Essential oil of Foeniculum vulgare subsp. piperitum fruits exerts an anti‑tumor effect in triple‑negative breast cancer cells

At present, the growing spread of tumor cases worldwide renders the research of new promising and selective anticancer drugs urgent. The biological action of extracts of medicinal plants or their essential oils (EOs) is an emerging field of interest, since they could comprise a rich source of phytochemicals that can prove promising. In the present study, the biological activity and mechanism of action of the EO of Foeniculum vulgare subsp. piperitum fruits (FVPEO) were investigated using MTT assays, morphological analyses and western blotting in MDA‑MB231 cells, a triple‑negative breast cancer cell line. The findings revealed that FVPEO could exert strong anticancer effects, causing a dose‑…

A Deadly Liaison between Oxidative Injury and p53 Drives Methyl-Gallate-Induced Autophagy and Apoptosis in HCT116 Colon Cancer Cells

Methyl gallate (MG), which is a gallotannin widely found in plants, is a polyphenol used in traditional Chinese phytotherapy to alleviate several cancer symptoms. Our studies provided evidence that MG is capable of reducing the viability of HCT116 colon cancer cells, while it was found to be ineffective on differentiated Caco-2 cells, which is a model of polarized colon cells. In the first phase of treatment, MG promoted both early ROS generation and endoplasmic reticulum (ER) stress, sustained by elevated PERK, Grp78 and CHOP expression levels, as well as an upregulation in intracellular calcium content. Such events were accompanied by an autophagic process (16–24 h), where prolonging the …

The effect of 3-aminobenzamide, inhibitor of poly(ADP-ribose) polymerase, on human osteosarcoma cells

This study demonstrates that in human osteosarcoma cells treatment with 3-aminobenzamide (3-AB), a potent inhibitor of poly(ADP-ribose) polymerase (PARP), induces morphological and biochemical features of differentiation, the duration of which depends on whether or not the normal RB gene is expressed. In Saos-2 cells expressing a non-functional Rb protein, 3-AB treatment induced the formation of transient, short dendritic-like protrusions. In RB-transfected-Saos-2 cells (a clone previously generated in our laboratory that shows stable expression of wild-type Rb protein), 3-AB induced marked and prolonged changes with the formation of long dendritic-like protrusions and the appearance of ste…

pRb suppresses camptothecin-induced apoptosis in human osteosarcoma Saos-2 cells by inhibiting c-Jun N-terminal kinase

AbstractThis paper studies the cytotoxic effect induced by the topoisomerase I inhibitor camptothecin in human osteosarcoma Saos-2 cells, which lack p53 and contain a non-functional form of the product of the retinoblastoma gene, pRb. Cytotoxicity induced by camptothecin was dose- and time-dependent; the treatment with 100 nM camptothecin reduced cell viability by 50% at 32 h and by 75% at 72 h of exposure. The cytotoxic effect was caused by apoptosis, as ascertained by morphological evidence, acridine orange-ethidium bromide staining and flow cytometric analysis. Apoptosis was accompanied by both the activation of caspase-3 and the fragmentation of poly(ADP-ribose) polymerase. Treatment wi…

The Synergistic Effect of SAHA and Parthenolide in MDA-MB231 Breast Cancer Cells

The sesquiterpene lactone Parthenolide (PN) exerted a cytotoxic effect on MDA-MB231 cells, a triple-negative breast cancer (TNBC) cell line, but its effectiveness was scarce when employed at low doses. This represents an obstacle for a therapeutic utilization of PN. In order to overcome this difficulty we associated to PN the suberoylanilide hydroxamic acid (SAHA), an histone deacetylase inhibitor. Our results show that SAHA synergistically sensitized MDA-MB231 cells to the cytotoxic effect of PN. It is noteworthy that treatment with PN alone stimulated the survival pathway Akt/mTOR and the consequent nuclear translocation of Nrf2, while treatment with SAHA alone induced autophagic activity…

ER+-derived breast cancer stem cells reveal a high expression of the serpin protease inhibitor PI-9.

Introduction: Breast cancers (BC) are the major cause of death in women. More than 70% of BCs express high levels of estrogen receptor-α (ERα) and are sustained for their growth by the hormone. Estrogens seem to protect BC cells from apoptosis mediated by immunosurveillance associated with cytotoxic T lymphocytes and NK cells granzyme B release. However, the production of granzyme B inhibitor PI-9 by tumor cells causes a short-circuit in immunosurveillance’s signalling. Although it has been shown the role of PI-9 in BC cells, its presence has not been investigated in tumor stem cells so far. Methods: Cell viability was evaluated by MTT, cell cycle by propidium iodide staining; mRNA and prot…

Apoptotic effects of different drugs on cultured retinoblastoma Y79 cells

This paper deals with the apoptotic effect exerted in human retinoblastoma Y79 cells by a number of compounds. A remarkable effect was observed after treatment with DNA-damaging agents, such as camptothecin, etoposide, cisplatin and carboplatin; camptothecin was found to be the most efficacious. Treatment with these compounds induced the appearance of morphological features of apoptosis in the cells together with the distinct fragmentation of DNA, as shown by agarose gel electrophoresis. These effects were also accompanied by a remarkable increase in the level of p53. Many other compounds, which are not DNA-damaging agents, induced the morphological features of apoptosis but none of them we…

The Good and Bad of Nrf2: An Update in Cancer and New Perspectives in COVID-19

Nuclear factor erythroid 2-related factor 2 (Nrf2) is a well-known transcription factor best recognised as one of the main regulators of the oxidative stress response. Beyond playing a crucial role in cell defence by transactivating cytoprotective genes encoding antioxidant and detoxifying enzymes, Nrf2 is also implicated in a wide network regulating anti-inflammatory response and metabolic reprogramming. Such a broad spectrum of actions renders the factor a key regulator of cell fate and a strategic player in the control of cell transformation and response to viral infections. The Nrf2 protective roles in normal cells account for its anti-tumour and anti-viral functions. However, Nrf2 over…

Multifaceted Health Benefits of Mangifera indica L. (Mango): The Inestimable Value of Orchards Recently Planted in Sicilian Rural Areas

Historically, Mangifera indica L. cultivations have been widely planted in tropical areas of India, Africa, Asia, and Central America. However, at least 20 years ago its spreading allowed the development of some cultivars in Sicily, an island to the south of Italy, where the favourable subtropical climate and adapted soils represent the perfect field to create new sources of production for the Sicilian agricultural supply chain. Currently, cultivations of Kensington Pride, Keitt, Glenn, Maya, and Tommy Atkins varieties are active in Sicily and their products meet the requirements of local and European markets. Mango plants produce fleshy stone fruits rich in phytochemicals with an undispute…

Composizioni farmaceutiche per il trattamento di tumori epatici

The Histone Deacetylase Inhibitor ITF2357 (Givinostat) Targets Oncogenic BRAF in Melanoma Cells and Promotes a Switch from Pro-Survival Autophagy to Apoptosis.

Histone deacetylase inhibitors (HDACI) are epigenetic compounds that have been widely considered very promising antitumor agents. Here, we focus on the effects of the pan-HDAC inhibitor ITF2357 (Givinostat) in comparison with SAHA (Vorinostat) in melanoma cells bearing BRAF V600E oncogenic mutation. Our results indicate both ITF2357 and SAHA dose-dependently reduce the viability of BRAF-mutated SK-MEL-28 and A375 melanoma cells. The comparison of IC50 values revealed that ITF2357 was much more effective than SAHA. Interestingly, both inhibitors markedly decreased oncogenic BRAF protein expression levels, ITF2357 being the most effective compound. Moreover, the BRAF decrease induced by ITF23…

Multifaceted Healthy Benefits of Mangifera Indica L. (Mango): The Inestimable Value of an Orchard Recently Rooted in Sicilian Rural Areas

Historically, Mangifera indica L. cultivations have been widely rooted in tropical areas of India, Africa, Asia and Central America. However, at least 20 years ago its spreading allowed the development of some cultivars, also in Sicily, the South of Italy, where the favorable subtropical climate and adapted soils represent the perfect field to create new sources of production for Sicilian agricultural supply chain. Currently, cultivations of Kensington Pride, Keitt, Klenn, Maya and Tommy Atkins varieties are active in Sicilian island and their products meet the requirements of local and European markets. Mango plants produce fleshy stone fruits rich in phytochemicals with an undisputed nutr…

Chemical composition, cytotoxic effects, antimicrobial and antibiofilm activity of Artemisia arborescens (Vaill.) L. growing wild in the province of Agrigento, Sicily, Italy

Artemisia arborescens (Vaill.) L. is a perennial shrubby plant growing along the coastal strips of the Mediterranean region. It is used in traditional medicine. Its essential oil and solvent extracts exhibit a very interesting chemotherapeutic potential, which makes this plant useful in maintaining human health. The goal of this study was to determine the phytochemical composition of the petroleum ether and methanol extracts, as well as to evaluate anticancer activities and antimicrobial and biofilm formation reduction. Thirty-nine phytochemical compounds in negative ion mode, and 25 in positive ion mode were identified by HPLC-ESI-QTOF-MS. All four extracts reduced the viability of human M…

Role of insulin-like growth factors in autocrine growth of human retinoblastoma Y79 cells.

