V Sica

Publications (54)167.48 Total impact

• Article: Genista sessilifolia DC. extracts induce apoptosis across a range of cancer cell lines.

  P Bontempo, D Rigano, A Doto, C Formisano, M Conte, A Nebbioso, V Carafa, G Caserta, V Sica, A M Molinari, L Altucci
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  ABSTRACT: Restorative properties of medicinal plants such as Genista sessilifolia DC. have often been suggested to occur, in epidemiological studies. However, full characterization of effective principles responsible for this action has never previously been performed. Here, we have characterized G. sessilifolia's anti-cancer effects and identified the chemical components involved in this anti-tumour action. Cell cycle, apoptosis, necrosis, differentiation analyses, high-performance liquid chromatography, western blotting, RNA extraction, real-time PCR and primers have all been observed/used in the study. We report that G. sessilifolia methanol extract has anti-cancer activity on solid and haematological cancer cells. G. sessilifolia extract's anti-proliferative action is closely bound to induction of apoptosis, whereas differentiation is only weakly modulated. Analysis of G. sessilifolia extract, by high-performance liquid chromatography, identifies fraction 18-22 as the pertinent component for induction of apoptosis, whereas fractions 11-13 and 27-30 both seem to contribute to differentiation. G. sessilifolia extract induces apoptosis mediated by caspase activation and p21, Rb, p53, Bcl2-associated agonist of cell death (BAD), tumour necrosis factor receptor super-family, member 10 (TRAIL) overexpression and death receptor 5 (DR5). Accordingly, fraction 18-22 inducing apoptosis was able to induce TRAIL. Our results indicate that G. sessilifolia extract and its fraction 18-22 containing genistin and isoprunetin, were able to induce anti-cancer effects supporting the hypothesis of a pro-apoptotic intrinsic content of this natural medicinal plant.
  Cell Proliferation 04/2013; 46(2):183-92. · 2.52 Impact Factor
• Article: Effect of Autologous Transplantation of Bone Marrow Cells Concentrated With the MarrowXpress System in Patients With Critical Limb Ischemia.

  C Maione, C Botti, C A Coppola, C Silvestroni, S Lillo, V Schiavone, G Sica, V Sica, V Kumar, G Cobellis
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  ABSTRACT: Critical limb ischemia (CLI), a vascular disease affecting lower limbs, with high morbidity and mortality, is becoming a challenge due to the aging of the population. Patients without direct revascularization options have the worst outcomes. To date, 25% to 40% of CLI patients are not candidates for surgical or endovascular approaches, facing a major amputation as the ultimate option. This study sought to assess the safety and efficacy of transplantation of autologous bone marrow concentrates in "no-option" patients to restore blood perfusion by collateral flow and limb salvage. We performed a nonrandomized, noncontrolled pilot study for no-option CLI patients using intra-arterial infusion of autologous bone marrow concentrate. Variation of blood perfusion parameters, evaluated by laser doppler flowmetry after 6 and 12 months, was set as primary endpoint. Thirteen enrolled patients showed improvements in objective measurements of perfusion. This uncontrolled study provided evidence that transplantation of autologous bone marrow concentrates was well tolerated by CLI patients without significant adverse effects, demonstrating improved perfusion, confirming the feasibility and safety of the procedure.
  Transplantation Proceedings 01/2013; 45(1):402-6. · 1.00 Impact Factor
• Source

  Available from: Daniela Rigano

  Article: Psidium guajava L. anti-neoplastic effects: induction of apoptosis and cell differentiation.

