58 results on '"Pellerito O"'
Search Results
2. The secreted protein acidic and rich in cysteine is a critical mediator of cell death program induced by WIN/TRAIL combined treatment in osteosarcoma cells
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Pellerito O, Selenia Sabella, Giuseppe Calvaruso, Renza Vento, Antonietta Notaro, Michela Giuliano, Notaro, A, Sabella, S, Pellerito, O, Vento, R, Calvaruso, G, and Giuliano, M
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0301 basic medicine ,Cancer Research ,Programmed cell death ,Cell Survival ,Morpholines ,Cell ,SPARC, cannabinoids, osteosarcoma, apoptosis, caspase-8 activation ,Apoptosis ,Bone Neoplasms ,Biology ,Naphthalenes ,TNF-Related Apoptosis-Inducing Ligand ,03 medical and health sciences ,0302 clinical medicine ,Protein Domains ,Settore BIO/10 - Biochimica ,Cell Line, Tumor ,medicine ,Cytotoxic T cell ,Humans ,Osteonectin ,Gene Silencing ,Caspase 8 ,Osteosarcoma ,Oncogene ,Cell Death ,Endoplasmic reticulum ,Cell Membrane ,Cell cycle ,Endoplasmic Reticulum Stress ,Cell biology ,Benzoxazines ,030104 developmental biology ,medicine.anatomical_structure ,Oncology ,030220 oncology & carcinogenesis ,Cancer cell ,RNA Interference - Abstract
Secreted protein acidic and rich in cysteine (SPARC) is a multi-functional protein which modulates cell-cell and cell-matrix interactions. In cancer cells, SPARC behaves as a tumor promoter in a number of tumors, but it can also act as a tumor suppressor factor. Our previous results showed that the synthetic cannabinoid WIN55,212-2 (WIN), a potent cannabinoid receptor agonist, is able to sensitize osteosarcoma MG63 cells to TNF-related apoptosis-inducing ligand (TRAIL)-induced apoptosis which is accompanied with endoplasmic reticulum (ER)-stress induction and the increase in autophagic markers. In the present investigation, we studied the role of SPARC in WIN/TRAIL-induced apoptosis demonstrating that WIN increased the level of SPARC protein and mRNA in a time-dependent manner. This event was functional to WIN/TRAIL-dependent apoptosis as demonstrated by RNA interfering analysis which indicated that SPARC-silenced cells were less sensitive to cytotoxic effects induced by the combined treatment. Our experiments also demonstrate that SPARC interacts with caspase-8 thus probably favoring its translocation to plasma membrane and the activation of extrinsic apoptotic pathway. In conclusion, to the best of our knowledge, our results are the first to show that WIN-dependent increase in the level of SPARC plays a critical role in sensitizing osteosarcoma cells to TRAIL action.
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- 2015
3. Cannabinoid-associated cell death mechanisms in tumor models (review)
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CALVARUSO, Giuseppe, GIULIANO, Michela, Pellerito, O, Notaro, A, Calvaruso, G, Pellerito, O, Notaro, A, and Giuliano, M
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Cannabinoids, apoptosis, autophagy, synergistic effects ,Settore BIO/10 - Biochimica - Abstract
In recent years, cannabinoids (the active components of Cannabis sativa) and their derivatives have received considerable interest due to findings that they can affect the viability and invasiveness of a variety of different cancer cells. Moreover, in addition to their inhibitory effects on tumor growth and migration, angiogenesis and metastasis, the ability of these compounds to induce different pathways of cell death has been highlighted. Here, we review the most recent results generating interest in the field of death mechanisms induced by cannabinoids in cancer cells. In particular, we analyze the pathways triggered by cannabinoids to induce apoptosis or autophagy and investigate the interplay between the two processes. Overall, the results reported here suggest that the exploration of molecular mechanisms induced by cannabinoids in cancer cells can contribute to the development of safe and effective treatments in cancer therapy.
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- 2012
4. p8 (candidate of metasiasis 1) drives ER-stress/autophagy/apoptosis axis induced by the synthetic cannabinoid WIN in HCC cells
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Pellerito, O, Portanova, P, Notaro, A, Marotta,D, Calvaruso, G, Giuliano,M., Pellerito, O, Portanova, P, Notaro, A, Marotta,D, Calvaruso, G, and Giuliano,M.
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Settore BIO/10 - Biochimica ,autophagy, apoptosis, HCCC cells, cannabinoids - Abstract
Background: Today, evidence is emerging for the role of autophagy in the regulation of life and death of tumour cells and its relationship with ER-stress signaling. Our previous results demonstrated that hepatoma HepG2 cells are sensitive to apoptotic effects induced by WIN, a synthetic cannabinoid, which acts through a mechanism involving the reduction in the levels of some survival factors and the activation of pro-apoptotic ones. Since WIN effects were observed after 36−48 hours of treatment, we investigated the possible activation of ER-stress and autophagic process in the first hours of WIN treatment focusing our attention on p8, a factor whose expression is upregulated in response to cannabinoid-mediated stress. Material and Methods: ER-stress- and autophagy-related proteins were studied by RT-PCR and western blotting analysis. The autophagic morphology was estimated by MDC staining and immunofluorescence. Gene silencing was performed using small interfering RNA against p8. Results: WIN induced ER-stress activating a pathway involving p8-CHOP-TRB3 proteins and increased the expression of the ER chaperone GRP78 which could mediate the transfer of the proapoptotic protein PAR-4 on plasma membrane. Our results indicate that WIN induced the increase in phospho-PAR-4(Thr163) level and the decrease of the pro-survival protein phospho-AKT which is responsible for an inactivating phosphorylation of PAR-4 in Ser249. Moreover, after 16 h of treatment, WIN induced the appearance of autophagic vacuoles and the increase in the lipidated form of LC3 (LC3-II) which is associated with the autophagosomal membrane. The study of beclin-1 revealed a non-canonical beclin-1 independent autophagy. To evaluate the role of p8 as an activator of death pathway we carried out experiments using specific siRNA (sip8). After p8 silencing, either the markers of ER-stress (CHOP, TRB3 and GRP78) as well as those of autophagic process (LC3-II and vacuoles formation) were significantly reduced with respect to the levels observed in WIN-treated non transfected cells. Conclusions: These findings demonstrate that ER-stress and autophagic activation are early events in WIN-induced apoptosis of HCC cells. In particular, ER-stress-related protein p8 seems to have a key role in triggering the WINdependent ER-stress/autophagy/apoptosis cascade in HCC cells. Moreover, the modulation of pAKT/pPAR4 balance contributes to these events.
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- 2010
5. The synthetic cannabinoid WIN sensitizes hepatocellular carcinoma cells to TRAIL-induced apoptosis by activating p8/CHOP/DR5 axis
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Pellerito, O, Portanova, P, CALVARUSO, Giuseppe, DE BLASIO, Anna, SANTULLI, Andrea, VENTO, Renza, TESORIERE, Giovanni, GIULIANO, Michela, Pellerito, O, Calvaruso, G, Portanova, P, De Blasio, A, Santulli, A, Vento, R, Tesoriere, G, and Giuliano, M
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Settore BIO/10 - Biochimica ,cannabinoids, TRAIL, ER-stress, hepatocarcinoma - Abstract
In this paper we demonstrate that the synthetic cannabinoid WIN sensitizes human hepatocellular carcinoma (HCC) cells to apoptosis mediated by TNF-related apoptosis inducing ligand (TRAIL). The apoptotic mechanism induced by treatment with WIN/TRAIL combination involved the loss of the mitochondrial transmembrane potential and led to the activation of caspases. In HCC cells WIN treatment induced up-regulation of TRAIL death receptor DR5, an effect which seemed to be related to the increase in the level of p8 and CHOP, two factors implicated in cellular stress response and apoptosis. This relationship was suggested by the observation that the down-regulation of p8 or CHOP by specific siRNAs attenuated both WIN-mediated DR5 up-regulation and the cytotoxicity induced by WIN/TRAIL cotreatment. Moreover, WIN induced a significant decrease in the levels of some survival factors (survivin, c-IAP2 and Bcl-2) and in particular in that of the active phosphorylated form of AKT. This event seemed to be dependent on the transcription factor PPARgamma whose level significantly increased after WIN treatment. Therefore, both the induction of DR5 via p8 and CHOP and the down-regulation of survival factors seem to be crucial for the marked synergistic effects induced by the two drugs in HCC cells. Taken together, the results reported in this paper indicate that WIN/TRAIL combination could represent a novel important tool for the therapy of HCC.
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- 2010
6. Nucleic Acid Extraction. Quaderni del Dottorato di Ricerca in Oncobiologia Sperimentale: Tecniche e Procedure di Ricerca
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Augello, G, Pellerito, O, MESSINA, Concetta Maria, Augello, G, Pellerito, O, and Messina, C.