In this study, we have demonstrated that human retinoblastoma Y79 cells produce insulin-like growth factors (IGFs) type I and type II and release them into the medium. We have also ascertained, by means of competitive studies and cross-linking procedure, that Y79 cells contain the type-I IGF receptor (IGF-IR). Furthermore, surface-bound IGF-I is internalised by the receptor, then degraded to amino acids. Insulin, IGF-I and IGF-II caused down-regulation of IGF-IR; the effect is concentration and time dependant. Scatchard analysis demonstrated that incubation with insulin markedly decreased the binding capacity measured for IGF-I while the apparent Kd value calculated for IGF-I binding was no…

Insulin and IGFs induce apoptosis in chick embryo retinas deprived of L-glutamine

In chick embryo retinas, cultured in serum-free medium lacking L-glutamine, IGF-I, IGF-II and insulin induced apoptotic DNA fragmentation and cell death, IGF-I being the most efficacious compound. The apoptotic effect, which was particularly evident in retinas removed from 7-day-old chick embryos, declined with the age of the embryos and disappeared after day 11. Apoptosis appeared after a time lag of 8 h and then increased with time up to 16 h. Cycloheximide, an inhibitor of protein synthesis, was capable of entirely abolishing apoptotic cell death. The effect induced by IGFs or insulin was suppressed by the addition of glutamine. Cytokine-mediated apoptosis was also observed after withdra…

Parthenolide induces EGF receptor phosphorylation and superoxide anion production in MDA-MB231 breast cancer cells.

Amminoacidi e proteine

Le proteine sono macromolecole che svolgono svariate e importanti funzioni sia dinamiche che strutturali all’interno degli organismi viventi. Le funzioni dinamiche comprendono la catalisi enzimatica, il trasporto, il controllo metabolico e la contrazione. Dal punto di vista strutturale, le proteine sono componenti fondamentali del tessuto muscolare, connettivo e della matrice delle ossa. Tutte le proteine sono polimeri non ramificati formati dalla combinazione di soli 20 diversi amminoacidi, detti proteici, uniti tra loro tramite il legame peptidico. La vasta gamma di attività che possono svolgere le proteine dipende proprio dalla loro composizione amminoacidica variabile. Lo studio delle p…

The proteasome inhibitor bortezomib in programmed cell death and cancer therapy

The 26S proteasome is a ubiquitous enzyme complex which is responsible for degrading proteins that regulate essential cellular functions, such as cell-cycle control, cellular adhesion, proliferation, apoptosis and angiogenesis. The inhibition of proteasome dysregulates these signalling pathways, ultimately leading to cell cycle arrest and apoptosis in many cell types. Importantly, preclinical research has shown that cancer cells seem to be more sensitive to the proapoptotic effects of proteasome inhibition than normal cells. First-generation proteasome inhibitors lacked usefulness because of broad specificity and irreversible binding to the proteasome. However, the peptide boronic acid prot…

“Acetilazione di p53 e degli istoni nell’apoptosi indotta dal SAHA in cellule di epatoma umano HepG2”

The mechanism by which histone deacetylase inhibitors sensitize hepatoma and colon cancer cells to TRAIL-induced apoptosis

Combined treatment of caffeic acid and DMAPT induces AMPK dependent death in MDA-MB231 cells

Proteasome inhibitor Velcade induces apoptosis in hepatoma HepG2 cells stimulating both the extrinsic and the intrinsic apoptotic pathways.

5-Azacytidine Inhibits the Activation of Senescence Program and Promotes Cytotoxic Autophagy during Trdmt1-Mediated Oxidative Stress Response in Insulinoma β-TC-6 Cells

5-Azacytidine (5-azaC), a methyltransferase inhibitor and anticancer drug, can promote several cellular stress responses such as apoptosis, autophagy, and senescence. The action of 5-azaC is complex and can be modulated by dose, time of treatment, and co-administration with oxidants. Insulinoma is a rare pancreatic neuroendocrine tumor with limited chemotherapeutic options. In the present study, two cellular models of insulinoma were considered, namely NIT-1 and β-TC-6 mouse cells, to evaluate the effects of 5-azaC post-treatment during hydrogen peroxide-induced oxidative stress. 5-azaC attenuated the development of oxidant-induced senescent phenotype in both cell lines. No pro-apoptotic ac…

Apoptosis induced in hepatoblastoma HepG2 cells by the proteasome inhibitor MG132 is associated with hydrogen peroxide production, expression of Bcl-Xs and activation of caspase-3

This report is focused on the apoptotic effect induced by MG132, an inhibitor of 26S proteasome, in human hepatoma HepG2 cells. The results were compared with those obtained with non-transformed human Chang liver cells. MG132 reduced the viability of HepG2 cells in a time- and dose-dependent manner. The effect was in tight connection with the induction of apoptosis, as indicated by fluorescence microscopy and cytometric analysis, and was accompanied by a remarkable increase in the production of H2O2 and a reduction in mitochondrial transmembrane potential (Deltapsim). In addition cell death was prevented by antioxidants such as GSH, N-acetylcysteine or catalase. Western blot analysis showed…

JNK and AP-1 mediate apoptosis induced by bortezomib in HepG2 cells via FasL/caspase-8 and mitochondria-dependent pathways

The proteasome inhibitor bortezomib is an efficacious apoptotic agent in many tumor cells. This paper shows that bortezomib induced apoptosis in human hepatoma HepG2 cells associated with many modifications in the expression of survival or death factors. Although bortezomib increased the level of the protective factors HSP70 and HSP27, the effects of the drug that favour cell death were predominant. These events include accumulation of c-Jun, phospho-c-Jun and p53; increase in FasL level with activation of caspase-8; changes related to members of Bcl-2 family with increase in the level of pro-apoptotic members and decrease in that of anti-apoptotic ones; dissipation of mitochondrial potenti…

The sensitization of HepG2 and HT29 cells to TRAIL-induced apoptosis by histone deacetylase inhibitors is mediated by down-regulation of AKT and NF-kB.

Induction of apoptosis by arachidonic acid in human retinoblastoma Y79 cells: involvement of oxidative stress

Arachidonic acid administration caused apoptosis in Y79 cells, as shown by typical morphological changes, phosphatidylserine externalization, chromatin condensation, processing and activation of caspase-3 and cleavage of the endogenous caspase substrate poly-(ADP-ribose)-polymerase. Arachidonic acid also caused lamin B cleavage, suggesting caspase-6 activation. Arachidonic acid treatment was accompanied by increased formation of the lipid peroxidation end products malondialdehyde and 4-hydroxy-2-nonenal, lowering in reduced glutathione content and in mitochondrial membrane potential. Inhibiting glutathione synthesis sensitized Y79 cells to apoptosis-inducing stimuli, whilst replenishing red…

The Anti-Cancer Effect of Mangifera indica L. Peel Extract is Associated to γH2AX-mediated Apoptosis in Colon Cancer Cells

Ethanolic extracts from Mangifera indica L. have been proved to possess anti-tumor properties in many cancer systems. However, although most effects have been demonstrated with fruit pulp extract, the underlying molecular mechanisms of mango peel are still unclear. This study was designed to explore the effects of mango peel extract (MPE) on colon cancer cell lines. MPE affected cell viability and inhibited the colony formation trend of tumor cells, while no effects were observed in human dermal fibroblasts used as a non-cancerous cell line model. These events were a consequence of the induction of apoptosis associated to reactive oxygen species (ROS) production, activation of players of th…

Phytochemical-rich extracts of Helianthemum lippii possess antimicrobial, anticancer, and anti-biofilm activities

Helianthemum lippii is a perennial shrubby plant growing in the sandy environments of Italy, Mediterranean countries of North Africa and Middle East. H. lippii is used in traditional medicine but there are very few reports referring to the phytochemical characterization, the ethnopharmacology, and the biological activity of H. lippii. The goal of this study was todetermine the phytochemical composition of different H. lippii extracts, cold (CME) and hot (HME) methanol, cold (CPEE) and hot (HPEE) petroleum ether, as well as to evaluate their anticancer and antimicrobial activities and biofilm formation reduction. Fifty-fours phytocompounds have been determined by HPLC-UV-ESI-QTOF-MS analysis…

Parthenolide sensitizes human hepatocarcinoma cells to TRAIL-induced apoptosis

Induction of programmed cell death in human retinoblastoma Y79 cells by C2-ceramide.