  P Bontempo, A Doto, M Miceli, L Mita, R Benedetti, A Nebbioso, M Veglione, D Rigano, M Cioffi, V Sica, A M Molinari, L Altucci
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  ABSTRACT: Curative properties of medicinal plants such as Psidium guajava L. (Myrtaceae) have often been indicated by epidemiological studies on populations in which these fruits are consumed daily. However, complete characterization of the active principles responsible for this ability has never been performed. Here, we have characterized P. guajava's anti-cancer potential and identified the parts of the fruit involved in its anti-neoplastic action. We studied morphology of our cells, cell cycle characteristics and apoptosis and performed immunostaining, differentiation and western blot analyses. We report that the P. guajava extract exerted anti-cancer control on both haematological and solid neoplasias. P. guajava extract's anti-tumour properties were found to be tightly bound to induction of apoptosis and differentiation. Use of ex vivo myeloid leukaemia blasts corroborated that P. guajava was able to induce cell death but did not exhibit anti-cancer effects on all malignant cells investigated, indicating selective activity against certain types of tumour. Analyses of P. guajava pulp, peel and seeds identified the pulp as being the most relevant component for causing cell cycle arrest and apoptosis, whereas peel was responsible for causing cell differentiation. P. guajava itself and its pulp-derived extract were found to induce apoptosis accompanied by caspase activation and p16, p21, Fas ligand (FASL TNF super-family, member 6), Bcl-2-associated agonist of cell death (BAD) and tumour necrosis factor receptor super-family, member 10b (DR5), overexpression. Our findings showed that P. guajava L. extract was able to exert anti-cancer activity on cultures in vitro and ex vivo, supporting the hypothesis of its anti malignant pro-apoptotic modulation.
  Cell Proliferation 12/2011; 45(1):22-31. · 2.52 Impact Factor
• Article: Differential accumulation of BPA in some tissues of offspring of Balb-C mice exposed to different BPA doses.

  L Mita, A Baldi, N Diano, E Viggiano, M Portaccio, C Nicolucci, L Grumiro, C Menale, D G Mita, E P Spugnini, R Viceconte, G Citro, R Pierantoni, V Sica, M Marino, P G Signorile, M Bianco
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  ABSTRACT: Pregnant adult Balb-C mice were exposed daily to two different doses of Bisphenol A (BPA) by subcutaneous injection beginning on gestational day 1 through the seventh day after delivery. The mothers were sacrificed on postpartum day 21, and the offspring were sacrificed at 3 months of age. Control mice were subjected to the same experimental protocol but received saline injections. The liver, muscles, hindbrain and forebrain of the offspring were dissected and processed using HPLC to assess the level of BPA in the tissues and to determine its dependence on the exposure dose and gender. For comparison, the same tissues were dissected from the mothers and analysed. We report the following results: (1) the level of BPA that accumulated in a given tissue was dependent on the exposure dose; (2) the rank order of BPA accumulation in the various tissues was dependent on the gender of the offspring; (3) the average BPA concentrations in the liver and muscle of the female offspring were higher than in the males; and (4) the average BPA concentration in the central nervous system (i.e., the hindbrain and forebrain) of the male offspring was higher than in the females.
  Environmental toxicology and pharmacology. 10/2011; 33(1):9-15.
• Article: Differential accumulation levels in the brain of rats exposed to the endocrine disruptor 4-tert-octylphenol (OP).

  M Bianco, L Mita, M Portaccio, N Diano, V Sica, B De Luca, D G Mita, C Romano Carratelli, E Viggiano
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  ABSTRACT: Octylphenol (OP) is an endocrine-disrupting chemical that accumulates in various organs. It has also been shown to exert noxious effects on the central nervous system. In the present study, we measured in Sprague-Dawley rats the degree of OP accumulation in different areas of the brain and investigated the effect of OP in pain modulation. Two groups of male Sprague-Dawley rats were treated for 20 days with 50mg/kg BW/day of OP (group 1) or vehicle (group 2). At the end of the treatment, the formalin test was performed to evaluate the effect of OP exposure on pain. Soon after, rats were sacrificed, and the accumulation of OP in the cerebral cortex, hippocampus, hypothalamus, cerebellum, thalamus, striatum, mesencephalus and ventral hindbrain was measured by HPLC analysis. The results showed a greater accumulation of OP in the cerebral cortex compared to all the other areas; there was also more accumulation in the cerebellum compared to the mesencephalus and thalamus. No accumulation was found in the striatum. These results suggest that there is a preferential accumulation of OP in different areas of the brain with consequences to neural behaviour. On the contrary, experiments on facial grooming did not show significant effects of OP on pain.
  Environmental toxicology and pharmacology. 01/2011; 31(1):198-204.
• Article: Bisphenol A content in fish caught in two different sites of the Tyrrhenian Sea (Italy).

