceticus (DSM 30006), Serratia plymuthica (DSM 4540), Pseudomonas stutzeri (DSM 4166) and Escherichia coli (DSM 1116) were employed for this purpose. The new iridoid, named 6-oxo-genipin (1), demonstrated significant inhibitory activity against all microbial strains tested, especially the pathogen Staphylococcus aureus. In addition, the compounds 3, 4 and 9 exhibited antiplasmodial activity against Plasmodium falciparum strain K1 and weak cytotoxicity against L6 cell lines.

Topics: Animals; Anti-Bacterial Agents; Antineoplastic Agents, Phytogenic; Antiparasitic Agents; Bacteria; Cameroon; Cell Line, Tumor; Iridoids; Molecular Structure; Monoterpenes; Neoplasms; Phytotherapy; Plant Components, Aerial; Plant Extracts; Plants, Medicinal; Plasmodium falciparum; Rats; Rubiaceae

Iridoids belong to a group of monoterpene compounds with cyclopentane ring and found as mostly the glycoside forms in nature. They act primarily as the defense substances and found in various medicinal plants.. Although many iridoids exhibit anti-inflammatory and anticancer activities, their molecular targets/pathways are not fully understood. Here, the antiproliferative effect of the hydrolyzed-iridoid product (H-iridoid) form through the STAT3 signaling pathways on tumor cells was investigated.. H-iridoids were obtained from five iridoid glycosides with β-glucosidase treatment. The effects of several H-iridoids on cell viability and cell proliferation in tumor cells were measured by the MTT assay. The phosphorylation levels of STAT3, its regulatory molecules, and apoptosis by H-geniposide treatment in DU145 cells were investigated by immunoblots and flow cytometry.. No single iridoid glycoside exerted any cytotoxicity in the tumor cells, whereas H-iridoids had significant cytotoxic, antiproliferative, and STAT3 inhibitory effects and revealed different potencies depending on their chemical structures. Among the H-iridoids tested, H-geniposide inhibited constitutive STAT3 activation through inhibiting upstream JAK1 and c-Src. Consistent with STAT3 inactivation, H-geniposide downregulated the expressions of Bcl-2, Bcl-xL, survivin, and cyclin D1; this correlated with the accumulation of cells in the sub-G1 phase of the cell cycle and the induction of apoptosis.. Our results indicate that the hydrolysis of the glycosidic bond from iridoid glycoside is required for exhibiting cytotoxicity in tumor cells. H-geniposide is the most potent agent and a novel blocker of STAT3 activation in DU145 cells.

Topics: Antineoplastic Agents, Phytogenic; Apoptosis; Cell Cycle; Cell Line, Tumor; Cell Proliferation; Flow Cytometry; Gene Expression Regulation, Neoplastic; Humans; Hydrolysis; Iridoid Glycosides; Iridoids; Neoplasms; Signal Transduction; STAT3 Transcription Factor

Cancer cells exhibit an endogenous constitutive oxidative stress higher than that of normal cells, which renders tumours vulnerable to further reactive oxygen species (ROS) production. Mitochondrial uncoupling protein 2 (UCP2) can mitigate oxidative stress by increasing the influx of protons into the mitochondrial matrix and reducing electron leakage and mitochondrial superoxide generation. Here, we demonstrate that chemical uncouplers or UCP2 over-expression strongly decrease mitochondrial superoxide induction by the anticancer drug gemcitabine (GEM) and protect cancer cells from GEM-induced apoptosis. Moreover, we show that GEM IC(50) values well correlate with the endogenous level of UCP2 mRNA, suggesting a critical role for mitochondrial uncoupling in GEM resistance. Interestingly, GEM treatment stimulates UCP2 mRNA expression suggesting that mitochondrial uncoupling could have a role also in the acquired resistance to GEM. Conversely, UCP2 inhibition by genipin or UCP2 mRNA silencing strongly enhances GEM-induced mitochondrial superoxide generation and apoptosis, synergistically inhibiting cancer cell proliferation. These events are significantly reduced by the addition of the radical scavenger N-acetyl-l-cysteine or MnSOD over-expression, demonstrating a critical role of the oxidative stress. Normal primary fibroblasts are much less sensitive to GEM/genipin combination. Our results demonstrate for the first time that UCP2 has a role in cancer cell resistance to GEM supporting the development of an anti-cancer therapy based on UCP2 inhibition associated to GEM treatment.