C2-ceramide, a cell-permeable analogue of ceramide, induced significant, dose- and time-dependent death in human retinoblastoma Y79 cells. Dying cells strongly displayed the morphology of apoptosis as characterized by microscopic evidence of cell shrinkage, membrane blebbing, nuclear and chromatin condensation and degeneration of the nucleus into membrane-bound apoptotic bodies. Upon induction of apoptosis Y79 cells evidence early phosphatidylserine externalization, as shown by annexin V-FITC. Apoptosis was also assessed by monitoring changes in cell granularity by staining with the combined fluorescent dyes acridine orange and ethidium bromide. C2-ceramide induced these morphological chang…

Natural and Synthetic Compounds for Management, Prevention and Treatment of Obesity

For a long time, adipose tissue has been considered an inert tissue involved in fat accumulation. Indeed, this tissue acts as an energy reserve, synthesizing and storing triacylglycerols from an excess of lipids and carbohydrates in feeding conditions (or degrading them in fasting ones). However, over the last few decades, emerging evidences has highlighted that adipose tissue serves as endocrine organ which is able to synthesize and secrete a significant amount of hormones, cytokines, and enzymes [1]. The substances produced and released by adipose tissue are known as adipokines and are able to act locally through autocrine/paracrine mechanisms or to influence the response of many organs a…

Chick embryo retina development in vitro: the effect of insulin.

In this paper we study the development of chick embryo retina cultured in vitro and the effects exerted by insulin. Retinas were removed from 7-day embryos and cultured in serum- and hormone-free medium for 7 additional days. Under these conditions retinal cells survived and underwent cholinergic differentiation, as previously ascertained by Hausman et al. (Dev. Brain Res., 1991, 59: 31-37). However, a great retardation of development was noted compared to uncultured control, 14-day retina. In fact both wet weight and DNA and protein content increased much slower than in ovo and the tubulin content decreased below even the starting value. In addition, although after 7 days in culture retina…

Anthranilamide-based 2-phenylcyclopropane-1-carboxamides, 1,1'-biphenyl-4-carboxamides and 1,1'-biphenyl-2-carboxamides: Synthesis biological evaluation and mechanism of action

Abstract Several anthranilamide-based 2-phenylcyclopropane-1-carboxamides 13a-f, 1,1’-biphenyl-4-carboxamides 14a-f and 1,1’-biphenyl-2-carboxamides 17a-f were obtained by a multistep procedure starting from the (1S,2S)-2-phenylcyclopropane-1-carbonyl chloride 11, the 1,1'-biphenyl-4-carbonyl chloride 12 or the 1,1'-biphenyl-2-carbonyl chloride 16 with the appropriate anthranilamide derivative 10a-f. Derivatives 13a-f, 14a-f and 17a-f showed antiproliferative activity against human leukemia K562 cells. Among these derivatives 13b, 14b and 17b exerted a particular cytotoxic effect on tumor cells. Derivative 17b showed a better antitumoral effect on K562 cells than 13b and 14b. Analyses perfo…

SICILIAN MANGO PEEL INDUCES CELLULAR STRESS ACCOMPANIED TO MITOCHONDRIAL DYSFUNCTION IN COLON CANCER CELLS

Currently, cellular stresses as the oxidative, metabolic and genotoxic stress are considered the cause of many different human pathologies as neurodegenerative diseases (e.g.,Alzheimer’s, Parkinson’s, amyotrophic lateral sclerosis), alcoholic liver disease, chronic obstructive pulmonary disease, and also cancer. Although the role of cellular stress has been largely debated in cancer, nowadays some therapies aim to target the intracellular pro-oxidant/anti-oxidant balance triggering the tumor commitment to cell death. Therefore, it has become more necessary an improved understanding of cancer response to cellular stress that could be advantageous to develop cancer tailored therapies. In this…

Role of the acetylation of p53 and histones in SAHA-induced apoptosis in human hepatoma HepG2 cells.

Insulin synthesis in chick embryo retinas during development.

Retinas of chick embryos contain insulin (1) and further, are capable of synthesizing it, as demonstrated by incubating retinas at different ages (7th–18th day) with [3H]leucine. The synthesized radioactive insulin was isolated and assayed by means of a HPLC procedure. The synthesis of insulin was found to be highest in the youngest retinas studied (day 7), afterwards it declined with age except for an increment found at 14–15 day. Explants of chick embryo retinas, cultured in vitro, rapidly degraded insulin. Nevertheless, the content of immunoreactive insulin in retinal explants diminished slowly with the age of culture, so that, after 8 days of incubation, it was about 60% of the content …

Histone deacetylase inhibitors: Epigenetic drugs acting by pleiotropic apoptotic mechanism in tumor cells and highly potent in combination with other antitumor agents.

Histone deacetylase inhibitors induce in human hepatoma HepG2 cells acetylation of p53 and histones in correlation with apoptotic effects

This report shows that histone deacetylase inhibitors (HDACIs) induced apoptosis in human hepatoma HepG2 cells in a dose- and time-dependent manner. Trichostatin A (TSA), ITF2357 and suberoylanilide hydroxamic acid (SAHA), which were very effective agents, caused apoptotic effects after a lag phase of 12-16 h. In order to elucidate the mechanism of HDACIs action in HepG2 cells we have studied the effects of TSA, ITF2357 and SAHA on acetylation of p53 and histones H2A, H2B, H3 and H4. It was observed that HDACIs rapidly induced acetylation of these proteins, being the effects clearly visible already at 30 min of treatment at the same doses which caused apoptosis. Analysis of the immunocomple…

Parthenolide induces caspase-independent cell death mediated by AIF in osteosarcoma and melanoma cells.

Parthenolide, the major bioactive sesquiterpene lactone present in Feverfew (Tanacetum parthenium), has recently attracted considerable attention because of its complex pharmacological action involving anti-microbial, anti-inflammatory and anti-cancer effects. However, the mechanism of its cytotoxic effect on tumor cells still remains scarcely defined today. The aim of this study was to analyse the mechanism of parthenolide action on two lines of cancer cells, the human osteosarcoma MG63 and the melanoma SK-MEL-28 cells, on which parthenolide exerted its action inducing similar effects. Staining with Hoechst 33342 showed that parthenolide induced in the first phase of treatment (0-5 h) in m…

THE ROLE OF THE EXTRINSIC PATHWAY OF APOPTOSIS IN THE EFFECT INDUCED BY SAHA IN HUMAN HEPATOMA CELLS.

Parthenolide generates reactive oxygen species and autophagy in MDA-MB231 cells. A soluble parthenolide analogue inhibits tumour growth and metastasis in a xenograft model of breast cancer.

Triple-negative breast cancers (TNBCs) are clinically aggressive forms associated with a poor prognosis. We evaluated the cytotoxic effect exerted on triple-negative MDA-MB231 breast cancer cells both by parthenolide and its soluble analogue dimethylamino parthenolide (DMAPT) and explored the underlying molecular mechanism. The drugs induced a dose- and time-dependent decrement in cell viability, which was not prevented by the caspase inhibitor z-VAD-fmk. In particular in the first hours of treatment (1–3 h), parthenolide and DMAPT strongly stimulated reactive oxygen species (ROS) generation. The drugs induced production of superoxide anion by activating NADPH oxidase. ROS generation caused…

Parthenolide sensitizes hepatocellular carcinoma cells to trail by inducing the expression of death receptors through inhibition of STAT3 activation

This article shows that HepG2, Hep3B, and SK-Hep1 cells, three lines of human hepatocellular carcinoma (HCC) cells, are resistant to apoptosis induced by tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). Parthenolide, a sesquiterpene lactone found in European feverfew, has been shown to exert both anti-inflammatory and anti-cancer activities. This article demonstrates that co-treatment with parthenolide and TRAIL-induced apoptosis with synergistic interactions in the three lines of HCC cells. In order to explain these effects we ascertained that parthenolide increased either at protein or mRNA level the total content of death receptors TRAIL-R1 and -R2 as well as their surfac…

The analysis of estrogen receptor-α positive breast cancer stem-like cells unveils a high expression of the serpin proteinase inhibitor PI-9: Possible regulatory mechanisms

Abstract Breast cancer stem cells seem to play important roles in breast tumor recurrence and endocrine therapy resistance, although the underlying mechanisms have not been well established. Moreover, in some tumor systems the immunosurveillance failure against cancer cells has been related to the presence of the granzyme B inhibitor PI-9. This study explored the status of PI-9 in tumorspheres isolated from estrogen receptor-α positive (ERα+) breast cancer MCF7 cells. Studies were performed in tertiary tumorspheres which possess high levels of stemness markers (Nanog, Oct3/4 and Sox2) and self-renewal ability. The exposure to estrogens (17-β estradiol and genistein) increased the number and…

Post-translational modifications of hsp60 and its extracellular release via exosomes are induced by the histone deacetylase inhibitor (HDACi) SAHA in the mucoepidermoid tumor H292 cells.