  L Mita, M Bianco, E Viggiano, F Zollo, U Bencivenga, V Sica, G Monaco, M Portaccio, N Diano, A Colonna, M Lepore, P Canciglia, D G Mita
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  ABSTRACT: Bisphenol A (BPA) is an endocrine disruptor (ED) that is abundant in the environment because of its extensive use in human-manufactured products. In this study, the BPA concentration was measured in the muscle and liver of five edible fish, characterized by different habitat and habits, caught in two different sites of the Tyrrhenian Sea (Italy). Our results show that: (i) fish livers are about 2.5 times more polluted than muscle; (ii) fish caught in the Gulf of Naples are more polluted than those from the Latium coasts, ranging from 1.2-fold more for White Bream to 6.6-fold for Grey Mullet; and (iii) the percentages of fish found to be BPA-polluted in the Gulf of Naples ranged from 73% (for Bass) to 90% (for Mullet), while the Latium fish range from 60% (for Bass) to 90% (for Mullet). These data indicate that consumers of fish caught in the Gulf of Naples are at a greater risk for BPA-induced endocrine pathologies compared to those who consume fish caught along the Latium coasts.
  Chemosphere 10/2010; 82(3):405-10. · 3.21 Impact Factor
• Source

  Available from: Gilda Cobellis

  Article: Successful bone marrow transplantation reveals the lack of endothelial progenitor cells mobilization in a patient with critical limb ischemia: a case report.

  G Cobellis, C Botti, A Taddeo, A Silvestroni, S Lillo, A Da Ponte, M L Villa, V Sica, S Della Bella
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  ABSTRACT: Restoring blood flow to ischemic tissue is a prerequisite for treatment of ischemic diseases. Cell-based therapy based on bone marrow transplantation is a promising option for patients with critical limb ischemia (CLI). The efficacy of cell therapies to augment neovascularization seems to involve endothelial progenitor cells (EPCs); however, the mechanisms underlying the efficacy have not been fully elucidated. Herein we have described the case of a young patient with severe CLI, who experienced a 24-month beneficial clinical response to autologous bone marrow transplantation. The exceptional amelioration enabled him to perform standardized maximal treadmill exercise test that demonstrated lack of exercise-induced EPC mobilization, despite adequate stromal-derived factor 1 and vascular endothelial growth factor responses. Therefore, tissue ischemia is not sufficient to promote the recruitment of EPCs that have been demonstrated to be involved in the recovery from ischemia. The local implantation of marrow-derived elements may provide cells and/or trophic factors, which have the capacity to augment angiogenesis, opening new approaches to the etiopathogenesis of the disease.
  Transplantation Proceedings 09/2010; 42(7):2816-20. · 1.00 Impact Factor
• Article: Employment of immobilized Lipase from Candida rugosa for bioremediation of waters polluted by dimethylphthalate taken as model of endocrine disruptors

  L. Mita, V. Sica, M. Guida, C. Nicolucci, T. Grimaldi, L. Caputo, M.Bianco, S. Rossi, U.Bencivenga, M. S. Mohy Eldin, D.G. Mita, N. Diano
  Journal of Molecular Catalysis B Enzymatic 01/2010; 62:133-141. · 2.73 Impact Factor
• Source

  Available from: Gilda Cobellis

  Article: Long-term effects of repeated autologous transplantation of bone marrow cells in patients affected by peripheral arterial disease.

  G Cobellis, A Silvestroni, S Lillo, G Sica, C Botti, C Maione, V Schiavone, S Rocco, G Brando, V Sica
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  ABSTRACT: Long-term effects of autologous mononuclear bone marrow cell transplantation were studied in patients with severe peripheral arterial disease (PAD) and critical limb ischemia. Ten patients with end-stage disease were infused twice with autologous bone marrow cells and they completed the 12-month follow-up study. Substantial improvement of blood flow and increasing capillary densities were seen when compared with a concomitant control group comprising patients who did not enroll in the study. The ankle-brachial index (ABI) and pain-free walking distance improved significantly in treated patients. The improvement was sustained 12 months after treatment. These results confirm that the autologous bone marrow transplantation is an effective therapeutic strategy in critical limb ischemia.
  Bone marrow transplantation 09/2008; 42(10):667-72. · 3.00 Impact Factor
• Article: Cooperation between Myc and YY1 provides novel silencing transcriptional targets of alpha3beta1-integrin in tumour cells.