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Nucleic Acid Extraction - Published
- 2008
7. 140 p8 (Candidate Of Metastasis 1) drives ER-stress/autophagy/apoptosis axis induced by the synthetic cannabinoid WIN in HCC cells
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Pellerito, O., primary, Portanova, P., additional, Notaro, A., additional, Marotta, D., additional, Calvaruso, G., additional, and Giuliano, M., additional
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- 2010
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8. The Synthetic Cannabinoid WIN 55,212-2 Sensitizes Hepatocellular Carcinoma Cells to Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand (TRAIL)-Induced Apoptosis by Activating p8/CCAAT/Enhancer Binding Protein Homologous Protein (CHOP)/Death Receptor 5 (DR5) Axis
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Pellerito, O., primary, Calvaruso, G., additional, Portanova, P., additional, De Blasio, A., additional, Santulli, A., additional, Vento, R., additional, Tesoriere, G., additional, and Giuliano, M., additional
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- 2010
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9. Involvement of PAR-4 in Cannabinoid-Dependent Sensitization of Osteosarcoma Cells to TRAIL-Induced Apoptosis
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Michela Giuliano, Riccardo Di Fiore, Ornella Pellerito, Giuseppe Calvaruso, Antonietta Notaro, Renza Vento, Selenia Sabella, Anna De Blasio, Notaro, A, Sabella, S, Pellerito, O, Di Fiore, R, De Blasio, A, Vento, R, Calvaruso, G, and Giuliano, M
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Autophagosome ,autophagy ,Programmed cell death ,Cannabinoids, ER stress, autophagy, TRAIL, osteosarcoma cells, GRP78/PAR-4 complex ,Cannabinoid receptor ,Morpholines ,Cell ,Apoptosis ,TRAIL ,Naphthalenes ,Biology ,GRP78/PAR-4 complex ,Applied Microbiology and Biotechnology ,TNF-Related Apoptosis-Inducing Ligand ,Cadaverine ,Cell Line, Tumor ,Settore BIO/10 - Biochimica ,medicine ,Humans ,RNA, Small Interfering ,Endoplasmic Reticulum Chaperone BiP ,Molecular Biology ,Heat-Shock Proteins ,Ecology, Evolution, Behavior and Systematics ,Cell Proliferation ,Cannabinoid Receptor Agonists ,Osteosarcoma ,Cannabinoids ,Autophagy ,Cell Cycle Checkpoints ,osteosarcoma cells ,Cell Biology ,Cell cycle ,Endoplasmic Reticulum Stress ,Acridine Orange ,Benzoxazines ,Cell biology ,medicine.anatomical_structure ,Autophagosome membrane ,Apoptosis Regulatory Proteins ,ER stress ,Microtubule-Associated Proteins ,Research Paper ,Developmental Biology - Abstract
The synthetic cannabinoid WIN 55,212-2 is a potent cannabinoid receptor agonist with anticancer potential. Experiments were performed to determine the effects of WIN on proliferation, cell cycle distribution, and programmed cell death in human osteosarcoma MG63 and Saos-2 cells. Results show that WIN induced G2/M cell cycle arrest, which was associated with the induction of the main markers of ER stress (GRP78, CHOP and TRB3). In treated cells we also observed the conversion of the cytosolic form of the autophagosome marker LC3-I into LC3-II (the lipidated form located on the autophagosome membrane) and the enhanced incorporation of monodansylcadaverine and acridine orange, two markers of the autophagic compartments such as autolysosomes. WIN also induced morphological effects in MG63 cells consisting in an increase in cell size and a marked cytoplasmic vacuolization. However, WIN effects were not associated with a canonical apoptotic pathway, as demonstrated by the absence of specific features, and only the addition of TRAIL to WIN-treated cells led to apoptotic death probably mediated by up-regulation of the tumor suppressor factor PAR-4, whose levels increased after WIN treatment, and by the translocation of GRP78 on cell surface.
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- 2014
10. WIN induces apoptotic cell death in human colon cancer cells through a block of autophagic flux dependent on PPARγ down-regulation
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Selenia Sabella, Renza Vento, Giuseppe Calvaruso, Ornella Pellerito, Antonietta Notaro, Anna De Blasio, Michela Giuliano, Pellerito, O, Notaro, A, Sabella, S, De Blasio, A, Vento, R, Calvaruso, G, and Giuliano M
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Cancer Research ,Morpholines ,Clinical Biochemistry ,Pharmaceutical Science ,Down-Regulation ,Antineoplastic Agents ,Apoptosis ,Biology ,Naphthalenes ,Downregulation and upregulation ,Settore BIO/10 - Biochimica ,Cell Line, Tumor ,medicine ,Autophagy ,Gene silencing ,Humans ,Viability assay ,Pharmacology ,Endoplasmic reticulum ,Biochemistry (medical) ,Cannabinoids, PPARγ, ER stress, autophagy/apoptosis interplay, colon carcinoma cells ,Cell Biology ,Endoplasmic Reticulum Stress ,Cell biology ,Benzoxazines ,Mitochondria ,PPAR gamma ,Mechanism of action ,Colonic Neoplasms ,Unfolded protein response ,medicine.symptom ,Signal Transduction - Abstract
Cannabinoids have been reported to possess anti-tumorigenic activity in cancer models although their mechanism of action is not well understood. Here, we show that the synthetic cannabinoid WIN55,212-2 (WIN)-induced apoptosis in colon cancer cell lines is accompanied by endoplasmic reticulum stress induction. The formation of acidic vacuoles and the increase in LC3-II protein indicated the involvement of autophagic process which seemed to play a pro-survival role against the cytotoxic effects of the drug. However, the enhanced lysosomal membrane permeabilization (LMP) blocked the autophagic flux after the formation of autophagosomes as demonstrated by the accumulation of p62 and LC3, two markers of autophagic degradation. Data also provided evidence for a role for nuclear receptor peroxisome proliferator-activated receptor γ (PPARγ) in cannabinoid signalling. PPARγ expression, at both protein and mRNA levels, was significantly down-regulated after WIN treatment and its inhibition, either by specific antagonists or by down-regulation via gene silencing, induced effects on cell viability as well as on ER stress and autophagic markers similar to those obtained in the presence of WIN. Moreover, the observation that the increase in p62 level and the induction of LMP were also modified by PPARγ antagonists seemed to indicate that PPARγ down-regulation was crucial to determinate the block of autophagic flux, thus confirming the critical role of PPARγ in WIN action. In conclusion, at our knowledge, our results are the first to show that the reduction of PPARγ levels contributes to WIN-induced colon carcinoma cell death by blocking the pro-survival autophagic response of cells.
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- 2014
11. Notch inhibition restores TRAIL-mediated apoptosis via AP1-dependent upregulation of DR4 and DR5 TRAIL receptors in MDA-MB-231 breast cancer cells
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Patrizia Portanova, Ornella Pellerito, Selenia Sabella, Michela Giuliano, Giuseppe Calvaruso, Antonietta Notaro, Portanova, P, Notaro, A, Pellerito, O, Sabella, S, Giuliano, M, and Calvaruso, G
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Cancer Research ,Notch signaling pathway ,Apoptosis ,Breast Neoplasms ,Biology ,medicine.disease_cause ,TNF-Related Apoptosis-Inducing Ligand ,Downregulation and upregulation ,Genes, jun ,Settore BIO/10 - Biochimica ,Survivin ,medicine ,Humans ,Transcription factor ,Receptors, Notch ,Cell Differentiation ,Cell biology ,Gene Expression Regulation, Neoplastic ,Receptors, TNF-Related Apoptosis-Inducing Ligand ,Oncology ,Cancer cell ,MCF-7 Cells ,Female ,notch signaling, γ-secretase inhibitor-I/TRAIL combined treatment, apoptosis, breast cancer cells, AP-1 ,Signal transduction ,Amyloid Precursor Protein Secretases ,Carcinogenesis ,Signal Transduction - Abstract
Notch is a family of transmembrane receptors whose activation through proteolytic cleavage by γ-secretase targets genes which participate in cell development, differentiation and tumorigenesis. Notch signaling is constitutively activated in various cancers, including breast cancer and its upregulation is usually related with poor clinical outcomes. Therefore, targeting Notch signaling with γ-secretase inhibitors (GSIs) is considered a promising strategy for cancer treatment. We report that the γ-secretase inhibitor-I (GSI-I) sensitizes human breast cancer cells to apoptosis mediated by tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). The antiproliferative GSI-I/TRAIL synergism was stronger in ER-negative MDA-MB-231 breast cancer cells compared with ER-positive MCF-7 cells. In MDA-MB-231 cells, GSI-I treatment induced upregulation of DR4 and DR5 TRAIL receptors. This effect seemed to be related to the activation of the transcription factor AP1 that was a consequence of Notch inhibition, as demonstrated by Notch-1 silencing experiments. Combined treatment induced loss of the mitochondrial transmembrane potential and activation of caspases. GSI-I alone and/or GSI-I/TRAIL combination also induced a significant decrease in the levels of some survival factors (survivin, c-IAP-2, Bcl-xL, BimEL and pAKT) and upregulation of pro-apoptotic factors BimL, BimS and Noxa, enhancing the cytotoxic potential of the two drugs. Taken together, these results indicate for the first time that GSI-I/TRAIL combination could represent a novel and potentially effective tool for breast cancer treatment.