The chaperonin Hsp60 has multiple functions, among which that of supporting the growth of some type of tumours (1). HDACi (histone-deacetylase inhibitors) are drugs that regulate gene expression via modulation of epigenetic mechanisms, and induce tumor-cell death (2). Here, we show that in the tumor cells H292 the HDACi SAHA decreases the intracellular level of Hps60 and promotes its extracellular trafficking by exosomal vesicles. SAHA caused a time- and dose-dependent decrease in cell viability with a G/2M cell-cycle arrest at 24 h and cell death at 48 h. These effects were accompanied by production of reactive oxygen species and mitochondrial membrane-potential dissipation. The marked dec…

p62: Friend or Foe? Evidences for OncoJanus and NeuroJanus Roles

p62 is a versatile protein involved in the delicate balance between cell death and survival, which is fundamental for cell fate decision in the context of both cancer and neurodegenerative diseases. As an autophagy adaptor, p62 recognizes polyubiquitin chains and interacts with LC3, thereby targeting the selected cargo to the autophagosome with consequent autophagic degradation. Beside this function, p62 behaves as an interactive hub in multiple signalling including those mediated by Nrf2, NF-κB, caspase-8, and mTORC1. The protein is thus crucial for the control of oxidative stress, inflammation and cell survival, apoptosis, and metabolic reprogramming, respectively. As a multifunctional pr…

Parthenolide induces caspase-independent and AIF mediated cell death in tumor cells

Anti-adipogenic potential of bio-waste products of Sicilian mango in 3T3-L1 cells

Synthesis, antiproliferative activity and possible mechanism of action of novel 2-acetamidobenzamides bearing the 2-phenoxy functionality.

Several new 2-(2-phenoxyacetamido)benzamides 17a-v, 21 and 22 were synthesized by stirring in pyridine the acid chlorides 16a-e and the appropriate5-R-4-R1-2-aminobenzamide 15a-e and initially evaluated in vitro for antiproliferative activity against the K562 (human chronic myelogenous leukemia) cell line. Some of synthesized compounds were evaluated for their in vitro antiproliferative activity against the full NCI tumor cell line panel derived from nine clinically isolated cancer types (leukemia, non-small cell lung, colon, CNS, melanoma, ovarian, renal, prostate and breast). The most active compounds caused an arrest of K562 cells in the G0-G1 phase of cell cycle and induction of apoptos…

Synthesis and antiproliferative activity of new derivatives containing the polycyclic system 5,7:7,13-dimethanopyrazolo[3,4-b]pyrazolo[3’,4’:2,3]azepino[4,5-f]azocine

The reaction under reflux between 1-phenyl-3-R-5-methylaminopyrazoles and 2,5-hexanedione lead to 5,7:7,13-dimethanopyrazolo[3,4-b]pyrazolo[3′,4′:2,3]azepino[4,5-f]azocine derivatives 3b–g. These unusual molecules show the structural complexity of many biologically active natural products and are endowed with the chemical diversity that is required in drug discovery. The compounds 3b,e were reduced by hydrogen in the presence of Palladium on activated charcoal to give the dihydro derivatives 5b,e. Compounds 3b–f and 5b,e were selected by the NCI to evaluate their in vitro antiproliferative activity against 60 human cell lines derived from nine clinically isolated cancer types (leukaemia, lu…

Ethanol-Mediated Stress Promotes Autophagic Survival and Aggressiveness of Colon Cancer Cells via Activation of Nrf2/HO-1 Pathway

Epidemiological studies suggest that chronic alcohol consumption is a lifestyle risk factor strongly associated with colorectal cancer development and progression. The aim of the present study was to examine the effect of ethanol (EtOH) on survival and progression of three different colon cancer cell lines (HCT116, HT29, and Caco-2). Our data showed that EtOH induces oxidative and endoplasmic reticulum (ER) stress, as demonstrated by reactive oxygen species (ROS) and ER stress markers Grp78, ATF6, PERK and, CHOP increase. Moreover, EtOH triggers an autophagic response which is accompanied by the upregulation of beclin, LC3-II, ATG7, and p62 proteins. The addition of the antioxidant N-acetyl…

SYNERGISTIC APOPTOTIC INTERACTION BETWEEN THE HDAC INHIBITOR SAHA AND THE PROTEASOME INHIBITOR BORTEZOMIB IN HUMAN HEPATOMA CELLS.

JNK AND AP-1 MEDIATE APOPTOSIS INDUCED BY BORTEZOMIB IN HEPATOMA HEPG2 CELLS.

The synergistic effect of SAHA and parthenolide in MDA-MB231 breast cancer cells

Abstract: The sesquiterpene lactone Parthenolide (PN) exerted a cytotoxic effect on MDA-MB231 cells, a triple-negative breast cancer (TNBC) cell line, but its effectiveness was scarce when employed at low doses. This represents an obstacle for a therapeutic utilization of PN. In order to overcome this difficulty we associated to PN the suberoylanilide hydroxamic acid (SAHA), an histone deacetylase inhibitor. Our results show that SAHA synergistically sensitized MDA-MB231 cells to the cytotoxic effect of PN. It is noteworthy that treatment with PN alone stimulated the survival pathway Akt/mTOR and the consequent nuclear translocation of Nrf2, while treatment with SAHA alone induced autophagi…

Histone deacetylase inhibitors: apoptotic effects and clinical implications (Review).

It has been shown that epigenetic modifications play an important role in tumorigenesis. Thus, affecting epigenetic tumorigenic alterations can represent a promising strategy for anticancer targeted therapy. Among the key chromatin modifying enzymes which influence gene expression, histone acetyltransferases (HATs) and histone deacetylases (HDACs) have recently attracted interest because of their impact on tumor development and progression. Increased expression of HDACs and disrupted activities of HATs have been found in several tumor types, with a consequent hypoacetylated state of chromatin that can be strictly correlated with low expression of either tumor suppressor or pro-apoptotic gen…

Evaluation of the in vitro and in vivo antineoplastic effects of Parthenolide on MDA-MB231 breast cancer cells

Triple-negative breast cancer refers to an aggressive subtype of breast cancer in which the tumor cells lack receptors for estrogen, progesterone and the HER2 protein on their surfaces. This type of breast cancer does not respond to treatments such as hormone therapy, like tamoxifen and aromatase inhibitors, or drugs that target HER2, like Herceptin. It is important, therefore, the identification of new selective drugs for the treatment of these tumors. Parthenolide (PN), a sesquiterpene lactone extracted from the medical plant Tanacetum parthenium, exerts anticancer activity on several tumor cell lines in culture, acting through diverse molecular mechanisms. Our previous studies have shown…

Staurosporine-induced apoptosis in Chang liver cells is associated with down-regulation of Bcl-2 and Bcl-XL.