  F de Nigris, C Botti, R Rossiello, E Crimi, V Sica, C Napoli
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  ABSTRACT: We show that human osteosarcoma cells (Saos-2) have downregulation of alpha3beta1-integrin compared to normal bone cells; this was further described in human osteosarcomas and in a primary murine sarcoma. The alpha3 gene was silenced in Saos-2 cells causing a low expression of alpha3beta1-integrin and reduction in collagen attachment with increasing migratory capacity. Chromatin immunoprecipitation assay performed on alpha3 promoter established that Myc and Yin Yang protein (YY1) cooperate in tandem to downregulate the alpha3 gene. This silencing mechanism involves the binding of Myc and YY1 to DNA and formation of complexes among Myc/Max, YY1, CREB-binding protein and deacetylation activity. The promoter containing deletions of E-boxes or YY1 cassettes failed to downregulate the transcription of a reporter gene as well as the inhibition of deacetylation activity. Overexpression of both Myc and YY1 was necessary to determine the alpha3-integrin promoter downregulation in normal osteoblasts. This downregulation of alpha3beta1-integrin can contribute to the acquisition of a more aggressive phenotype. YY1 regulated negatively the Myc activity through a direct interaction with the Myc/Max and deacetylase complexes. This represents a novel silencing mechanism with broad implications in the transcription machinery of tumours.
  Oncogene 02/2007; 26(3):382-94. · 6.37 Impact Factor
• Article: Glycoxidation of low–density lipoprotein promotes multiple apoptotic pathways and NFk B activation in human coronary cells

  F. de Nigris, L. Gallo, V. Sica, Claudio Napoli
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  ABSTRACT: Apoptosis of arterial cells induced by oxidized low–density lipoprotein (oxLDL) is thought to contribute to the progression of vascular dysfunction and atherogenesis. It is well established that diabetes mellitus is accompanied by both glycosylation and oxidation LDL, but the biological effects of these modified lipoproteins are poorly understood. We demonstrate here that glycosylated oxLDL (glc–oxLDL) promotes apoptotic signaling in human coronary smooth muscle cells. This was associated by a decrease of the antiapoptotic protein Bcl–2, an increase of the pro–apoptotic protein Bax, and activation of caspase 3. Glc–oxLDL also activated NFkB and decreased IkB, these effects were more pronounced than those achieved with oxLDL. Our study shows that glc–oxLDL influences a broad cascade of signaling transduction pathways, which may not only result in apoptosis, but also could affect NFkB in human coronary cells. This cascade of events may influence the evolution of atherogenesis and vascular complications in diabetic patients.
  Archiv für Kreislaufforschung 02/2006; 101(2):101-108. · 7.35 Impact Factor
• Article: In vivo veritas: thrombosis mechanisms in animal models.

  C Napoli, F De Nigris, O Pignalosa, A Lerman, G Sica, C Fiorito, V Sica, A Chade, L O Lerman
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  ABSTRACT: Experimental models have enhanced our understanding of atherothrombosis pathophysiology and have played a major role in the search for adequate therapeutic interventions. Various animal models have been developed to simulate thrombosis and to study in vivo parameters related to hemodynamics and rheology that lead to thrombogenesis. Although no model completely mimics the human condition, much can be learned from existing models about specific biologic processes in disease causation and therapeutic intervention. In general, large animals such as pigs and monkeys have been better suited to study atherosclerosis and arterial and venous thrombosis than smaller species such as rats, rabbits, and dogs. On the other hand, mouse models of arterial and venous thrombosis have attracted increasing interest over the past two decades, owing to direct availability of a growing number of genetically modified mice, improved technical feasibility, standardization of new models of local thrombosis, and low maintenance costs. To simulate rupture of an atherosclerotic plaque, models of arterial thrombosis often involve vascular injury, which can be achieved by several means. There is no animal model that is sufficiently tall, that can mimic the ability of humans to walk upright, and that possesses the calf muscle pump that plays an important role in human venous hemodynamics. A number of spontaneous or genetically engineered animals with overexpression or deletion of various elements in the coagulation, platelet, and fibrinolysis pathways are now available. These animal models can replicate important aspects of thrombosis in humans, and provide a valuable resource in the development of novel concepts of disease mechanisms in human patients.
  Scandinavian Journal of Clinical and Laboratory Investigation 02/2006; 66(5):407-27. · 1.38 Impact Factor
• Article: Childhood infection and endothelial dysfunction: a potential link in atherosclerosis?