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- 2013
12. Synthesis, chemical characterization and biological activity of new histone acetylation/deacetylation specific inhibitors: a novel and potential approach to cancer therapy
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Elisabetta Foresti, Girolamo Casella, Michelangelo Scopelliti, Giulia Grasso, Tiziana Fiore, Piera Sabatino, Michela Giuliano, Ornella Pellerito, Cristina Prinzivalli, Michele Abbate, Claudia Pellerito, Lorenzo Pellerito, O. Pellerito, C. Prinzivalli, E. Foresti, P. Sabatino, M. Abbate, G. Casella, T. Fiore, M. Scopelliti, C. Pellerito, M. Giuliano, G. Grasso, L. Pellerito, Pellerito, O, Prinzivalli, C, Foresti, E, Sabatino, P, Abbate, M, Casella, G, Fiore, T, Scopelliti, M, Pellerito, C, Giuliano, M, Grasso, G, and Pellerito, L
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Stereochemistry ,Cell Survival ,Antineoplastic Agents ,Biochemistry ,Inorganic Chemistry ,Histones ,Histone H3 ,Organotin Compounds ,Cytotoxic T cell ,Humans ,Viability assay ,Cells, Cultured ,MOSSBAUER SPECTROSCOPY ,OrganoTin(IV) ,biology ,X-RAY DIFFRACTION ,Chemistry ,Mössbauer spectroscopy ,Valproic Acid ,ESI-MS ,Biological activity ,Acetylation ,Hep G2 Cells ,Ligand (biochemistry) ,NMR ,Histone ,Apoptosis ,Settore CHIM/03 - Chimica Generale E Inorganica ,biology.protein ,X-ray spectroscopy - Abstract
Three new triorganotin(IV) complexes of valproic acid (vp1, Me3Sn-valproate; vp2, Bu3Sn-valproate; vp3, Ph3Sn-valproate) have been synthesized and investigated by spectroscopic and biological methods. An anionic, monodentate valproate ligand was observed, ester-like coordinating the tin atom on a tetra-coordinated, monomeric environment. The structures, though, can distort towards a penta-coordination, as a consequence of a long range O center dot center dot center dot Sn interaction. Crystallographic and NMR findings confirm this situation both in solid state and solution. Biological finding evidenced a clear cytotoxic action of the complexes in hepatocellular carcinoma cell cultures: one of the complexes induced an 80% cell viability reduction after 24 h treatment in HepG2 cells. This effect was accompanied by the appearance of biochemical signs of apoptosis. In Chang liver cells, the same compound induced only modest effects, suggesting a potential use as anti-cancer drug. Preliminary evaluations on hyperacetylation state of histone H3 in tributyltin-valproate treated HepG2 cells showed an increase in Ac-H3 (histone H3 acetylated at lys-9 and lys-14), suggesting that the compound maintains the deacetylation inhibition activity of its ligand valproate. (c) 2013 Elsevier Inc. All rights reserved.
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- 2013
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13. A comparison between the role of SPARC in osteogenic differentiation of mesenchymal stem cells and in WIN/TRAIL-induced apoptosis in osteosarcoma cells
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NOTARO, Antonietta, SABELLA, Selenia, PELLERITO, Ornella, GIULIANO, Michela, CALVARUSO, Giuseppe, Notaro, A, Sabella, S, Pellerito, O, Giuliano, M, and Calvaruso, G
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cancer cells, cell death pathway, cannabinoids ,Settore BIO/10 - Biochimica - Published
- 2012
14. Autophagy and ER-stress participate to cannabinoid-induced apoptosis in colon carcinoma cells
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PELLERITO, Ornella, NOTARO, Antonietta, SABELLA, Selenia, CALVARUSO, Giuseppe, GIULIANO, Michela, Pellerito, O, Notaro, A, Sabella, S, Calvaruso, G, and Giuliano, M
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Settore BIO/10 - Biochimica ,Autophagy, colon carcinoma cells, cannabinoids - Published
- 2012
15. Different expression of PPARs in WIN-treated cells: the game of roles
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NOTARO, Antonietta, SABELLA, Selenia, PELLERITO, Ornella, CALVARUSO, Giuseppe, GIULIANO, Michela, Notaro, A, Sabella, S, Pellerito, O, Calvaruso, G, and Giuliano, M
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Cancer cells, PPAR factors, cannabinoids, cell death ,Settore BIO/10 - Biochimica - Published
- 2012
16. New histone acetylation/deacetylation specific inhibitors: a novel and potential approach to cancer therapy
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PELLERITO, Claudia, ABBATE, Michele, CASELLA, Girolamo, FIORE, Tiziana, SCOPELLITI, Michelangelo, PELLERITO, Ornella, GIULIANO, Michela, PELLERITO, Lorenzo, Prinzivalli C, Foresti E, Sabatino P, Grasso G, Pellerito C, Prinzivalli C, Foresti E, Sabatino P, Abbate M, Casella G, Fiore T, Scopelliti M, Pellerito O, Giuliano M, Grasso G, and Pellerito L
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Histone ,Settore CHIM/03 - Chimica Generale E Inorganica ,cancer ,organotin - Abstract
The acetylation status of histones is regulated in eukaryotes by two kinds of enzymes, histone acetyltransferases (HATs) and histone deacetylases (HDACs), which are responsible for acetylation and deacetylation of lysines residues in N-terminal tails of histone.[1] Thus acetylation, together with phosphorylation and methylation of N-terminal tail of histones, are involved in regulating fundamental processes, such as proliferation and cell death.[2-3] Sodium butyrate, which belongs together with valproic acid to the class of short chain fatty acids, was the first HDAC inhibitor (HDACI) to be identified.[1] Organotin compounds have various influences on physical function including the hormone and immune systems, embryogenesis, and development. Dibutyltin and diphenyltin, metabolites of TBT and TPT, respectively, also promoted HAT activity.[4] New triorganotin(IV) complexes of valproic acid have been synthesized and investigated by spectroscopical and biological methods. An anionic, monodentate valproate ligand was observed, ester-like coordinating the tin atom on a tetra-coordinated, monomeric environment. The structures, though, can distort towards a pentacoordination, as a consequence of a long range O-Sn interaction. Crystallographic and NMR findings confirm this situation both in solid state and solution. Biological finding evidenced a clear cytotoxic action of the complexes in hepatocellular carcinoma cell cultures: one of the complexes induced an 80% cell viability reduction after 24 h treatment in HepG2 cells. This effect was accompanied by the appearance of biochemical signs of apoptosis. In Chang liver cells, the same compound induced only modest effects, suggesting a potential use as anti-cancer drug.
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- 2011
17. USO TERAPEUTICO COMBINATO DI ORGANOSTAGNO(IV) ED INIBITORI DELLE DEACETILASI ISTONICHE
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PELLERITO, Claudia, PRINZIVALLI, Cristina, GIULIANO, Michela, PELLERITO, Ornella, Pellerito, C, Prinzivalli, C, Giuliano, M, and Pellerito, O
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organostagno - Published
- 2010
18. Diorganotin(IV) N-acetyl-L-cysteinate complexes: synthesis, solid state, solution phase, DFT and biological investigations
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Cristina Prinzivalli, Tiziana Fiore, Girolamo Casella, Michelangelo Scopelliti, Michela Giuliano, Lorenzo Pellerito, Claudia Pellerito, Ornella Pellerito, PELLERITO, L, PRINZIVALLI, C, CASELLA, G, FIORE, T, PELLERITO,O, GIULIANO, M, SCOPELLITI, M, and PELLERITO, C
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Binding Sites ,Molecular Structure ,Ligand ,Stereochemistry ,Cell Survival ,Spectrum Analysis ,chemistry.chemical_element ,Antineoplastic Agents ,Nuclear magnetic resonance spectroscopy ,Biochemistry ,Medicinal chemistry ,Acetylcysteine ,Cell Line ,Inorganic Chemistry ,chemistry.chemical_compound ,Trigonal bipyramidal molecular geometry ,Deprotonation ,chemistry ,Mössbauer spectroscopy ,Organotin Compounds ,Organotin(IV), FTIR, Mössbauer, NMR, DFT, Antitumor activity ,Humans ,Density functional theory ,Carboxylate ,Tin - Abstract
Diorganotin(IV) complexes of N-acetyl-L-cysteine (H(2)NAC; (R)-2-acetamido-3-sulfanylpropanoic acid) have been synthesized and their solid and solution-phase structural configurations investigated by FTIR, Mössbauer, (1)H, (13)C and (119)Sn NMR spectroscopy. FTIR results suggested that in R(2)Sn(IV)NAC (R = Me, Bu, Ph) complexes NAC(2-) behaves as dianionic tridentate ligand coordinating the tin(IV) atom, through ester-type carboxylate, acetate carbonyl oxygen atom and the deprotonated thiolate group. From (119)Sn Mössbauer spectroscopy it could be inferred that the tin atom is pentacoordinated, with equatorial R(2)Sn(IV) trigonal bipyramidal configuration. In DMSO-d(6) solution, NMR spectroscopic data showed the coordination of one solvent molecule to tin atom, while the coordination mode of the ligand through the ester-type carboxylate and the deprotonated thiolate group was retained in solution. DFT (Density Functional Theory) study confirmed the proposed structures in solution phase as well as the determination of the most probable stable ring conformation. Biological investigations showed that Bu(2)SnCl(2) and NAC2 induce loss of viability in HCC cells and only moderate effects in non-tumor Chang liver cells. NAC2 showed lower cytotoxic activity than Bu(2)SnCl(2), suggesting that the binding with NAC(2-) modulates the marked cytotoxic activity exerted by Bu(2)SnCl(2). Therefore, these novel butyl derivatives could represent a new class of anticancer drugs.