A potent inhibitor of serine/threonine kinases, staurosporine exerts antiproliferative and apoptotic effects in many cancer cells, although the exact mechanism of its action is still unclear. This study examines the effects of staurosporine on Chang liver cells, an immortalized non-tumor cell line, in comparison with those caused in HuH-6 and HepG2 cells, two human hepatoma cell lines. Our results provide evidence that staurosporine promotes apoptosis in Chang liver cells as observed by flow cytometric analysis and acridine orange/ethidium bromide staining. The effect appeared already after 8 h of treatment and increased with treatment time and dose. After 48 h of exposure to 200 nM stauros…

Phytochemical investigation and antitumor activity of coumarins from Sicilian accession of Ferulago nodosa (L.) Boiss. roots

Ferulago nodosa (L.) Boiss. (Apiaceae) is a species occurring in the Balkan-Tyrrhenian area being present in Crete, Greece, Albania, and probably in Macedonia. From the roots of this accession of species, not previously investigated, four coumarins, grandivittin, aegelinol benzoate, felamidin and aegelinol, and two terpenoids, (2E)-3-methyl-4-[(3-methyl-1-oxo-2-buten-1yl)oxy]-2-butenoic acid and pressafonin-A, were isolated and spectroscopically characterized. The last one was never detected in Ferulago species. The evaluation of the anti-tumor effects of F. nodosa coumarins on colon cancer HCT116 cells showed only a modest effect on reduction of tumor cell viability. For aegelinol, the red…

Oxidative stress induced by the novel compound tributyltin(iv) ferulate promotes ER stress and autophagy in colon cancer cells

Synthesis and antiproliferative activity of a natural like glycoconjugate polycyclic compound

Abstract A natural like O -glycoconjugate polycyclic compound 4 was obtained by a multistep procedure starting from N -(3-methyl-1-(4-nitrophenyl)-1 H -pyrazol-5-yl)acetamide. The glycosyl derivative 4 showed antiproliferative activity against all the tumoral cell lines of the NCI panel in the range 0.47–5.43  μ M. Cytofluorimetric analysis performed on MDA-MB231, a very aggressive breast cancer cell line, which does not express estrogen, progesterone and HER-2/neu receptors, showed that 4 is able to induce prolonged cell cycle arrest at G2/M phase and morphological signs of differentiation. These events are correlated with down-regulation of both cyclin B1 and cdc2, the cyclins involved in…

ATTIVITÀ ANTIPROLIFERATIVA DI UN DERIVATO POLICICLICO CON STRUTTURA COMPLESSA

Un nuovo derivato policiclico glicosilato è stato ottenuto partendo dal derivato policiclico iodurato, utilizzando la reazione di Sonogashira.Il composto glicosilato saggiato presso l’NCI è risultato attivo su tutte le 60 linee cellulari tumorali del panel, risultando più attivo degli altri composti policiclici precedentemente saggiati. Il composto induce l’arresto del ciclo cellulare in fase G2/M nella linea cellulare MDA-MB231, fa diminuire i livelli di ciclina B1e Cdc-2 mentre produce un aumento dell’inibitore p21WAF1, una chinasi ciclino-dipendente.

Sodium phenylbutyrate induces apoptosis in human retinoblastoma Y79 cells: The effect of combined treatment with the topoisomerase I-inhibitor topotecan

Our results demonstrate that sodium phenylbutyrate, a compound with a low degree of toxicity, exerted a cytotoxic effect on human retinoblastoma Y79 cells in a time- and dose-dependent manner. Treatment of Y79 cells for 72 h with phenylbutyrate reduced cell viability by 63% at 2 mM and 90% at 4 mM. Cell death caused by phenylbutyrate exhibited the typical features of apoptosis, as shown by light and fluorescent microscopy. Western blot analysis demonstrated that exposure of Y79 cells to phenylbutyrate decreased the level of the antiapoptotic factor Bcl-2 and induced the activation of caspase-3, a key enzyme in the execution phase of apoptosis. Moreover, treatment with phenylbutyrate markedl…

Multimodal Strategies to Fight Obesity: Research on Tailored Therapies Based on Natural and Synthetic Compounds for Prevention, Management and Treatment

Synergistic cytotoxic interaction of the HDAC inhibitor SAHA with the natural compound parthenolide in MDA-MB231 breast cancer cells.

THE APOPTOTIC EFFECT INDUCED IN HepG2 CELLS BY INHIBITORS OF HISTONE DEACETYLASES IS CORRELATED WITH ACETYLATION OF p53 AND HISTONES.

Parthenolide and Its Soluble Analogues: Multitasking Compounds with Antitumor Properties

Due to its chemical properties and multiple molecular effects on different tumor cell types, the sesquiterpene lactone parthenolide (PN) can be considered an effective drug with significant potential in cancer therapy. PN has been shown to induce either classic apoptosis or alternative caspase-independent forms of cell death in many tumor models. The therapeutical potential of PN has been increased by chemical design and synthesis of more soluble analogues including dimethylaminoparthenolide (DMAPT). This review focuses on the molecular mechanisms of both PN and analogues action in tumor models, highlighting their effects on gene expression, signal transduction and execution of different ty…

The histone deacetylase inhibitor SAHA induces HSP60 nitration and its extracellular release by exosomal vesicles in human lung-derived carcinoma cells

// Claudia Campanella 1, 2, * , Antonella D'Anneo 3, * , Antonella Marino Gammazza 1, 2, * , Celeste Caruso Bavisotto 1, 2 , Rosario Barone 1, 2 , Sonia Emanuele 4 , Filippa Lo Cascio 1 , Emanuele Mocciaro 1 , Stefano Fais 5 , Everly Conway De Macario 6 , Alberto J.L. Macario 2, 6 , Francesco Cappello 1, 2 , Marianna Lauricella 4 1 Department of Experimental Biomedicine and Clinical Neurosciences, Section of Human Anatomy “Emerico Luna”, University of Palermo, Palermo, Italy 2 Euro-Mediterranean Institute of Science and Technology, Palermo, Italy 3 Department of Biological, Chemical and Pharmaceutical Sciences and Technologies, Laboratory of Biochemistry, University of Palermo, Palermo, Ita…

Doxorubicin anti-tumor mechanisms include Hsp60 post-translational modifications leading to the Hsp60/p53 complex dissociation and instauration of replicative senescence.

Hsp60 is a pro-carcinogenic chaperonin in certain tumor types by interfering with apoptosis and with tumor cell death. In these tumors, it is not known whether or not doxorubicin anti-tumor effects include a blockage of the pro-carcinogenic action of this protein. We used the human lung mucoepidermoid cell line NCI-H292 and different doses of doxorubicin to measure cell viability, cell cycle progression, cell senescence indicators, Hsp60 levels and its post-translational modifications as well as the release of the chaperonin into the extracellular environment. Cell viability was reduced in relation to doxorubicin dose and this was paralleled by the appearance of cell senescence markers. Con…

Synergistic effect of the HDAC inhibitor SAHA and the sesquiterpene lactone parthenolide in triple negative breast cancer cells.

The histone deacetylase inhibitor suberoylanilide hydroxamic acid sensitizes human hepatocellular carcinoma cells to TRAIL-induced apoptosis by TRAIL-DISC activation

Abstract This paper shows that the histone deacetylase inhibitor SAHA sensitised at sub-toxic doses human hepatocellular carcinoma cells (HepG2, Hep3B and SK-Hep1) to TRAIL-induced apoptosis, while it was ineffective in primary human hepatocytes (PHHs). In particular in HCC cells SAHA increased the expression of death receptor 5 (DR5) and caused a decrement of c-Flip. These two modifications provoked in the presence of TRAIL the rapid production of TRAIL-DISC and the activation of caspase-8. Consequently SAHA/TRAIL combination induced many apoptotic events, such as a cleavage of Bid into tBid, dissipation of mitochondrial membrane potential, activation of caspase-3 with the consequent cleav…

Il partenolide stimola la produzione di ROS e autofagia in cellule di carcinoma mammario MDA-MB231.Il suo analogo solubile DMAPT inibisce la crescita e le metastasi di xenotrapianti di tumori mammari.

Synergistic cytotoxic interactions between sodium butyrate, MG132 and camptothecin in human retinoblastoma Y79 cells.

This paper studies the effects caused in human retinoblastoma Y79 cells by treatment with combinations of sodium butyrate, the inhibitor of topoisomerase I camptothecin and the inhibitor of 26S proteasome MG132. The combination of sodium butyrate and camptothecin resulted in a strong synergistic cytotoxicity, as revealed by combination indices of 0.77 and 0.52 calculated at IC(50) and IC(75). Synergistic interactions were also demonstrated for combinations of sodium butyrate and MG132, camptothecin and MG132 and for a combination of all three compounds. The cytotoxic effects observed after the combined treatments can be considered a consequence of apoptosis, as suggested by the appearance o…

Oncogenic BRAF protein as a molecular target of HDAC inhibitors in melanoma cells

Isoxazolo[3,4-d]pyridazin-7(6H)-one derivatives endowed with anti-proliferative Activity.