  C Napoli, O Pignalosa, F de Nigris, V Sica
  Circulation 05/2005; 111(13):1568-70. · 14.74 Impact Factor
• Article: New trends in anti-atherosclerotic agents.

  C Napoli, V Sica, O Pignalosa, F de Nigris
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  ABSTRACT: New approaches to atherosclerosis-related diseases include novel uses of proven treatments and development of innovative agents. Several commonly used cardiovascular drugs such as dihydropyridine calcium antagonists, ACE inhibitors containing the sulphydryl group, or highly lipophilic beta-blockers have some anti-atherosclerotic activities. Moreover, new clinical trials suggesting that additional reduction of low-density lipoprotein cholesterol levels with statin therapy results in additional benefit in coronary heart disease prevention. Notably, new cholesterol transport or bile acid transport inhibitors have been found to produce significant reductions in intestinal cholesterol absorption and experimental atherosclerosis. Inhibitors of acyl coenzyme A:cholesterol acyltransferase, which can reduce cholesterol storage in macrophages and in arterial lesions, have also been developed. Finally, newer therapeutical strategies against atherogenesis may include the use of antioxidants and cholestyramine during pregnancy or the development of metalloproteinase inhibitors.
  Current Medicinal Chemistry 02/2005; 12(15):1755-72. · 4.86 Impact Factor
• Article: Sulfhydryl angiotensin-converting enzyme inhibition induces sustained reduction of systemic oxidative stress and improves the nitric oxide pathway in patients with essential hypertension.

  C Napoli, V Sica, F de Nigris, O Pignalosa, M Condorelli, L J Ignarro, A Liguori
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  ABSTRACT: Essential hypertension is associated with enhanced LDL oxidation and impaired endothelium-dependent vasodilation. The antioxidant status is linked to the nitric oxide (NO) pathway. Sulfhydryl angiotensin-converting enzyme (ACE) inhibitors inhibit oxidative stress and atherogenesis in experimental models; therefore we tested whether this beneficial antioxidant activity could be also clinically relevant in patients with essential hypertension. Plasma LDL oxidizability was investigated initially in untreated normocholesterolemic patients with moderate essential hypertension without clinically evident target organ damage (n = 96) and in control normotensive subjects (n = 46). Patients were then randomly assigned into two age- and sex-matched groups to receive the new sulfhydryl ACE inhibitor zofenopril (15 to 30 mg/d; n = 48) or enalapril (20 mg/d, n = 48). LDL oxidizability was evaluated (generation of malondialdehyde, MDA) and systemic oxidative stress was evaluated by isoprostanes (8-isoPGF2alpha). Asymmetrical dimethyl-L-arginine (ADMA), a competitive inhibitor of endothelial NO synthase, and plasma nitrite and nitrates (NOx) were also measured. LDL from hypertensive subjects had enhanced susceptibility to oxidation in vitro compared with that in control subjects (P <.05). Similarly, isoprostanes were significantly increased (P <.01) in hypertensive subjects versus control subjects. After 12-week treatment, MDA levels were significantly reduced by zofenopril (P <.05) but not enalapril treatment (P = not significant). Isoprostanes were normalized after zofenopril treatment (P <.03), whereas enalapril was ineffective. After treatment with both ACE inhibitors, plasma NOx concentrations were significantly reduced (P <.05). Similarly, hypertension increased ADMA concentration compared with the normotensive state, whereas ACE inihibition elicited a significant decrease. However, the reduction of ADMA concentration was significantly higher in patients receiving sulfhydryl ACE inhibition (P <.05 vs enalapril). The sulfhydryl ACE inhibitor zofenopril reduces oxidative stress and improves the NO pathway in patients with essential hypertension. If confirmed in a large multicenter clinical trial, our data suggest a possible vasculoprotective effect of the compound in retarding vascular dysfunction and atherogenesis that often develops rapidly in hypertensive patients.
  American heart journal 07/2004; 148(1):e5. · 4.65 Impact Factor
• Source

  Available from: John Lawrence Wallace

  Article: Evidence that protease activated receptor 2 expression is enhanced in human coronary atherosclerotic lesions.