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- 2009
19. The transcription factor CHOP is critical for WIN-mediated DR5 up-regulation in apoptosis induced by WIN/TRAIL co-treatment in hepatoma cells
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PELLERITO, Ornella, PORTANOVA, Patrizia, NOTARO, Antonietta, CALVARUSO, Giuseppe, GIULIANO, Michela, VENTO, Renza, TESORIERE, Giovanni, Piazza, A, Randazzo, P, Pellerito, O, Portanova, P, Piazza, A, Randazzo, P, Notaro, A, Calvaruso, G, Giuliano, M, Vento, R, and Tesoriere, G
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TRAIL, cannabinoid, CHOP - Published
- 2009
20. COINVOLGIMENTO DELLO STRESS DEL RETICOLO E DEL PROCESSO AUTOFAGICO NELL’APOPTOSI INDOTTA DAL CANNABINOIDE SINTETICO WIN IN CELLULE DI EPATOMA UMANO IN COLTURA
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PELLERITO, Ornella, PORTANOVA, Patrizia, CALVARUSO, Giuseppe, GIULIANO, Michela, TESORIERE, Giovanni, Notaro, A, Pellerito, O, Portanova, P, Notaro, A, Calvaruso, G, Giuliano, M, and Tesoriere, G
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autophagy, cannabinoids, hepatoma cells ,Settore BIO/10 - Biochimica - Abstract
Studi da noi condotti precedentemente hanno dimostrato la capacità del cannabinoide sintetico WIN di indurre apoptosi in cellule di epatocarcinoma umano HepG2 attraverso un meccanismo, dipendente dal fattore trascrizionale PPARg, che prevede riduzione dei livelli di alcuni fattori di sopravvivenza e attivazione di fattori pro-apoptotici della famiglia Bcl-2 (M. Giuliano et al. Biochimie. 2009). Recentemente è, inoltre, emerso che in cellule di glioma i cannabinoidi possono stimolare l’apoptosi attraverso induzione di stress del reticolo endoplasmatico seguito da autofagia. Scopo L'obiettivo del presente studio è stato quello di valutare il coinvolgimento dell’autofagia nel percorso di morte indotto dal WIN in cellule HepG2 e la dipendenza dell’apoptosi da tale evento. Metodi I livelli dei fattori coinvolti nella risposta all’ER stress e nel meccanismo autofagico sono stati analizzati mediante Western blotting e RT-PCR. La formazione dei vacuoli autofagici è stata valutata marcando le cellule con il composto autofluorescente monodansylcadaverina (MDC) e successiva osservazione al microscopio a fluorescenza. Risultati Il trattamento delle cellule HepG2 con 10 mM WIN determina, già a tempi precoci (8-16 ore), up-regulation di p8 e CHOP, due fattori con attività pro-apoptotica associati alla risposta allo stress del reticolo. Parallelamente, WIN induce la marcata caduta dei livelli di AKT e della sua forma fosforilata attiva. Poichè è noto che l’inibizione di AKT può promuovere l’autofagia causata dalla mancata attivazione di mTORC1 AKT-dipendente, abbiamo investigato la formazione dei vacuoli autofagici. WIN determina in cellule HepG2, dopo 8 ore di trattamento, la comparsa di un elevato numero di vacuoli autofagici, visibili come granuli brillanti dopo colorazione con MDC. Parallelamente si osserva, dopo trattamento, un marcato incremento nei livelli della forma lipidata attiva di LC3 (LC3-II), un marker della formazione dell’autofagosoma. Per confermare la relazione tra induzione dell’ER stress, autofagia e apoptosi WIN-dipendente, sono stati condotti esperimenti di silenziamento genico su CHOP. Tali studi hanno indicato che la down-regulation di CHOP contrasta la riduzione dei livelli di AKT e parallelamente la citotossicità indotta dal WIN. Conclusioni I risultati riportati, sebbene preliminari, sembrano indicare che l’autofagia sia parte del meccanismo attraverso il quale WIN induce apoptosi nelle cellule di epatoma.
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- 2009
21. The cannabinoid WIN induces DR5 receptor expression in hepatoma cells sensitizing them to TRAIL signal
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PELLERITO, Ornella, PORTANOVA, Patrizia, CALVARUSO, Giuseppe, GIULIANO, Michela, VENTO, Renza, TESORIERE, Giovanni, Pellerito, O, Portanova, P, Calvaruso, G, Giuliano, M, Vento, R, and Tesoriere, G
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cannabinoids, apoptosis, TRAIL signalling - Published
- 2009
22. Apoptosis induced in HepG2 cells by the synthetic cannabinoid WIN: involvement of the transcription factor PPARgamma
- Author
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Andrea Santulli, Giuseppe Calvaruso, Renza Vento, Ornella Pellerito, Anna De Blasio, Patrizia Portanova, Michela Giuliano, Giovanni Tesoriere, Giuliano, M, Pellerito, O, Portanova, P, Calvaruso, G, Santulli, A, De Blasio, A, Vento, R, and Tesoriere, G
- Subjects
Cannabinoid receptor ,Carcinoma, Hepatocellular ,Cell Survival ,Pyridines ,medicine.medical_treatment ,p38 mitogen-activated protein kinases ,Morpholines ,Apoptosis ,Biology ,Naphthalenes ,Biochemistry ,Receptor, Cannabinoid, CB2 ,Membrane Microdomains ,cannabinoids, PPARgamma factor, apoptosis, cancer cells ,Settore BIO/10 - Biochimica ,Cell Line, Tumor ,Survivin ,medicine ,Humans ,Anilides ,Viability assay ,Cannabinoids ,Liver Neoplasms ,General Medicine ,Cell biology ,Benzoxazines ,PPAR gamma ,Cancer cell ,Benzamides ,Cannabinoid ,Signal transduction ,Apoptosis Regulatory Proteins ,Protein Kinases ,Signal Transduction - Abstract
It has recently been shown that cannabinoids induce growth inhibition and apoptosis in different tumour cell lines. In the current study, the effects of WIN 55,212-2 (WIN), a synthetic and potent cannabinoid receptor agonist, are investigated in hepatoma HepG2 cells and a possible signal transduction pathway is proposed. In these cells, WIN induces a clear apoptotic effect which was accompanied by up-regulation of the death-signalling factors Bax, Bcl-X(S), t-Bid and down-regulation of the survival factors survivin, phospho-AKT, Hsp72 and Bcl-2. Moreover, WIN-induced apoptosis is associated with JNK/p38 MAPK pathway activation and mitochondrial depolarisation demonstrated by a cytofluorimetric assay. The results also show that in HepG2 cells WIN markedly increases the level of the transcription factor PPARgamma in a dose- and time-dependent manner. The addition of the PPARgamma antagonists GW9662 and T0070907 significantly reduces the effects of the drug on both cell viability and the levels of survivin, phospho-AKT and phospho-BAD, suggesting that PPARgamma plays a key role in WIN-induced apoptosis. Altogether, the results seem to indicate a potential therapeutic role of WIN in hepatic cancer treatment.
- Published
- 2008
23. The role of oxidative stress in apoptosis induced by the histone deacetylase inhibitor suberoylanilide hydroxamic acid in human colon adenocarcinoma HT-29 cells
- Author
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Ornella Pellerito, Renza Vento, Patrizia Portanova, Tiziana Russo, Giovanni Tesoriere, Giuseppe Calvaruso, Michela Giuliano, Portanova, P, Russo, T, Pellerito, O, Calvaruso, G, Giuliano, M, Vento, R, and Tesoriere, G
- Subjects
Cancer Research ,Programmed cell death ,medicine.drug_class ,Cell Survival ,p38 mitogen-activated protein kinases ,Blotting, Western ,Apoptosis ,Adenocarcinoma ,medicine.disease_cause ,Hydroxamic Acids ,Antioxidants ,Settore BIO/10 - Biochimica ,medicine ,Humans ,Enzyme Inhibitors ,Protein kinase B ,Caspase ,Membrane Potential, Mitochondrial ,Vorinostat ,biology ,Histone deacetylase inhibitor ,Enzyme Activation ,Histone Deacetylase Inhibitors ,Oxidative Stress ,Oncology ,Biochemistry ,Caspases ,Colonic Neoplasms ,Cancer research ,biology.protein ,Histone deacetylase ,Reactive Oxygen Species ,colon adenomacarcinoma cells, histone deacetylase inhibitors, apoptosis ,HT29 Cells ,Oxidative stress ,Signal Transduction - Abstract
Histone deacetylase inhibitors (HDACIs) activate genes that promote cell cycle arrest and apoptosis in a number of tumor cells. This study showed that suberoylanilide hydroxamic acid (SAHA), a potent and commonly used HDACI, induced apoptosis in human colon adenocarcinoma HT-29 cells in a time- and dose-dependent manner. This effect was accompanied by the induction of oxidative stress, dissipation of mitochondrial transmembrane potential and activation of executioner caspases. Moreover, SAHA increased the levels of phosphorylated active forms of p38 and JNK. The addition of either the antioxidant N-acetylcysteine or the specific inhibitor of NADPH oxidase diphenylene iodonium chloride reduced the cytotoxic effects of SAHA in HT-29 cells, suggesting that the induction of oxidative stress represents a crucial event in the apoptotic mechanism. In addition, SAHA up-regulated the death receptor DR5, inducing the activation of caspase-8 with the consequent cleavage of Bid. Furthermore, SAHA downregulated FLIP L and Akt, two proteins which exert an inhibitory role in apoptosis.