Isoxazolo[3,4-d]pyridazin-7(6H)-one derivatives endowed with antiproliferative Activity B. Maggio1, G. Cancemi1, D. Raffa1, M. V. Raimondi1, F. Plescia1, A. D’Anneo2,M. Lauricella3, G. Barone4, R. Bonsignore4, G. Daidone1 1. Department of Biological, Chemical and Pharmaceutical Sciences and Technologies, Medicinal Chemistry and Pharmaceutical Technologies Section, University of Palermo, ViaArchirafi 32, 90123, Palermo, Italy 2. Department of Biological, Chemical and Pharmaceutical Sciences and Technologies, Laboratory of Biochemistry, University of Palermo. 3.Department of Experimental Biomedicine and Clinical Neurosciences, Laboratory of Biochemistry, University of Palermo. 4. Department o…

Novel 4-(3-phenylpropionamido), 4-(2-phenoxyacetamido) and 4-(cinnamamido) substituted benzamides bearing the pyrazole or indazole nucleus: synthesis, biological evaluation and mechanism of action

Based on some common structural features of known compounds interfering with p53 pathways and our previously synthesized benzamides, we synthesized new ethyl 5-(4-substituted benzamido)-1-phenyl-1H-pyrazole-4-carboxylates 26a-c, ethyl 5-(4-substituted benzamido)-1-(pyridin-2-yl)-1H-pyrazole-4-carboxylates 27a-c and N-(1H-indazol-6-yl)-4-substituted benzamides 31a,b bearing in the 4 position of the benzamido moiety the 2-phenylpropanamido or 2-phenoxyacetamido or cinnamamido groups. A preliminary test to evaluate the antiproliferative activity against human lung carcinoma H292 cells highlighted how compound 26c showed the best activity. This last was therefore selected for further studies wi…

Redox Imbalance and Mitochondrial Release of Apoptogenic Factors at the Forefront of the Antitumor Action of Mango Peel Extract

Today, an improved understanding of cancer cell response to cellular stress has become more necessary. Indeed, targeting the intracellular pro-oxidant/antioxidant balance triggering the tumor commitment to cell demise could represent an advantageous strategy to develop cancer-tailored therapies. In this scenario, the present study shows how the peel extract of mango—a tropical fruit rich in phytochemicals with nutraceutical properties—can affect the cell viability of three colon cancer cell lines (HT29, Caco-2 and HCT116), inducing an imbalance of cellular redox responses. By using hydro-alcoholic mango peel extract (MPE), we observed a consistent decline in thiol group content, which was a…

Insulin-like growth factors in chick embryo retina during development.

Evidence exists supporting an important role for insulin-like growth factors (IGFs) during fetal growth. In the present report we performed studies to define whether developing chick retina contains IGFs and whether IGFs play a role in the growth of this tissue. We have shown that both IGF-I and IGF-II are present in chick embryo retina throughout development (7th-18th day). The highest values, when expressed as ng/g of tissue, were found in the youngest retinas studied (7th-9th day) and at 16th-18th day of development. During whole development the content of IGF-II was about two to three times higher than that ascertained for IGF-I. The tissue also contains cell-surface binding for IGFs. H…

Synthesis and antiproliferative activity of a natural like glucosyl polycyclic compound

A new polycylic compound was synthesized and evaluated for its antiproliferative activity against the NCI panel of human tumoral cell lines showing IC50 values in the range 0.47-5.43 µM. The compound induced a decrease of the level of cyclin B1, whereas increased the level of the inhibitor p21 WAF1

Synergistic interaction between Parthenolide and TRAIL induces apoptosis in human hepatocarcinoma cells.

Partenolide, a natural compound used in traditional medicine for its anti-inflammatory activity, has recently shown anti-tumor and apoptotic effects. Our studies demonstrated that HepG2; Hep3B and SK-Hep1 hepatocarcinoma cells, which are resistant to human recombinant TRAIL, are potently sensitized to TRAIL-induced apoptosis by low doses of parthenolide resulting in a marked synergist effect. To clarify the mechanism that accounts for this interaction, we demonstrated that parthenolide/TRAIL combination markedly increased DR4 and DR5. These effects might be correlated with STAT proteins modifications. In fact parthenolide and parthenolide/TRAIL combination decreased STAT3 and STAT5 and thei…

“Effects of histone deacetylase inhibitors in human hepatoma cells and synergistic apoptotic interaction with the proteasome inhibitor Bortezomib”

Parthenolide induces caspase-independent cell death in osteosarcoma, melanoma and breast cancer cells through the induction of oxidative stress.

Parthenolide, a sesquiterpene lactone found in European feverfew, is used in traditional medicine for its anti-inflammatory activity. In addition, parthenolide has been considered as a novel and effective anti-tumor agent because it induces cytotoxic effects in several tumor cell lines. Our studies demonstrated that parthenolide exerted strong cytotoxic effects in osteosarcoma MG63 and melanoma SK-Mel28 cells in culture. Staining with Hoechst 33342 revealed in most cells after brief periods of treatments (3-5h) chromatin condensation and fragmentation, while only few cells were PI-positive. Prolonging the treatment (5-14h) PI-positive cells strongly augmented, denouncing the increase of nec…

New complex polycyclic compounds: Synthesis, antiproliferative activity and mechanism of action

Abstract Polycyclic or O-glycoconiugate polycyclic compounds 1a-g were previously tested for their in vitro antiproliferative activity. In this series of compounds, activity increases as log P decreases. Specifically, compounds 1d and 1g showed lower log P values together with the best antiproliferative profiles. With the aim of extending our understanding of the structure–activity relationship (SAR) of this class of compounds, we prepared new polycyclic derivatives 2a-c, which bear on each of the two phenyl rings hydrophilic substituents (OH, SO2NH2 or NHCOCH3). These substituents are able to form hydrogen bonds and to decrease the partition coefficient value as compared with compound 1d. …

The Beneficial Effects of Essential Oils in Anti-Obesity Treatment

Obesity is a complex disease caused by an excessive amount of body fat. Obesity is a medical problem and represents an important risk factor for the development of serious diseases such as insulin resistance, type 2 diabetes, cardiovascular disease, and some types of cancer. Not to be overlooked are the psychological issues that, in obese subjects, turn into very serious pathologies, such as depression, phobias, anxiety, and lack of self-esteem. In addition to modifying one’s lifestyle, the reduction of body mass can be promoted by different natural compounds such as essential oils (EOs). EOs are mixtures of aromatic substances produced by many plants, particularly in medicinal and aromatic…

Anti tumor action of the natural compound parthenolide

SAHA induces acetylation of p53 and histones in human hepatoma HepG2 cells

Parthenolide induces caspase-independent and AIF-mediated cell death in human osteosarcoma and melanoma cells

The mechanism of the cytotoxic effect exerted by parthenolide on tumor cells is not clearly defined today. This article shows that parthenolide stimulates in human osteosarcoma MG63 and melanoma SK-MEL-28 cells a mechanism of cell death, which is not prevented by z-VAD-fmk and other caspase inhibitors. In particular treatment with parthenolide rapidly stimulated (1-2 h) reactive oxygen species (ROS) generation by inducing activation of extracellular signal-regulated kinase 1/2 (ERK 1/2) and NADPH oxidase. This event caused depletion of thiol groups and glutathione, NF-κB inhibition, c-Jun N-terminal kinase (JNK) activation, cell detachment from the matrix, and cellular shrinkage. The increa…

THE APOPTOTIC EFFECT EXERTED IN HUMAN HEPATOMA CELLS BY THE INHIBITOR OF HISTONE DEACETYLASE SAHA EITHER ALONE OR IN COMBINATION WITH BORTEZOMIB.

Histone deacetylase inhibitors in cancer therapy: Biological and clinical implications.

Influencing epigenetic tumorigenic modifications is an exciting strategy for anticancer drug development. Acetylation/deacetylation of histones, a process catalysed by histone acetyltransferases (HATs) and Histone deacetylases (HDACs) respectively, is an important modality to regulate chromatin remodelling and consequent gene expression. Aberrant expression of HDACs and disrupted activities of HATs have been found in several tumor types, implicating their involvement in cancer. Histone deacetylase inhibitors (HDACi) represent a new and promising class of anti-tumor drugs that influence gene expression by enhancing the acetylation of histones. HDAC inhibitors have been shown to have potent a…

WIN55,212-2-induced expression of Mir-29b1 favours the suppression of osteosarcoma cell migration in a SPARC-independent manner

WIN55,212-2 (WIN) is a synthetic agonist of cannabinoid receptors that displays promising antitumour properties. The aim of this study is to demonstrate that WIN is able to block the migratory ability of osteosarcoma cells and characterize the mechanisms involved. Using wound healing assay and zymography, we showed that WIN affects cell migration and reduces the activity of the metalloproteases MMP2 and MMP9. This effect seemed to be independent of secreted protein acidic and rich in cysteine (SPARC), a matricellular protein involved in tissue remodeling and extracellular matrix deposition. SPARC release was indeed prevented by WIN, and SPARC silencing by RNA interference did not influence …