  C Napoli, F de Nigris, J L Wallace, M D Hollenberg, G Tajana, G De Rosa, V Sica, G Cirino
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  ABSTRACT: To investigate protease activated receptor 2 (PAR-2) expression in human coronary atherosclerotic lesions because PAR-2 is involved in the modulation of inflammatory events and vascular function. An immunohistochemical analysis was performed on serial arterial sections, using the following antibodies: MDA2, a murine monoclonal antibody against malondialdehyde lysine epitopes of oxidised low density lipoprotein (oxLDL); HAM-56, a monoclonal antibody against human macrophages/foam cells; B5, a rabbit polyclonal antibody against PAR-2; and SAM11, a mouse monoclonal antibody against human PAR-2. Sections containing at least one lesion showing substantial immunostaining were counted as positive, and results were expressed as per cent of all sections of the same artery. PAR-2 expression was enhanced in human coronary atherosclerotic lesions. This phenomenon correlated with an increase in oxLDL epitopes in the coronary artery. This study shows for the first time that PAR-2 expression is enhanced in human coronary atherosclerotic lesions, and suggests that PAR-2 dependent cellular trafficking may be one of the regulatory signalling responses to vascular injury. Further pharmacological studies will establish whether modulation (and in which direction) of PAR-2 represents a possible therapeutic target for controlling the vascular response to injury.
  Journal of Clinical Pathology 06/2004; 57(5):513-6. · 2.31 Impact Factor
• Article: Microarray analysis: a novel research tool for cardiovascular scientists and physicians.

  C Napoli, L O Lerman, V Sica, A Lerman, G Tajana, F de Nigris
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  ABSTRACT: The massive increase in information on the human DNA sequence and the development of new technologies will have a profound impact on the diagnosis and treatment of cardiovascular diseases. The microarray is a micro-hybridisation based assay. The filter, called microchip or chip, is a special kind of membrane in which are spotted several thousands of oligonucleotides of cDNA fragments coding for known genes or expressed sequence tags. The resulting hybridisation signal on the chip is analysed by a fluorescent scanner and processed with a software package utilising the information on the oligonucleotide or cDNA map of the chip to generate a list of relative gene expression. Microarray technology can be used for many different purposes, most prominently to measure differential gene expression, variations in gene sequence (by analysing the genome of mutant phenotypes), or more recently, the entire binding site for transcription factors. Measurements of gene expression have the advantage of providing all available sequence information for any given experimental design and data interpretation in pursuit of biological understanding. This research tool will contribute to radically changing our understanding of cardiovascular diseases.
  Heart (British Cardiac Society) 07/2003; 89(6):597-604. · 4.22 Impact Factor
• Article: Effects of nitric oxide-releasing aspirin versus aspirin on restenosis in hypercholesterolemic mice.

  C Napoli, G Cirino, P Del Soldato, R Sorrentino, V Sica, M Condorelli, A Pinto, L J Ignarro
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  ABSTRACT: Restenosis is due to neointimal hyperplasia, which occurs in the coronary artery after percutaneous transluminal coronary angioplasty (PTCA). During restenosis, an impairment of nitric oxide (NO)-dependent pathways may occur. Concomitant hypercholesterolemia may exacerbate restenosis in patients undergoing PTCA. Here, we show that a NO-releasing aspirin derivative (NCX-4016) reduces the degree of restenosis after balloon angioplasty in low-density lipoprotein receptor-deficient mice and this effect is associated with reduced vascular smooth muscle cell (VSMC) proliferation and macrophage deposition at the site of injury. Drugs were administered following both therapeutic or preventive protocols. We demonstrate that NCX-4016 is effective both in prevention and treatment of restenosis in the presence of hypercholesterolemia. These data indicate that impairment of NO-dependent mechanisms may be involved in the development of restenosis in hypercholesterolemic mice. Although experimental models of restenosis may not reflect restenosis in humans in all details, we suggest that a NO-releasing aspirin derivative could be an effective drug in reducing restenosis following PTCA, especially in the presence of hypercholesterolemia and/or gastrointestinal damage.
  Proceedings of the National Academy of Sciences 03/2001; 98(5):2860-4. · 9.68 Impact Factor
• Article: 17beta-Estradiol induces cyclin D1 gene transcription, p36D1-p34cdk4 complex activation and p105Rb phosphorylation during mitogenic stimulation of G(1)-arrested human breast cancer cells.