- Published
- 2008
24. TWO-DIMENSIONAL ANALYSIS OF PROTEIN EXPRESSION PATTERNS
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PELLERITO, Ornella, CIRAOLO, Anna, GIULIANO, Michela, and PELLERITO O, CIRAOLO A, GIULIANO M
- Subjects
PROTEOMIC ANALYSIS, ELECTROPHORESIS ,Settore BIO/10 - Biochimica - Published
- 2008
25. The synthetic cannabinoid WIN55,212-2 synergizes with the death receptor ligand TRAIL to induce apoptotic effect in HepG2 hepatoma cells
- Author
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PELLERITO, Ornella, PORTANOVA, Patrizia, GIULIANO, Michela, CALVARUSO, Giuseppe, VENTO, Renza, TESORIERE, Giovanni, PELLERITO O, PORTANOVA P, GIULIANO M, CALVARUSO G, and VENTO R AND TESORIERE G
- Subjects
CANNABINOIDS, HEPATOMA CELLS, APOPTOSIS - Published
- 2008
26. Synergistic effects induced by combinations of the synthetic cannabinoid WIN55,212-2 and the death receptor ligand TRAIL in hepatoma HepG2 cells
- Author
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PELLERITO, Ornella, PORTANOVA, Patrizia, GIULIANO, Michela, CALVARUSO, Giuseppe, VENTO, Renza, TESORIERE, Giovanni, PELLERITO O, PORTANOVA P, GIULIANO M, CALVARUSO G, VENTO R, and TESORIERE G
- Subjects
synergistic effect ,Settore BIO/10 - Biochimica ,TRAIL ,cannabinoid - Published
- 2008
27. Hsp72 controls bortezomib-induced HepG2 cell death via interaction with pro-apoptotic factors
- Author
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Ornella Pellerito, Renza Vento, Patrizia Portanova, Michela Giuliano, Giuseppe Calvaruso, Giovanni Tesoriere, CALVARUSO, G, GIULIANO, M, PORTANOVA, P, PELLERITO, O, VENTO, R, and TESORIERE, G
- Subjects
Cancer Research ,Programmed cell death ,Carcinoma, Hepatocellular ,Time Factors ,Cell ,Blotting, Western ,Apoptosis ,HSP72 Heat-Shock Proteins ,Amino Acid Chloromethyl Ketones ,Bortezomib ,Cell Line, Tumor ,medicine ,Humans ,Immunoprecipitation ,Protease Inhibitors ,cardiovascular diseases ,Caspase ,bcl-2-Associated X Protein ,Oncogene ,biology ,Reverse Transcriptase Polymerase Chain Reaction ,Liver Neoplasms ,Apoptosis Inducing Factor ,proteasome inhibitor, hepatocarcinoma, apoptosis ,General Medicine ,Cell cycle ,Boronic Acids ,medicine.anatomical_structure ,Apoptotic Protease-Activating Factor 1 ,Oncology ,Pyrazines ,Proteasome inhibitor ,Cancer research ,biology.protein ,Tumor Suppressor Protein p53 ,Apoptosis Regulatory Proteins ,medicine.drug ,Protein Binding - Abstract
The proteasome inhibitor bortezomib is an efficacious inducer of apoptosis in the hepatoma HepG2 cell line. This study shows that bortezomib increased in these cells the level of the survival factor Hsp72 in a time- and dose-dependent manner. In a first phase of treatment, Hsp72 rapidly increased so that at 24 h of incubation with 50 nM bortezomib its level was approximately five-fold higher than the control. In this phase Hsp72 seemed to play a role in preventing HepG2 cell death, since it interacted with and sequestered the pro-apoptotic factors p53, AIF, Bax and Apaf-1. During a second day of treatment, although the nuclear levels of Hsp72, p53 and AIF increased, the interaction of Hsp72 with these factors diminished. In addition, bortezomib induced the activation of caspases, which stimulated Hsp72 degradation. In conclusion, in the second day of treatment with bortezomib the protective ability of Hsp72 decreased thus favouring the appearance of apoptosis.
- Published
- 2007
28. WIN55,212-2, a synthetic agonist of cannabinoid receptors, sensitizes tumor cells to TRAIL-induced apoptosis
- Author
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GIULIANO, Michela, CALVARUSO, Giuseppe, DI LEONARDO, Elvira Rosalia, PORTANOVA, Patrizia, PELLERITO, Ornella, VENTO, Renza, TESORIERE, Giovanni, EMANUELE, Sonia, GIULIANO M, CALVARUSO G, DI LEONARDO E, PORTANOVA P, PELLERITO O, VENTO R, TESORIERE G, and Emanuele, S.
- Published
- 2007
29. Role of PPARγ in apoptosis induced by cannabinoids in hepatoma HepG2 cells
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GIULIANO, Michela, CALVARUSO, Giuseppe, PELLERITO, Ornella, PORTANOVA, Patrizia, TESORIERE, Giovanni, GIULIANO M, CALVARUSO G, PELLERITO O, PORTANOVA P, and TESORIERE G
- Published
- 2007
30. Anandamide-induced apoptosis in Chang liver cells involves ceramide and JNK/AP-1 pathway
- Author
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Renza Vento, Michela Giuliano, Giuseppe Calvaruso, Daniela Carlisi, Ornella Pellerito, Patrizia Portanova, Giovanni Tesoriere, GIULIANO, M, CALVARUSO, G, PELLERITO, O, PORTANOVA, P, CARLISI, D, VENTO, R, and TESORIERE, G
- Subjects
Ceramide ,Programmed cell death ,Fas Ligand Protein ,Cell Survival ,Polyunsaturated Alkamides ,Liver cytology ,p38 mitogen-activated protein kinases ,Blotting, Western ,Apoptosis ,Arachidonic Acids ,Biology ,Ceramides ,Cell Line ,Membrane Potentials ,chemistry.chemical_compound ,Cell Line, Tumor ,Proto-Oncogene Proteins ,Genetics ,Humans ,Enzyme Inhibitors ,Membrane Glycoproteins ,Bcl-2-Like Protein 11 ,Dose-Response Relationship, Drug ,Desipramine ,JNK Mitogen-Activated Protein Kinases ,Membrane Proteins ,Free Radical Scavengers ,General Medicine ,Anandamide ,Endocannabinoid system ,Acetylcysteine ,Cell biology ,Enzyme Activation ,Transcription Factor AP-1 ,cannabinoids, apoptosis, tumor cells, JNK/AP1 ,Liver ,chemistry ,Caspases ,Mitochondrial Membranes ,Tumor Necrosis Factors ,Apoptosis Regulatory Proteins ,Sphingomyelin ,Endocannabinoids ,Signal Transduction - Abstract
In the present study we demonstrate that anandamide, the most important endogenous cannabinoid, markedly induced apoptosis in Chang liver cells, an immortalized non-tumor cell line derived from normal liver tissue, while it induced only modest effects in a number of hepatoma cell lines. The apoptotic effect was reduced by methyl-beta-cyclodextrin, a membrane cholesterol depletor, suggesting an interaction between anandamide and the membrane microdomains named lipid rafts. Anandamide effects were mediated by the production of ceramide, as demonstrated by experiments performed with the sphingomyelinase inhibitor, desipramine, or with the sphingomyelinase activator, melittin. This conclusion was confirmed by the observation that exogenous C2-ceramide induced a remarkable apoptotic effect in the same cells. Anandamide-induced apoptosis in Chang liver cells involved oxidative stress and activation of p38/JNK pathway, which was accompanied by a remarkable increase in AP-1 DNA-binding activity. Moreover, the levels of both c-Jun and JunB, two components of the AP-1 complex, and those of FasL and Bim, two transcriptional targets of AP-1, also increased during anandamide treatment. In addition, anandamide increased the level of Bax and caused degradation of full-length Bid with the production of the active truncated form. These effects were accompanied by dissipation of mitochondrial transmembrane potential with the consequent activation of both caspase-3 and caspase-6. On the contrary, in hepatoma cells, anandamide did not induce apoptotic effects and it was not possible to observe any increase in p38/JNK pathway and AP-1 activity after drug treatment. Our results suggest that the induction of cell death in non-tumor Chang liver cells by anandamide was mediated by ceramide, JNK and AP-1 and was dependent on the activation of both the extrinsic and intrinsic pathways of apoptosis.
- Published
- 2006
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31. Hsp-72 contrasta l'effetto apoptotico indotto dal bortezomib in cellule di epatoblastoma umano Hep-G2
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PORTANOVA, Patrizia, PELLERITO, Ornella, GIULIANO, Michela, CALVARUSO, Giuseppe, VENTO, Renza, TESORIERE G., PORTANOVA P, PELLERITO O, GIULIANO M, CALVARUSO G, VENTO R, and TESORIERE G
- Published
- 2006
32. Complessi di nuova sintesi di derivati della cisteina con ioni metallici
- Author
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ABBATE, Michele, PRINZIVALLI, Cristina, GIULIANO, Michela, PELLERITO, Claudia, PELLERITO, Ornella, SCIACCA, Ivan Diego, PELLERITO, Lorenzo, BARBIERI G, COSTA MA, ABBATE M, PRINZIVALLI C, BARBIERI G, COSTA MA, GIULIANO M, PELLERITO C, PELLERITO O, SCIACCA ID, and PELLERITO L
- Published
- 2006
33. Factors that protect HepG2 cells by anandamide-induced cell death
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PELLERITO, Ornella, CALVARUSO, Giuseppe, GIULIANO, Michela, PELLERITO O, CALVARUSO G, and GIULIANO M
- Published
- 2006
34. THE CANNABINOID AGONIST WIN55,212-2 INDUCES APOPTOSIS IN HUMAN HEPATOMA CELLS
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GIULIANO, Michela, CALVARUSO, Giuseppe, PELLERITO, Ornella, PORTANOVA, Patrizia, RUSSO, Tiziana, TESORIERE, Giovanni, GIULIANO M, CALVARUSO G, PELLERITO O, PORTANOVA P, RUSSO T, and TESORIERE G
- Published
- 2006
35. Synthesis, structural investigation and biological activity of metal ions complexes of N-acetylcysteine and carbocysteine
- Author
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ABBATE, Michele, PRINZIVALLI, Cristina, PELLERITO, Claudia, PELLERITO, Ornella, SCIACCA, Ivan Diego, PELLERITO, Lorenzo, GIULIANO, Michela, BARBIERI G, COSTA M, ABBATE M, PRINZIVALLI C, BARBIERI G, COSTA M, PELLERITO C, PELLERITO O, SCIACCA ID, PELLERITO L, and Giuliano, M.
