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1.
Future Med Chem ; 9(1): 25-36, 2017 01.
Article in English | MEDLINE | ID: mdl-27957876

ABSTRACT

Autophagy is a self-digestive process regulated by an intricate network of factors able either to ensure the prosurvival function of autophagy or to convert it in a death pathway. Recently, the involvement of miRNAs in the regulation of autophagy networks has been reported. This review will summarize the main features of these small noncoding endogenous RNAs, focusing on their relevance in cancer and finally addressing their impact on autophagy.


Subject(s)
Autophagy/genetics , MicroRNAs/metabolism , Neoplasms/genetics , Neoplasms/pathology , Animals , Humans
2.
Chem Asian J ; 11(7): 1107-15, 2016 Apr 05.
Article in English | MEDLINE | ID: mdl-26865223

ABSTRACT

The interaction between 13-phenylalkyl and 13-diphenylalkyl berberine derivatives (NAX) and human telomeric DNA G4 structures has been investigated by both spectroscopic and crystallographic methods. NAX042 and NAX053 are the best compounds improving the performance of the natural precursor berberine. This finding is in agreement with the X-ray diffraction result for the NAX053-Tel12 adduct, showing the ligand which interacts via π-stacking, sandwiched at the interface of two symmetry-related quadruplex units, with its benzhydryl group contributing to the overall stability of the adduct by means of additional π-stacking interactions with the DNA residues. The berberine derivatives were also investigated for their cytotoxic activity towards a panel of human cancer cell lines. Compounds NAX042 and NAX053 affect the viability of cancer cell lines in a dose-dependent manner.


Subject(s)
Antineoplastic Agents/chemistry , Berberine/analogs & derivatives , Berberine/chemistry , G-Quadruplexes , Telomere/chemistry , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/pharmacology , Berberine/pharmacology , Cell Line, Tumor , Cell Proliferation/drug effects , Cell Survival/drug effects , Crystallography, X-Ray , Dose-Response Relationship, Drug , Drug Screening Assays, Antitumor , Humans , Ligands , Models, Molecular , Molecular Structure , Solutions , Structure-Activity Relationship
3.
IEEE Trans Nanobioscience ; 14(7): 797-805, 2015 Oct.
Article in English | MEDLINE | ID: mdl-26353377

ABSTRACT

In this work, silicon micromachined structures (SMS), consisting of arrays of 3- µ m-thick silicon walls separated by 50- µm-deep, 5- µ m-wide gaps, were applied to investigate the behavior of eight tumor cell lines, with different origins and biological aggressiveness, in a three-dimensional (3D) microenvironment. Several cell culture experiments were performed on 3D-SMS and cells grown on silicon were stained for fluorescence microscopy analyses. Most of the tumor cell lines recognized in the literature as highly aggressive (OVCAR-5, A375, MDA-MB-231, and RPMI-7951) exhibited a great ability to enter and colonize the narrow deep gaps of the SMS, whereas less aggressive cell lines (OVCAR-3, Capan-1, MCF7, and NCI-H2126) demonstrated less penetration capability and tended to remain on top of the SMS. Quantitative image analyses of several fluorescence microscopy fields of silicon samples were performed for automatic cell recognition and count, in order to quantify the fraction of cells inside the gaps, with respect to the total number of cells in the examined field. Our results show that higher fractions of cells in the gaps are obtained with more aggressive cell lines, thus supporting in a quantitative way the observation that the behavior of tumor cells on the 3D-SMS depends on their aggressiveness level.


Subject(s)
Cell Culture Techniques/instrumentation , Lab-On-A-Chip Devices , Neoplasms, Experimental/pathology , Neoplasms, Experimental/physiopathology , Printing, Three-Dimensional , Silicon/chemistry , Cell Proliferation , Equipment Design , Equipment Failure Analysis , Humans , Neoplasm Invasiveness
4.
Acta Biochim Biophys Sin (Shanghai) ; 47(10): 824-33, 2015 Oct.
Article in English | MEDLINE | ID: mdl-26341980

ABSTRACT

The natural alkaloid berberine has been recently described as a promising anticancer drug. In order to improve its efficacy and bioavailability, several derivatives have been designed and synthesized and found to be even more potent than the lead compound. Among the series of berberine derivatives we have produced, five compounds were identified to be able to heavily affect the proliferation of human HCT116 and SW613-B3 colon carcinoma cell lines. Remarkably, these active compounds exhibit high fluorescence emission property and ability to induce autophagy.