Hypertrophy and ER Stress Induced by Palmitate Are Counteracted by Mango Peel and Seed Extracts in 3T3-L1 Adipocytes

A diet rich in saturated fatty acids (FAs) has been correlated with metabolic dysfunction and ROS increase in the adipose tissue of obese subjects. Thus, reducing hypertrophy and oxidative stress in adipose tissue can represent a strategy to counteract obesity and obesity-related diseases. In this context, the present study showed how the peel and seed extracts of mango (Mangifera indica L.) reduced lipotoxicity induced by high doses of sodium palmitate (PA) in differentiated 3T3-L1 adipocytes. Mango peel (MPE) and mango seed (MSE) extracts significantly lowered PA-induced fat accumulation by reducing lipid droplet (LDs) and triacylglycerol (TAGs) content in adipocytes. We showed that MPE a…

Oncogenic BRAF and p53 Interplay in Melanoma Cells and the Effects of the HDAC Inhibitor ITF2357 (Givinostat)

Oncogenic BRAF mutations have been widely described in melanomas and promote tumour progression and chemoresistance. We previously provided evidence that the HDAC inhibitor ITF2357 (Givinostat) targets oncogenic BRAF in SK-MEL-28 and A375 melanoma cells. Here, we show that oncogenic BRAF localises to the nucleus of these cells, and the compound decreases BRAF levels in both the nuclear and cytosolic compartments. Although mutations in the tumour suppressor p53 gene are not equally frequent in melanomas compared to BRAF, the functional impairment of the p53 pathway may also contribute to melanoma development and aggressiveness. To understand whether oncogenic BRAF and p53 may cooperate, a po…

Effetti benefici degli oli essenziali nel trattamento anti-obesità

The involvement of the c-Jun/JNK/AP-1 pathway and HSPs in apoptosis induced by the proteasome inhibitor PS-341 (Velcade) in human hepatoma cells.

The apoptotic effects of cisplatin and carboplatin in retinoblastoma Y79 cells.

This study demonstrated that cisplatin and carboplatin stimulate apoptosis in human retinoblastoma Y79 cells, cisplatin being the most effective compound. The apoptotic effect appeared after 8 h and then increased in a time-dependent manner. Treatment with cisplatin and carboplatin also provoked an increase in the level of p53 and p21, and a lowering in Bcl-2. The prolonged exposure of Y79 cells to cisplatin induced resistance to cisplatin, carboplatin and etoposide. The basal level of p53 was in resistant cells higher than in untreated cells, while Bcl-2 was not modified. p53 and Bcl-2 levels did not change after treating of resistant cells with cisplatin, carboplatin or etoposide. However…

METHYL GALLATE, A PHYTOCHEMICAL DERIVATIVE OF GALLIC ACID, INDUCES AUTOPHAGY AND APOPTOTIC CELL DEMISE IN HUMAN COLON CANCER CELLS

The mechanism of parthenolide-induced cell death in tumor cell lines.

Western Blotting Analysis

Sodium butyrate induces apoptosis in human hepatoma cells by a mitochondria/caspase pathway, associated with degradation of beta-catenin, pRb and Bcl-XL.

Butyrate can promote programmed cell death in a number of tumour cells in vitro. This paper provides evidence that butyrate induces apoptosis in human hepatoma HuH-6 and HepG2 cells but is ineffective in Chang liver cells, an immortalised non-tumour cell line. In both HuH-6 and HepG2 cells, apoptosis appeared after a lag period of approximately 16 h and increased rapidly during the second day of treatment. In particular, the effect was stronger in HuH-6 cells, which were, therefore, chosen for ascertaining the mechanism of butyrate action. In HuH-6 cells, beta-catenin seemed to exert an important protective role against apoptosis, since pretreatment with beta-catenin antisense ODN reduced t…

SAHA/TRAIL combination induces detachment and anoikis of MDA-MB231 and MCF-7 breast cancer cells

Abstract SAHA, an inhibitor of histone deacetylase activity, has been shown to sensitize tumor cells to apoptosis induced by TRAIL, a member of TNF-family. In this paper we investigated the effect of SAHA/TRAIL combination in two breast cancer cell lines, the ERα−positive MCF-7 and the ERα−negative MDA-MB231. Treatment of MDA-MB231 and MCF-7 cells with SAHA in combination with TRAIL caused detachment of cells followed by anoikis, a form of apoptosis which occurs after cell detachment, while treatment with SAHA or TRAIL alone did not produce these effects. The effects were more evident in MDA-MB231 cells, which were chosen for ascertaining the mechanism of SAHA/TRAIL action. Our results show…

Possible regulatory mechanisms responsible for the high expression of serpin protease inhibitor PI-9 in ER+ -derived breast cancer stem cells.

Breast cancer (BC) is the most common endocrine cancer and the second leading cause of cancer-related death in women. About 75% of BCs expresses high levels of estrogen receptors that sustain the tumor growth. Moreover, in BC estrogens prevent apoptosis induced by granzyme B released by cytotoxic T lymphocytes and NK cells through the production of the granzyme B inhibitor PI-9. As a consequence, cancer cells acquire the ability to escape immune surveillance’s signaling. Although some studies explored the role of PI-9 in BC cells, its presence has not been investigated in cancer stem cells so far. In this research, tertiary tumorspheres were obtained from estrogen receptor-alfa positive (ER…

HISTONE DEACETYLASE INHIBITORS SENSITIZE HEPATOMA CELLS TO TRAIL_INDUCED APOPTOSIS

Identification of Protein Complexes by Coimmunoprecipitation

Sicilian Litchi Fruit Extracts Induce Autophagy versus Apoptosis Switch in Human Colon Cancer Cells

Litchi chinensis Sonnerat is a tropical tree whose fruits contain significant amounts of bioactive polyphenols. Litchi cultivation has recently spread in Sicily where the climate conditions are particularly favorable for this crop. Recent findings have shown that Litchi extracts display anti-tumor and pro-apoptotic effects in vitro, but the precise underlying mechanisms have not been fully elucidated. In this study, we report for the first time the effects of Sicilian litchi fruit extracts on colon cancer cells. The results indicated that litchi exocarp, mesocarp and endocarp fractions reduce the viability and clonogenic growth of HT29 cells. These effects were due to cell cycle arrest in t…

Litchi chinensis as a Functional Food and a Source of Antitumor Compounds: An Overview and a Description of Biochemical Pathways.

Litchi is a tasty fruit that is commercially grown for food consumption and nutritional benefits in various parts of the world. Due to its biological activities, the fruit is becoming increasingly known and deserves attention not only for its edible part, the pulp, but also for its peel and seed that contain beneficial substances with antioxidant, cancer preventive, antimicrobial, and anti-inflammatory functions. Although literature demonstrates the biological activity of Litchi components in reducing tumor cell viability in in vitro or in vivo models, data about the biochemical mechanisms responsible for these effects are quite fragmentary. This review specifically describes, in a comprehe…

Induction of apoptosis in human osteosarcoma Saos-2 cells by the proteasome inhibitor MG132 and the protective effect of pRb

Induction of apoptosis in human osteosarcoma Saos-2 cells by the proteasome inhibitor MG132 and the protective effect of pRb

Lipid chaperones and associated diseases: a group of chaperonopathies defining a new nosological entity with implications for medical research and practice.

AbstractFatty acid–binding proteins (FABPs) are lipid chaperones assisting in the trafficking of long-chain fatty acids with functions in various cell compartments, including oxidation, signaling, gene-transcription regulation, and storage. The various known FABP isoforms display distinctive tissue distribution, but some are active in more than one tissue. Quantitative and/or qualitative changes of FABPs are associated with pathological conditions. Increased circulating levels of FABPs are biomarkers of disorders such as obesity, insulin resistance, cardiovascular disease, and cancer. Deregulated expression and malfunction of FABPs can result from genetic alterations or posttranslational mo…

Autophagic cell death induced by Litchi fruit extracts in human colon cancer cells.

Litchi chinensis is a tropical fruit which cultivation has been recently introduced in Sicily. Some findings have shown that Litchi extracts display antitumor effects but the underlying mechanisms have not been elucidated. This study focuses on the effects of Litchi hydro-alcoholic extracts in colorectal cancer cells. The results indicated that Litchi exocarp (peel), mesocarp (pulp) and endocarp (seeds) extracts reduce the viability of HT-29 colon cancer cells in a dose dependent manner. This effect was accompanied with G2/M arrest of the cell cycle followed by cell death. Interestingly, exocarp and endocarp extracts triggered an autophagic response in the first phase of treatment (16-24h) …

The Double-Edged Sword Profile of Redox Signaling: Oxidative Events As Molecular Switches in the Balance between Cell Physiology and Cancer.