- Published
- 2006
36. APOPTOTIC EFFECTS INDUCED BY ANANDAMIDE IN HEPATIC CELLS
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GIULIANO, Michela, CALVARUSO, Giuseppe, PELLERITO, Ornella, PORTANOVA, Patrizia, VENTO, Renza, TESORIERE, Giovanni, GIULIANO M, CALVARUSO G, PELLERITO O, PORTANOVA P, VENTO R, and TESORIERE G
- Published
- 2005
37. Degradation of IkBalfa during apoptosis induced by proteasome inhibitors in hepatoma cells
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PORTANOVA, Patrizia, PELLERITO, Ornella, GIULIANO, Michela, CALVARUSO, Giuseppe, VENTO, Renza, TESORIERE, Giovanni, PORTANOVA P, PELLERITO O, GIULIANO M, CALVARUSO G, VENTO R, and TESORIERE G
- Published
- 2004
38. Clearance of defective muscle stem cells by senolytics restores myogenesis in myotonic dystrophy type 1.
- Author
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Conte TC, Duran-Bishop G, Orfi Z, Mokhtari I, Deprez A, Côté I, Molina T, Kim TY, Tellier L, Roussel MP, Maggiorani D, Benabdallah B, Leclerc S, Feulner L, Pellerito O, Mathieu J, Andelfinger G, Gagnon C, Beauséjour C, McGraw S, Duchesne E, and Dumont NA
- Subjects
- Humans, Senotherapeutics, Muscle Fibers, Skeletal metabolism, Muscle Development genetics, Myotonic Dystrophy drug therapy, Myotonic Dystrophy genetics, Myotonic Dystrophy metabolism, Satellite Cells, Skeletal Muscle metabolism
- Abstract
Muscle stem cells, the engine of muscle repair, are affected in myotonic dystrophy type 1 (DM1); however, the underlying molecular mechanism and the impact on the disease severity are still elusive. Here, we show using patients' samples that muscle stem cells/myoblasts exhibit signs of cellular senescence in vitro and in situ. Single cell RNAseq uncovers a subset of senescent myoblasts expressing high levels of genes related to the senescence-associated secretory phenotype (SASP). We show that the levels of interleukin-6, a prominent SASP cytokine, in the serum of DM1 patients correlate with muscle weakness and functional capacity limitations. Drug screening revealed that the senolytic BCL-XL inhibitor (A1155463) can specifically remove senescent DM1 myoblasts by inducing their apoptosis. Clearance of senescent cells reduced the expression of SASP, which rescued the proliferation and differentiation capacity of DM1 myoblasts in vitro and enhanced their engraftment following transplantation in vivo. Altogether, this study identifies the pathogenic mechanism associated with muscle stem cell defects in DM1 and opens a therapeutic avenue that targets these defective cells to restore myogenesis., (© 2023. The Author(s).)
- Published
- 2023
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39. Resolvin-D2 targets myogenic cells and improves muscle regeneration in Duchenne muscular dystrophy.
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Dort J, Orfi Z, Fabre P, Molina T, Conte TC, Greffard K, Pellerito O, Bilodeau JF, and Dumont NA
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- Animals, Cell Differentiation drug effects, Cell Differentiation physiology, Cells, Cultured, Disease Models, Animal, Glucocorticoids pharmacology, Macrophages drug effects, Macrophages pathology, Male, Mice, Inbred mdx, Mice, Knockout, Muscle Contraction drug effects, Muscle Contraction physiology, Muscle Development physiology, Myoblasts drug effects, Utrophin genetics, Mice, Docosahexaenoic Acids pharmacology, Muscle Development drug effects, Muscular Dystrophy, Duchenne drug therapy, Muscular Dystrophy, Duchenne physiopathology
- Abstract
Lack of dystrophin causes muscle degeneration, which is exacerbated by chronic inflammation and reduced regenerative capacity of muscle stem cells in Duchenne Muscular Dystrophy (DMD). To date, glucocorticoids remain the gold standard for the treatment of DMD. These drugs are able to slow down the progression of the disease and increase lifespan by dampening the chronic and excessive inflammatory process; however, they also have numerous harmful side effects that hamper their therapeutic potential. Here, we investigated Resolvin-D2 as a new therapeutic alternative having the potential to target multiple key features contributing to the disease progression. Our in vitro findings showed that Resolvin-D2 promotes the switch of macrophages toward their anti-inflammatory phenotype and increases their secretion of pro-myogenic factors. Moreover, Resolvin-D2 directly targets myogenic cells and promotes their differentiation and the expansion of the pool of myogenic progenitor cells leading to increased myogenesis. These effects are ablated when the receptor Gpr18 is knocked-out, knocked-down, or blocked by the pharmacological antagonist O-1918. Using different mouse models of DMD, we showed that Resolvin-D2 targets both inflammation and myogenesis leading to enhanced muscle function compared to glucocorticoids. Overall, this preclinical study has identified a new therapeutic approach that is more potent than the gold-standard treatment for DMD., (© 2021. The Author(s).)
- Published
- 2021
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40. Bcl-2-associated athanogene 5 (BAG5) regulates Parkin-dependent mitophagy and cell death.
- Author
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De Snoo ML, Friesen EL, Zhang YT, Earnshaw R, Dorval G, Kapadia M, O'Hara DM, Agapova V, Chau H, Pellerito O, Tang MY, Wang X, Schmitt-Ulms G, Durcan TM, Fon EA, Kalia LV, and Kalia SK
- Subjects
- Carbonyl Cyanide m-Chlorophenyl Hydrazone pharmacology, Caspase 3 metabolism, Cell Line, Tumor, Gene Knockdown Techniques, HEK293 Cells, Humans, Membrane Potential, Mitochondrial drug effects, Mitochondria drug effects, Mitochondria metabolism, Models, Biological, Myeloid Cell Leukemia Sequence 1 Protein metabolism, Poly(ADP-ribose) Polymerases metabolism, Protein Stability drug effects, Proteolysis drug effects, Adaptor Proteins, Signal Transducing metabolism, Apoptosis drug effects, Mitophagy drug effects, Ubiquitin-Protein Ligases metabolism
- Abstract
As pathogenic Parkin mutations result in the defective clearance of damaged mitochondria, Parkin-dependent mitophagy is thought to be protective against the dopaminergic neurodegeneration observed in Parkinson's disease. Recent studies, however, have demonstrated that Parkin can promote cell death in the context of severe mitochondrial damage by degrading the pro-survival Bcl-2 family member, Mcl-1. Therefore, Parkin may act as a 'switch' that can shift the balance between protective or pro-death pathways depending on the degree of mitochondrial damage. Here, we report that the Parkin interacting protein, Bcl-2-associated athanogene 5 (BAG5), impairs mitophagy by suppressing Parkin recruitment to damaged mitochondria and reducing the movement of damaged mitochondria into the lysosomes. BAG5 also enhanced Parkin-mediated Mcl-1 degradation and cell death following severe mitochondrial insult. These results suggest that BAG5 may regulate the bi-modal activity of Parkin, promoting cell death by suppressing Parkin-dependent mitophagy and enhancing Parkin-mediated Mcl-1 degradation.
- Published
- 2019
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41. The Regenerative Potential of Amniotic Fluid Stem Cell Extracellular Vesicles: Lessons Learned by Comparing Different Isolation Techniques.
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Antounians L, Tzanetakis A, Pellerito O, Catania VD, Sulistyo A, Montalva L, McVey MJ, and Zani A
- Subjects
- Apoptosis, Cell Survival, Chromatography, Gel, Humans, Regeneration, Stem Cells cytology, Ultracentrifugation, Alveolar Epithelial Cells physiology, Amniotic Fluid cytology, Cell Separation methods, Extracellular Vesicles metabolism, Lung Injury therapy, Muscular Atrophy therapy, Stem Cells metabolism
- Abstract
Extracellular vesicles (EVs) derived from amniotic fluid stem cells (AFSCs) mediate anti-apoptotic, pro-angiogenic, and immune-modulatory effects in multiple disease models, such as skeletal muscle atrophy and Alport syndrome. A source of potential variability in EV biological functions is how EV are isolated from parent cells. Currently, a comparative study of different EV isolation strategies using conditioned medium from AFSCs is lacking. Herein, we examined different isolation strategies for AFSC-EVs, using common techniques based on differential sedimentation (ultracentrifugation), solubility (ExoQuick, Total Exosome Isolation Reagent, Exo-PREP), or size-exclusion chromatography (qEV). All techniques isolated AFSC-EVs with typical EV morphology and protein markers. In contrast, AFSC-EV size, protein content, and yield varied depending on the method of isolation. When equal volumes of the different AFSC-EV preparations were used as treatment in a model of lung epithelial injury, we observed a significant variation in how AFSC-EVs were able to protect against cell death. AFSC-EV enhancement of cell survival appeared to be dose dependent, and largely uninfluenced by variation in EV-size distributions, relative EV-purity, or their total protein content. The variation in EV-mediated cell survival obtained with different isolation strategies emphasizes the importance of testing alternative isolation techniques in order to maximize EV regenerative capacity.
- Published
- 2019
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42. Endoplasmic reticulum stress response is activated in pulmonary hypoplasia secondary to congenital diaphragmatic hernia, but is decreased by administration of amniotic fluid stem cells.