Subject(s)
Apoptosis/drug effects , Berberine/analogs & derivatives , Berberine/administration & dosage , Cell Proliferation/drug effects , Colonic Neoplasms/drug therapy , Colonic Neoplasms/pathology , Antineoplastic Agents/administration & dosage , Antineoplastic Agents/chemical synthesis , Cell Line, Tumor , Dose-Response Relationship, Drug , Drug Design , Humans , Treatment Outcome
5.
Mitochondrion ; 24: 56-63, 2015 Sep.
Article in English | MEDLINE | ID: mdl-26196946

ABSTRACT

Impaired mitochondrial structure and function are common features of neurodegenerative disorders, ultimately characterized by the death of neural cells promoted by still unknown signals. Among the possible modulators of neurodegeneration, the activation of poly(ADP-ribosylation), a post-translational modification of proteins, has been considered, being the product of the reaction, poly(ADP-ribose), a signaling molecule for different cell death paradigms. The basic properties of poly(ADP-ribosylation) are here described, focusing on the mitochondrial events; cell death paradigms such as apoptosis, parthanatos, necroptosis and mitophagy are illustrated. Finally, the promising use of poly(ADP-ribosylation) inhibitors to rescue neurodegeneration is addressed.


Subject(s)
Mitochondrial Proteins/metabolism , Neurodegenerative Diseases/pathology , Poly Adenosine Diphosphate Ribose/metabolism , Proteins/metabolism , Cell Death , Humans , Poly(ADP-ribose) Polymerase Inhibitors/metabolism
6.
Molecules ; 19(8): 12349-67, 2014 Aug 15.
Article in English | MEDLINE | ID: mdl-25153862

ABSTRACT

Alkaloids are used in traditional medicine for the treatment of many diseases. These compounds are synthesized in plants as secondary metabolites and have multiple effects on cellular metabolism. Among plant derivatives with biological properties, the isoquinoline quaternary alkaloid berberine possesses a broad range of therapeutic uses against several diseases. In recent years, berberine has been reported to inhibit cell proliferation and to be cytotoxic towards cancer cells. Based on this evidence, many derivatives have been synthesized to improve berberine efficiency and selectivity; the results so far obtained on human cancer cell lines support the idea that they could be promising agents for cancer treatment. The main properties of berberine and derivatives will be illustrated.


Subject(s)
Antineoplastic Agents, Phytogenic/pharmacology , Berberine/pharmacology , Neoplasms/drug therapy , Animals , Antineoplastic Agents, Phytogenic/therapeutic use , Berberine/therapeutic use , Drug Screening Assays, Antitumor , Humans
7.
Biomed Res Int ; 2014: 924585, 2014.
Article in English | MEDLINE | ID: mdl-25045712

ABSTRACT

The pharmacological use of the plant alkaloid berberine is based on its antibacterial and anti-inflammatory properties; recently, anticancer activity has been attributed to this compound. To exploit this interesting feature, we synthesized three berberine derivatives, namely, NAX012, NAX014, and NAX018, and we tested their effects on two human colon carcinoma cell lines, that is, HCT116 and SW613-B3, which are characterized by wt and mutated p53, respectively. We observed that cell proliferation is more affected by cell treatment with the derivatives than with the lead compound; moreover, the derivatives proved to induce cell cycle arrest and cell death through apoptosis, thus suggesting that they could be promising anticancer drugs. Finally, we detected typical signs of autophagy in cells treated with berberine derivatives.


Subject(s)
Antineoplastic Agents/administration & dosage , Berberine/administration & dosage , Cell Proliferation/drug effects , Colonic Neoplasms/drug therapy , Antineoplastic Agents/chemical synthesis , Apoptosis/drug effects , Autophagy/drug effects , Berberine/analogs & derivatives , Berberine/chemical synthesis , Colonic Neoplasms/genetics , Colonic Neoplasms/pathology , HCT116 Cells , Humans , Tumor Suppressor Protein p53/genetics
8.
Biochem Pharmacol ; 92(1): 157-63, 2014 Nov 01.
Article in English | MEDLINE | ID: mdl-24976506

ABSTRACT

Poly(ADP-ribosylation) results from the conversion of NAD(+) into ADP-ribose and the following addition of ADP-ribose units to form polymers, further bound to acceptor proteins; once post-translationally ADP-ribosylated, proteins could change their function in basic processes. Poly(ADP-ribosylation) is activated under critical situations represented by DNA damage and cellular stress, and modulated in different paradigms of cell death. The hallmarks of the main death processes, i.e. apoptosis, parthanatos, necroptosis and autophagy, will be described, focusing on the role of poly(ADP-ribose) as a signaling molecule.


Subject(s)
Cell Death/physiology , Poly Adenosine Diphosphate Ribose/metabolism , Signal Transduction/physiology , Animals , Humans
9.
Front Biosci (Elite Ed) ; 6(2): 308-17, 2014 06 01.
Article in English | MEDLINE | ID: mdl-24896207

ABSTRACT

Poly(ADP-ribosylation), an NAD dependent reaction culminating in the formation of ADP-ribose monomers, and their following polymerization, is activated as an emergency process in crucial situations such as DNA damage and cellular stress; due to this crucial function, the modulation of poly(ADP-ribosylation) during cell death has been investigated. This review will describe the properties of poly(ADP-ribose) as a signalling molecule in different paradigms of cell death, i.e.apoptosis, parthanatos, necroptosis and autophagy.