  L Altucci, R Addeo, L Cicatiello, S Dauvois, M G Parker, M Truss, M Beato, V Sica, F Bresciani, A Weisz
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  ABSTRACT: MCF-7 human breast cancer cells express functional estrogen receptor and grow in response to estrogen stimulation. G(1)-synchronized MCF-7 cells, made quiescent by exposure to the HMG-CoA reductase inhibitor Simvastatin in estrogen-free medium, readily resume cell cycle progression upon stimulation with 17beta-estradiol (E(2)), even under conditions where polypeptide growth factor-triggered signal transduction pathways are inhibited by the continuous presence of Simvastatin in the culture medium. Under these conditions, cyclin D(1) gene transcription is transiently induced within the first 1-9 h of stimulation, as shown by the accumulation of cyclin D(1) mRNA and protein (p36(D(1))) in the cell and by enhanced expression of stably transfected D(1) promoter-luciferase hybrid genes. Estrogen-induced p36(D(1)) associates readily with p32(cdk2) and p34(cdk4), but not with p31(cdk5), which is however abundantly expressed in these cells. Only p36(D(1))-p34(cdk4) complexes are activated by E(2), as detected in cell extracts by immunoprecipitation with anti-D(1) antibodies followed by assessment of phosphotransferase activity toward the retinoblastoma (Rb) gene product and by analysis of p105(Rb) phosphorylation in vivo. An estrogen-responsive regulatory region has been mapped within the first 944 bp upstream of the transcriptional startsite of the human D(1) gene. Sequence analysis of this DNA region reveals that the cis-acting elements responsive to estrogen are likely to be different in this case from the canonical EREs.
  Oncogene 07/1996; 12(11):2315-24. · 6.37 Impact Factor
• Article: 17 beta-Estradiol overcomes a G1 block induced by HMG-CoA reductase inhibitors and fosters cell cycle progression without inducing ERK-1 and -2 MAP kinases activation.

  I M Bonapace, R Addeo, L Altucci, L Cicatiello, M Bifulco, C Laezza, S Salzano, V Sica, F Bresciani, A Weisz
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  ABSTRACT: HMG-CoA reductase inhibitors, such as Lovastatin and Simvastatin, cause cell cycle arrest by interfering with the mitogenic activity of mitogens present in culture media. Cells are induced to pause in G1 and can readily resume growth upon removal of the enzymatic block. Estrogens, acting via their nuclear receptor, are mitogens for different normal and transformed cell types, where they foster cell cycle progression and cell division. In estrogen-responsive MCF-7 human breast cancer cells, but not in non responsive cells, 17 beta-estradiol (E2) induces cells arrested with Lovastatin or Simvastatin to proliferate in the presence of inhibitor, without restoring HMG-CoA reductase activity or affecting the protein prenylation pattern. Mitogenic stimulation of G1-arrested MCF-7 cells with E2 includes primary transcriptional activation of c-fos, accompanied by transient binding in vivo of the estrogen receptor and/or other factors to the ERE and the estrogen-responsive DNA region of this proto-oncogene, as detected by dimethylsulphate genomic footprinting analysis. Mitogenic stimulation of growth-arrested MCF-7 cells by E2 occurs, under these conditions, without evident activation of ERK-1 and -2 kinases, and thus independently from the mitogen-responsive signal transduction pathways that converge on these enzymes.
  Oncogene 03/1996; 12(4):753-63. · 6.37 Impact Factor