- Author
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Tzanetakis A, Antounians L, Belfiore A, Ma Q, Stasiewicz M, Pellerito O, and Zani A
- Subjects
- Abnormalities, Multiple embryology, Abnormalities, Multiple therapy, Animals, Apoptosis, Disease Models, Animal, Female, Hernias, Diaphragmatic, Congenital embryology, Hernias, Diaphragmatic, Congenital therapy, Lung embryology, Lung metabolism, Lung Diseases embryology, Lung Diseases therapy, Phenyl Ethers toxicity, Pregnancy, Rats, Rats, Sprague-Dawley, Abnormalities, Multiple metabolism, Amniotic Fluid cytology, Cell- and Tissue-Based Therapy methods, Endoplasmic Reticulum Stress, Hernias, Diaphragmatic, Congenital metabolism, Lung abnormalities, Lung Diseases metabolism, Pregnancy, Animal, Stem Cells cytology
- Abstract
Purpose: Pulmonary hypoplasia secondary to congenital diaphragmatic hernia (CDH) is characterized by impaired epithelial homeostasis. Recently, amniotic fluid stem cells (AFSCs) have been shown to promote growth in hypoplastic lungs of rat fetuses with CDH. Herein, we investigated whether CDH hypoplastic lungs mount an endoplasmic reticulum (ER) stress response and whether AFSCs could re-establish pulmonary epithelial homeostasis., Methods: Primary epithelial cells were isolated from fetal rat lungs at E14.5 from control and nitrofen-exposed dams at E9.5. Nitrofen-exposed epithelial cells were grown in medium alone or co-cultured with AFSCs. Epithelial cell cultures were compared for apoptosis (TUNEL), cytotoxicity (LIVE/DEAD assay), proliferation (5'EdU), and ER stress (CHOP, Bcl-2) using one-way ANOVA (Dunn's post-test)., Results: Compared to control, nitrofen-exposed epithelial cells had increased cytotoxicity and apoptosis, reduced proliferation, and activated ER stress. AFSCs restored apoptosis, proliferation, and ER stress back to control levels, and significantly reduced cytotoxicity., Conclusions: This study shows for the first time that ER stress-induced apoptosis is activated in the pulmonary epithelium of hypoplastic lungs from fetuses with CDH. AFSC treatment restores epithelial cellular homeostasis by attenuating the ER stress response and apoptosis, by increasing proliferation and migration ability, and by reducing cytotoxicity.
- Published
- 2019
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43. Changes in Drosophila mitochondrial proteins following chaperone-mediated lifespan extension confirm a role of Hsp22 in mitochondrial UPR and reveal a mitochondrial localization for cathepsin D.
- Author
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Morrow G, Kim HJ, Pellerito O, Bourrelle-Langlois M, Le Pécheur M, Groebe K, and Tanguay RM
- Subjects
- Animals, Cathepsin D genetics, Drosophila Proteins genetics, Drosophila melanogaster, Heat-Shock Proteins genetics, Mitochondria genetics, Mitochondrial Proteins genetics, Cathepsin D metabolism, Drosophila Proteins metabolism, Heat-Shock Proteins metabolism, Longevity physiology, Mitochondria metabolism, Mitochondrial Proteins metabolism, Unfolded Protein Response physiology
- Abstract
Hsp22 is a small mitochondrial heat shock protein (sHSP) preferentially up-regulated during aging in Drosophila melanogaster. Its developmental expression is strictly regulated and it is rapidly induced in conditions of stress. Hsp22 is one of the few sHSP to be localized inside mitochondria, and is the first sHSP to be involved in the mitochondrial unfolding protein response (UPR(MT)) together with Hsp60, mitochondrial Hsp70 and TRAP1. The UPR(MT) is a pro-longevity mechanism, and interestingly Hsp22 over-expression by-itself increases lifespan and resistance to stress. To unveil the effect of Hsp22 on the mitochondrial proteome, comparative IEF/SDS polyacrylamide 2D gels were done on mitochondria from Hsp22+ flies and controls. Among the proteins influenced by Hsp22 expression were proteins from the electron transport chain (ETC), the TCA cycle and mitochondrial Hsp70. Hsp22 co-migrates with ETC components and its over-expression is associated with an increase in mitochondrial protease activity. Interestingly, the only protease that showed significant changes upon Hsp22 over-expression in the comparative IEF/SDS-PAGE analysis was cathepsin D, which is localized in mitochondria in addition to lysosome in D. melanogaster as evidenced by cellular fractionation. Together the results are consistent with a role of Hsp22 in the UPR(MT) and in mitochondrial proteostasis., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)
- Published
- 2016
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44. The secreted protein acidic and rich in cysteine is a critical mediator of cell death program induced by WIN/TRAIL combined treatment in osteosarcoma cells.
- Author
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Notaro A, Sabella S, Pellerito O, Vento R, Calvaruso G, and Giuliano M
- Subjects
- Apoptosis, Benzoxazines chemistry, Bone Neoplasms pathology, Caspase 8 metabolism, Cell Death, Cell Line, Tumor, Cell Membrane metabolism, Cell Survival, Endoplasmic Reticulum Stress, Gene Silencing, Humans, Morpholines chemistry, Naphthalenes chemistry, Osteosarcoma pathology, Protein Domains, RNA Interference, Bone Neoplasms metabolism, Osteonectin metabolism, Osteosarcoma metabolism, TNF-Related Apoptosis-Inducing Ligand metabolism
- Abstract
Secreted protein acidic and rich in cysteine (SPARC) is a multi-functional protein which modulates cell-cell and cell-matrix interactions. In cancer cells, SPARC behaves as a tumor promoter in a number of tumors, but it can also act as a tumor suppressor factor. Our previous results showed that the synthetic cannabinoid WIN55,212-2 (WIN), a potent cannabinoid receptor agonist, is able to sensitize osteosarcoma MG63 cells to TNF-related apoptosis-inducing ligand (TRAIL)-induced apoptosis which is accompanied with endoplasmic reticulum (ER)-stress induction and the increase in autophagic markers. In the present investigation, we studied the role of SPARC in WIN/TRAIL-induced apoptosis demonstrating that WIN increased the level of SPARC protein and mRNA in a time-dependent manner. This event was functional to WIN/TRAIL-dependent apoptosis as demonstrated by RNA interfering analysis which indicated that SPARC-silenced cells were less sensitive to cytotoxic effects induced by the combined treatment. Our experiments also demonstrate that SPARC interacts with caspase-8 thus probably favoring its translocation to plasma membrane and the activation of extrinsic apoptotic pathway. In conclusion, to the best of our knowledge, our results are the first to show that WIN-dependent increase in the level of SPARC plays a critical role in sensitizing osteosarcoma cells to TRAIL action.
- Published
- 2016
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45. WIN induces apoptotic cell death in human colon cancer cells through a block of autophagic flux dependent on PPARγ down-regulation.
- Author
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Pellerito O, Notaro A, Sabella S, De Blasio A, Vento R, Calvaruso G, and Giuliano M
- Subjects
- Cell Line, Tumor, Colonic Neoplasms drug therapy, Down-Regulation, Endoplasmic Reticulum Stress drug effects, Humans, Mitochondria metabolism, PPAR gamma genetics, Signal Transduction drug effects, Antineoplastic Agents pharmacology, Apoptosis drug effects, Autophagy drug effects, Benzoxazines pharmacology, Colonic Neoplasms pathology, Morpholines pharmacology, Naphthalenes pharmacology, PPAR gamma metabolism
- Abstract
Cannabinoids have been reported to possess anti-tumorigenic activity in cancer models although their mechanism of action is not well understood. Here, we show that the synthetic cannabinoid WIN55,212-2 (WIN)-induced apoptosis in colon cancer cell lines is accompanied by endoplasmic reticulum stress induction. The formation of acidic vacuoles and the increase in LC3-II protein indicated the involvement of autophagic process which seemed to play a pro-survival role against the cytotoxic effects of the drug. However, the enhanced lysosomal membrane permeabilization (LMP) blocked the autophagic flux after the formation of autophagosomes as demonstrated by the accumulation of p62 and LC3, two markers of autophagic degradation. Data also provided evidence for a role for nuclear receptor peroxisome proliferator-activated receptor γ (PPARγ) in cannabinoid signalling. PPARγ expression, at both protein and mRNA levels, was significantly down-regulated after WIN treatment and its inhibition, either by specific antagonists or by down-regulation via gene silencing, induced effects on cell viability as well as on ER stress and autophagic markers similar to those obtained in the presence of WIN. Moreover, the observation that the increase in p62 level and the induction of LMP were also modified by PPARγ antagonists seemed to indicate that PPARγ down-regulation was crucial to determinate the block of autophagic flux, thus confirming the critical role of PPARγ in WIN action. In conclusion, at our knowledge, our results are the first to show that the reduction of PPARγ levels contributes to WIN-induced colon carcinoma cell death by blocking the pro-survival autophagic response of cells.