Topics: Acetylcysteine; Apoptosis; Cell Line, Tumor; Cell Proliferation; Deoxycytidine; Drug Resistance, Neoplasm; Gemcitabine; Gene Expression Regulation, Neoplastic; Humans; Ion Channels; Iridoids; Mitochondrial Proteins; Neoplasms; Poly(ADP-ribose) Polymerases; RNA, Messenger; Superoxide Dismutase; Superoxides; Uncoupling Agents; Uncoupling Protein 2

To study the antitumor effect of phlomiol extracted from Phlomis younghusbandii in vivo and in vitro. The inhibitory effect of phlomiol on two kinds of human tumor cells proliferation was assayed by MTT method. Transplant tumor models of S180 and H22 were used. After transplantation, different doses of phlomiol were given to the mice for 14 days. The inhibitory rates were calculated. MTT method was used to assess the proliferation of T spleen lymphocyte cells and the activity of NK cells in tumor-bearing mice with S180. Phlomiol (50-100 mg x L(-1)) inhibited the proliferation of three kinds of tumor cells in vitro, antitumor effect of phlomiol was in a dose-dependent manner (r = 0.989, P < 0.05). The inhibitory rates of phlomiol (2.5, 5, 10 mg x kg(-1)) were 28.5%-65.0% and 35.0%-74.5% in tumor-bearing mice with S180 and H22 respectively, It could stimulate the spleen T-cells in tumor-bearing mice with S180 and increase the activity of the NK cells. Phlomiol could inhibit the proliferation of three kinds of tumor cells in vitro, present antitumor effect on the tumor-bearing mice, and improve the immunological function.

Topics: Animals; Antineoplastic Agents, Phytogenic; Cell Line, Tumor; Cell Proliferation; Disease Models, Animal; Humans; Iridoid Glucosides; Iridoids; Lymphocytes; Male; Mice; Mice, Inbred ICR; Neoplasms; Phlomis

The cytotoxic activity of Stachys plants and of aucubin and harpagide against MCF7-breast adenocarcinoma, HeLa-cervix adenocarcinoma, A431-skin carcinoma of epithelial origin is reported in this study. Cisplatin and doxorubicin were use as reference compound.

Topics: Antineoplastic Agents, Phytogenic; Cell Line, Tumor; Cell Proliferation; Cytotoxins; Female; Glucosides; Humans; Iridoid Glucosides; Iridoid Glycosides; Iridoids; Neoplasms; Phytotherapy; Plant Components, Aerial; Plant Extracts; Pyrans; Stachys

The discovery of new topoisomerase I inhibitors is necessary since most of the antitumor drugs are targeted against type II and only a very few can specifically affect type I. Topoisomerase poisons generate toxic DNA damage by stabilization of the covalent DNA-topoisomerase cleavage complex and some have therapeutic efficacy in human cancer. Two iridoids, aucubin and geniposide, have shown antitumoral activities, but their activity against topoisomerase enzymes has not been tested. Here it was found that both compounds are able to stabilize covalent attachments of the topoisomerase I subunits to DNA at sites of DNA strand breaks, generating cleavage complexes intermediates so being active as poisons of topoisomerase I, but not topoisomerase II. This result points to DNA damage induced by topoisomerase I poisoning as one of the possible mechanisms by which these two iridoids have shown antitumoral activity, increasing interest in their possible use in cancer chemoprevention and therapy.

Topics: Camptothecin; DNA Damage; DNA Topoisomerases, Type I; DNA Topoisomerases, Type II; Enzyme Inhibitors; Glucosides; Humans; Iridoid Glucosides; Iridoids; Neoplasms; Pyrans; Topoisomerase I Inhibitors; Topoisomerase II Inhibitors; Tumor Cells, Cultured