The intracellular redox state in the cell depends on the balance between the level of reactive oxygen species (ROS) and the activity of defensive systems including antioxidant enzymes. This balance is a dynamic process that can change in relation to many factors and/or stimuli induced within the cell. ROS production is derived from physiological metabolic events. For instance, mitochondria represent the major ROS sources during oxidative phosphorylation, but other systems, such as NADPH oxidase or specific enzymes in certain metabolisms, may account for ROS production as well. Whereas high levels of ROS perturb the cell environment, causing oxidative damage to biological macromolecules, low…

Il partenolide induce morte in cellule di osteosarcoma umano MG63 mediante un meccanismi caspasi-indipendente, mediato da AIF.

Bio-Waste Products of Mangifera indica L. Reduce Adipogenesis and Exert Antioxidant Effects on 3T3-L1 Cells

Several studies highlighted the beneficial value of natural compounds in the prevention and treatment of obesity. Here, we investigated the anti-obesity effects of extracts of peel and seed of mango (Mangifera indica L.) cultivated in Sicily (Italy) in 3T3-L1 cells. Mango Peel (MPE) and Mango Seed (MSE) extracts at a 100 µg/mL concentration significantly reduced lipid accumulation and triacylglycerol contents during 3T3-L1 adipocyte differentiation without toxicity. HPLC-ESI-MS analysis showed that both the extracts contain some polyphenolic compounds that can account for the observed biological effects. The anti-adipogenic effect of MPE and MSE was the result of down-regulation of th…

Parthenolide induces superoxide anion production by stimulating EGF receptor in MDA-MB-231 breast cancer cells

The sesquiterpene lactone parthenolide (PN) has recently attracted considerable attention because of its anti-microbial, anti-inflammatory and anticancer effects. However, the mechanism of its cytotoxic action on tumor cells remains scarcely defined. We recently provided evidence that the effect exerted by PN in MDA-MB-231 breast cancer cells was mediated by the production of reactive oxygen species (ROS). The present study shows that PN promoted the phosphorylation of EGF receptor (phospho-EGFR) at Tyr1173, an event which was observed already at 1  h of incubation with 25  µM PN and reached a peak at 8-16  h. This effect seemed to be a consequence of ROS production, because N-acetylcystein…

Routes to cell death in animal and plant kingdoms: from classic apoptosis to alternative ways to die—a review

Programmed cell death is fundamental for multicellular organisms either in animal or plant kingdom. Classic apoptosis, which represents the best studied form of cell death, is dependent on caspase protease activity in animals. These proteases are not present in plants, where caspase-like activities, including metacaspases, are involved in the execution of plant cell death. Beyond apoptosis, various non-apoptotic forms of cell death also exist, including autophagy, necroptosis, pyroptosis, and ferroptosis. These types of cell death can be activated independently of apoptosis and sometimes occur when apoptosis is inhibited. Non-apoptotic forms of cell death are best characterized in animals, …

The oxygen radicals involved in the toxicity induced by parthenolide in MDA-MB-231 cells

It has been shown that the sesquiterpene lactone parthenolide lowers the viability of MDA-MB-231 breast cancer cells, in correlation with oxidative stress. The present report examined the different radical species produced during parthenolide treatment and their possible role in the toxicity caused by the drug. Time course experiments showed that in the first phase of treatment (0-8 h), and in particular in the first 3 h, parthenolide induced dichlorofluorescein (DCF) signal in a large percentage of cells, while dihydroethidium (DHE) signal was not stimulated. Since the effect on DCF signal was suppressed by apocynin and diphenyleneiodonium (DPI), two inhibitors of NADPH oxidase (NOX), we s…

The HDAC inhibitor SAHA synergistically stimulates the cytotoxic effect induced by Parthenolide in MDA-MB231 cells

We showed that the sesquiterpene lactone Parthenolide (PN) exerts strong cytotoxic effects on triple negative breast cancer MDA-MB231 cells. Our recent results suggest that PN exerts in these cells a cytoprotective effect, which is due to the activation of mTOR pathway. To inhibit this protective response we employ the HDAC inhibitor SAHA, which is known to prevent AKT/mTOR pathway. We show that PN activates Akt, mTOR, p70S6kinase and NRF2 while SAHA abolishes these effects. Further cell pretreatment with SAHA synergistically sensitizes the cells to the cytotoxic effect of PN. Moreover SAHA alone activates the autophagic process. The addition of PN to SAHA reduces this effect and induces ap…

SAHA induces apoptosis in hepatoma cells and synergistically interacts with the proteasome inhibitor Bortezomib.

Histone deacetylase (HDAC) inhibitors represent a promising group of anticancer agents. This paper shows that the HDAC inhibitor suberoylanilide hydroxamic acid (SAHA) stimulated at 5-10 microM apoptosis in human hepatoma HepG2 and Huh6 cells, but was ineffective in primary human hepatocytes (PHH). In HepG2 cells SAHA induced the extrinsic apoptotic pathway, increasing the expression of both FasL and FasL receptor and causing the activation of caspase-8. Moreover, SAHA enhanced the level of Bim proteins, stimulated alternative splicing of the Bcl-X transcript with the expression of the proapoptotic Bcl-Xs isoform, induced degradation of Bid into the apoptotic factor t-Bid and dephosphorylat…

Brain Opioid Activity and Oxidative Injury: Different Molecular Scenarios Connecting Celiac Disease and Autistic Spectrum Disorder

Celiac Disease (CD) is an immune-mediated disease triggered by the ingestion of wheat gliadin and related prolamins from other cereals, such as barley and rye. Immunity against these cereal-derived proteins is mediated by pro-inflammatory cytokines produced by both innate and adaptive system response in individuals unable to adequately digest them. Peptides generated in this condition are absorbed across the gut barrier, which in these patients is characterized by the deregulation of its permeability. Here, we discuss a possible correlation between CD and Autistic Spectrum Disorder (ASD) pathogenesis. ASD can be induced by an excessive and inappropriate brain opioid activity during the neon…

Derivati policiclici con struttura complessa dotati di attività antiproliferativa

Sono stati sintetizzati composti a struttura policiclica complessa. Tutti i composti sintetizzati sono stati saggiati dall'NCI (USA) su un panel di 60 linee cellulari tumorali umane. Sula base dei risultati ottenuti è stato possibile effettuare uno studio SAR che ha evidenziato come la presenza di gruppi idrofili è necessaria ai fini dell'attività antitumorale. E' stato inoltre studiato il meccanismo d'azione di queste molecole. E' stato notato un arresto delle cellule MDA-MB231 in fase G0/G1 correlato con la defosforilazione ed attivazione, indotta dai composti, della proteina pRb. Il meccanismo comunque varia arrestando il ciclo cellulare in fase G2/M quando per effetto della glicosilazio…

Heat shock protein 60 (Hsp60) modulation by the Histon Deacetylase Inhibitor (HDAC-i) SAHA in mucoepidermoid tumor H292 cells

ROS-Dependent ER Stress and Autophagy Mediate the Anti-Tumor Effects of Tributyltin (IV) Ferulate in Colon Cancer Cells

Organotin compounds represent potential cancer therapeutics due to their pro-apoptotic action. We recently synthesized the novel organotin ferulic acid derivative tributyltin (IV) ferulate (TBT-F) and demonstrated that it displays anti-tumor properties in colon cancer cells related with autophagic cell death. The purpose of the present study was to elucidate the mechanism of TBT-F action in colon cancer cells. We specifically show that TBT-F-dependent autophagy is determined by a rapid generation of reactive oxygen species (ROS) and correlated with endoplasmic reticulum (ER) stress. TBT-F evoked nuclear factor erythroid-2 related factor 2 (Nrf2)-mediated antioxidant response and Nrf2 silenc…

Gluten Free Diet for the Management of Non Celiac Diseases: The Two Sides of the Coin

A lifelong adherence to a gluten-free (GF) diet is currently the only treatment for Celiac disease (CD), an autoimmune disorder that arises after gluten ingestion in individuals who are genetically predisposed. The gluten intake exerts toxic effects through several pathways involving gut barrier integrity, intestinal microbiota composition and immune system stimulation. However, despite the great benefit of GF diet for CD patients, its use has been debated. Indeed, individuals who adopt this diet regime may be at risk of nutrient deficiencies. Emerging evidence supports a beneficial effect of a GF diet also for other pathological conditions, including gluten-related disorders (GRD) often as…

Synergistic apoptotic effect in HepG2 cells between bortezomib and hystone deacetylase inhibitors

La chimica organica e le macromolecole biologiche