- Published
- 2014
- Full Text
- View/download PDF
46. Involvement of PAR-4 in cannabinoid-dependent sensitization of osteosarcoma cells to TRAIL-induced apoptosis.
- Author
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Notaro A, Sabella S, Pellerito O, Di Fiore R, De Blasio A, Vento R, Calvaruso G, and Giuliano M
- Subjects
- Acridine Orange, Apoptosis drug effects, Cadaverine analogs & derivatives, Cell Cycle Checkpoints drug effects, Cell Line, Tumor, Cell Proliferation drug effects, Endoplasmic Reticulum Chaperone BiP, Endoplasmic Reticulum Stress drug effects, Humans, Microtubule-Associated Proteins metabolism, Osteosarcoma drug therapy, RNA, Small Interfering genetics, Apoptosis Regulatory Proteins metabolism, Benzoxazines pharmacology, Cannabinoid Receptor Agonists pharmacology, Heat-Shock Proteins metabolism, Morpholines pharmacology, Naphthalenes pharmacology, Osteosarcoma physiopathology, TNF-Related Apoptosis-Inducing Ligand metabolism
- Abstract
The synthetic cannabinoid WIN 55,212-2 is a potent cannabinoid receptor agonist with anticancer potential. Experiments were performed to determine the effects of WIN on proliferation, cell cycle distribution, and programmed cell death in human osteosarcoma MG63 and Saos-2 cells. Results show that WIN induced G2/M cell cycle arrest, which was associated with the induction of the main markers of ER stress (GRP78, CHOP and TRB3). In treated cells we also observed the conversion of the cytosolic form of the autophagosome marker LC3-I into LC3-II (the lipidated form located on the autophagosome membrane) and the enhanced incorporation of monodansylcadaverine and acridine orange, two markers of the autophagic compartments such as autolysosomes. WIN also induced morphological effects in MG63 cells consisting in an increase in cell size and a marked cytoplasmic vacuolization. However, WIN effects were not associated with a canonical apoptotic pathway, as demonstrated by the absence of specific features, and only the addition of TRAIL to WIN-treated cells led to apoptotic death probably mediated by up-regulation of the tumor suppressor factor PAR-4, whose levels increased after WIN treatment, and by the translocation of GRP78 on cell surface.
- Published
- 2014
- Full Text
- View/download PDF
47. Synthesis, chemical characterization and biological activity of new histone acetylation/deacetylation specific inhibitors: a novel and potential approach to cancer therapy.
- Author
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Pellerito O, Prinzivalli C, Foresti E, Sabatino P, Abbate M, Casella G, Fiore T, Scopelliti M, Pellerito C, Giuliano M, Grasso G, and Pellerito L
- Subjects
- Acetylation, Antineoplastic Agents chemistry, Antineoplastic Agents pharmacology, Cell Survival, Cells, Cultured, Hep G2 Cells, Histones chemistry, Humans, Organotin Compounds chemistry, Organotin Compounds pharmacology, Valproic Acid chemical synthesis, Valproic Acid pharmacology, Antineoplastic Agents chemical synthesis, Histones metabolism, Organotin Compounds chemical synthesis, Valproic Acid analogs & derivatives, Valproic Acid chemistry
- Abstract
Three new triorganotin(IV) complexes of valproic acid (vp1, Me3Sn-valproate; vp2, Bu3Sn-valproate; vp3, Ph3Sn-valproate) have been synthesized and investigated by spectroscopic and biological methods. An anionic, monodentate valproate ligand was observed, ester-like coordinating the tin atom on a tetra-coordinated, monomeric environment. The structures, though, can distort towards a penta-coordination, as a consequence of a long range O···Sn interaction. Crystallographic and NMR findings confirm this situation both in solid state and solution. Biological finding evidenced a clear cytotoxic action of the complexes in hepatocellular carcinoma cell cultures: one of the complexes induced an 80% cell viability reduction after 24h treatment in HepG2 cells. This effect was accompanied by the appearance of biochemical signs of apoptosis. In Chang liver cells, the same compound induced only modest effects, suggesting a potential use as anti-cancer drug. Preliminary evaluations on hyperacetylation state of histone H3 in tributyltin-valproate treated HepG2 cells showed an increase in Ac-H3 (histone H3 acetylated at lys-9 and lys-14), suggesting that the compound maintains the deacetylation inhibition activity of its ligand valproate., (Copyright © 2013 Elsevier Inc. All rights reserved.)
- Published
- 2013
- Full Text
- View/download PDF
48. Notch inhibition restores TRAIL-mediated apoptosis via AP1-dependent upregulation of DR4 and DR5 TRAIL receptors in MDA-MB-231 breast cancer cells.
- Author
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Portanova P, Notaro A, Pellerito O, Sabella S, Giuliano M, and Calvaruso G
- Subjects
- Amyloid Precursor Protein Secretases antagonists & inhibitors, Amyloid Precursor Protein Secretases genetics, Apoptosis genetics, Breast Neoplasms drug therapy, Breast Neoplasms pathology, Cell Differentiation genetics, Female, Gene Expression Regulation, Neoplastic, Humans, MCF-7 Cells, Receptors, Notch genetics, Receptors, TNF-Related Apoptosis-Inducing Ligand genetics, Receptors, TNF-Related Apoptosis-Inducing Ligand metabolism, Signal Transduction, TNF-Related Apoptosis-Inducing Ligand metabolism, Breast Neoplasms genetics, Genes, jun genetics, Receptors, TNF-Related Apoptosis-Inducing Ligand biosynthesis, TNF-Related Apoptosis-Inducing Ligand genetics
- Abstract
Notch is a family of transmembrane receptors whose activation through proteolytic cleavage by γ-secretase targets genes which participate in cell development, differentiation and tumorigenesis. Notch signaling is constitutively activated in various cancers, including breast cancer and its upregulation is usually related with poor clinical outcomes. Therefore, targeting Notch signaling with γ-secretase inhibitors (GSIs) is considered a promising strategy for cancer treatment. We report that the γ-secretase inhibitor-I (GSI-I) sensitizes human breast cancer cells to apoptosis mediated by tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). The antiproliferative GSI-I/TRAIL synergism was stronger in ER-negative MDA-MB-231 breast cancer cells compared with ER-positive MCF-7 cells. In MDA-MB-231 cells, GSI-I treatment induced upregulation of DR4 and DR5 TRAIL receptors. This effect seemed to be related to the activation of the transcription factor AP1 that was a consequence of Notch inhibition, as demonstrated by Notch-1 silencing experiments. Combined treatment induced loss of the mitochondrial transmembrane potential and activation of caspases. GSI-I alone and/or GSI-I/TRAIL combination also induced a significant decrease in the levels of some survival factors (survivin, c-IAP-2, Bcl-xL, BimEL and pAKT) and upregulation of pro-apoptotic factors BimL, BimS and Noxa, enhancing the cytotoxic potential of the two drugs. Taken together, these results indicate for the first time that GSI-I/TRAIL combination could represent a novel and potentially effective tool for breast cancer treatment.
- Published
- 2013
- Full Text
- View/download PDF
49. Cannabinoid-associated cell death mechanisms in tumor models (review).
- Author
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Calvaruso G, Pellerito O, Notaro A, and Giuliano M
- Subjects
- Animals, Antineoplastic Agents therapeutic use, Cannabinoids therapeutic use, Drug Synergism, Humans, Neoplasms drug therapy, Antineoplastic Agents pharmacology, Apoptosis drug effects, Autophagy drug effects, Cannabinoids pharmacology, Neoplasms pathology
- Abstract
In recent years, cannabinoids (the active components of Cannabis sativa) and their derivatives have received considerable interest due to findings that they can affect the viability and invasiveness of a variety of different cancer cells. Moreover, in addition to their inhibitory effects on tumor growth and migration, angiogenesis and metastasis, the ability of these compounds to induce different pathways of cell death has been highlighted. Here, we review the most recent results generating interest in the field of death mechanisms induced by cannabinoids in cancer cells. In particular, we analyze the pathways triggered by cannabinoids to induce apoptosis or autophagy and investigate the interplay between the two processes. Overall, the results reported here suggest that the exploration of molecular mechanisms induced by cannabinoids in cancer cells can contribute to the development of safe and effective treatments in cancer therapy.
- Published
- 2012
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50. Diorganotin(IV) N-acetyl-L-cysteinate complexes: synthesis, solid state, solution phase, DFT and biological investigations.
- Author
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Pellerito L, Prinzivalli C, Casella G, Fiore T, Pellerito O, Giuliano M, Scopelliti M, and Pellerito C
- Subjects
- Antineoplastic Agents chemical synthesis, Binding Sites, Cell Line, Humans, Molecular Structure, Organotin Compounds chemical synthesis, Organotin Compounds pharmacology, Spectrum Analysis, Acetylcysteine chemistry, Antineoplastic Agents chemistry, Cell Survival drug effects, Organotin Compounds chemistry
- Abstract
Diorganotin(IV) complexes of N-acetyl-L-cysteine (H(2)NAC; (R)-2-acetamido-3-sulfanylpropanoic acid) have been synthesized and their solid and solution-phase structural configurations investigated by FTIR, Mössbauer, (1)H, (13)C and (119)Sn NMR spectroscopy. FTIR results suggested that in R(2)Sn(IV)NAC (R = Me, Bu, Ph) complexes NAC(2-) behaves as dianionic tridentate ligand coordinating the tin(IV) atom, through ester-type carboxylate, acetate carbonyl oxygen atom and the deprotonated thiolate group. From (119)Sn Mössbauer spectroscopy it could be inferred that the tin atom is pentacoordinated, with equatorial R(2)Sn(IV) trigonal bipyramidal configuration. In DMSO-d(6) solution, NMR spectroscopic data showed the coordination of one solvent molecule to tin atom, while the coordination mode of the ligand through the ester-type carboxylate and the deprotonated thiolate group was retained in solution. DFT (Density Functional Theory) study confirmed the proposed structures in solution phase as well as the determination of the most probable stable ring conformation. Biological investigations showed that Bu(2)SnCl(2) and NAC2 induce loss of viability in HCC cells and only moderate effects in non-tumor Chang liver cells. NAC2 showed lower cytotoxic activity than Bu(2)SnCl(2), suggesting that the binding with NAC(2-) modulates the marked cytotoxic activity exerted by Bu(2)SnCl(2). Therefore, these novel butyl derivatives could represent a new class of anticancer drugs., (2010. Published by Elsevier Inc.)
- Published
- 2010
- Full Text
- View/download PDF
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