Subject(s)
Cell Death/physiology , Models, Biological , Poly Adenosine Diphosphate Ribose/metabolism , Signal Transduction/physiology , Humans
10.
Apoptosis ; 18(12): 1586-98, 2013 Dec.
Article in English | MEDLINE | ID: mdl-23996609

ABSTRACT

Amiloride derivatives are a class of new promising chemotherapeutic agents. A representative member of this family is the sodium-hydrogen antiporter inhibitor HMA (5-(N,N-hexamethylene amiloride), which has been demonstrated to induce cellular intracytosolic acidification and cell death through the apoptotic pathway(s). This work aims at characterizing drug response of human cancer cell lines to HMA. After a first screening revealing that HMA interferes with cancer cell survival, we focused our attention on SW613-B3 colon carcinoma cells, which are intrinsically resistant to a panel of drugs. Searching for the activation of canonical apoptosis, we found that this process was abortive, given that the final steps of this process, i.e. PARP-1 cleavage and DNA ladder, were not detectable. Thus, we addressed caspase-independent paradigms of cell death and we observed that HMA promotes the induction of the LEI/L-DNase II pathway as well as of parthanatos. Finally, we explored the possible impact of autophagy of cell response to HMA, providing the evidence that autophagy is activated in our experimental system. On the whole, our results defined the biochemical reactions triggered by HMA, and elucidated its multiple effects, thus adding further complexity to the intricate network leading to drug resistance.


Subject(s)
Amiloride/analogs & derivatives , Antineoplastic Agents/pharmacology , Colonic Neoplasms/metabolism , Sodium-Hydrogen Exchangers/antagonists & inhibitors , Sodium-Hydrogen Exchangers/metabolism , Amiloride/pharmacology , Apoptosis/drug effects , Autophagy/drug effects , Cell Line, Tumor , Cell Survival/drug effects , Colonic Neoplasms/drug therapy , Colonic Neoplasms/genetics , Colonic Neoplasms/physiopathology , Humans , Sodium-Hydrogen Exchangers/genetics
11.
J Photochem Photobiol B ; 125: 90-7, 2013 Aug 05.
Article in English | MEDLINE | ID: mdl-23770337

ABSTRACT

The addition of chemical groups to a photosensitizer makes it to act as a fluorogenic substrate, increasing its ability to enter the cells. In this work, the cytotoxic efficacy of Hypocrellin B modified by addition of two acetate groups (HypB-Ac) was investigated in HeLa cells. Using transmission electron microscopy, cytochemical and immunocytochemical techniques, and flow cytometry we demonstrated that light irradiation of HypB-Ac-loaded cells resulted in either necrosis or apoptosis, depending on the HypB-Ac concentration. Administration of Hyp-Ac at high concentration (1×10(-)(5) M) resulted in massive necrosis, while at low concentration (2.5×10(-)(7) M) apoptosis along with autophagy were induced. Focusing on cells still exhibiting non-apoptotic features, we provide the evidence of early involvement of different organelles in the photodamage, with the frequent presence of autophagic vacuoles already at very short post-irradiation times (30 min, when ultrastructural apoptotic features are rarely found). These findings suggest that the widespread photodamage rather than the target organelle(s) involved is crucial for inducing either a catastrophic or a regulated form of cell death. Fluorogenic substrates such as HypB-Ac have an increased capability to accumulate in cancer cells compared to the native photosensitizing molecules: this would allow to use lower drug doses in vivo, thus decreasing the risk of systemic cytotoxicity in the absence of irradiation improving the efficacy of photodynamic therapy. The ability of HypB-Ac at very low concentration to induce autophagy and apoptosis would additionally be advantageous for therapeutic application, as the preferential induction of regulated forms of cell death entails the rapid phagocytotic removal of dying cells without affecting the tissue and organ structure.


Subject(s)
Fluorescent Dyes/pharmacology , Perylene/analogs & derivatives , Apoptosis/drug effects , Autophagy/drug effects , HeLa Cells , Humans , Light , Necrosis/chemically induced , Perylene/chemistry , Perylene/pharmacology , Phenol , Photosensitizing Agents/chemistry , Quinones/chemistry
12.
J Cell Mol Med ; 17(1): 103-15, 2013 Jan.
Article in English | MEDLINE | ID: mdl-23205553

ABSTRACT

The pathogenesis of age-related macular degeneration (AMD) involves demise of the retinal pigment epithelium and death of photoreceptors. In this article, we investigated the response of human adult retinal pigmented epithelial (ARPE-19) cells to 5-(N,N-hexamethylene)amiloride (HMA), an inhibitor of Na(+) /H(+) exchangers. We observed that ARPE-19 cells treated with HMA are unable to activate 'classical' apoptosis but they succeed to activate autophagy. In the first 2 hrs of HMA exposure, autophagy is efficient in protecting cells from death. Thereafter, autophagy is impaired, as indicated by p62 accumulation, and this protective mechanism becomes the executioner of cell death. This switch in autophagy property as a function of time for a single stimulus is here shown for the first time. The activation of autophagy was observed, at a lesser extent, with etoposide, suggesting that this event might be a general response of ARPE cells to stress and the most important pathway involved in cell resistance to adverse conditions and toxic stimuli.


Subject(s)
Epithelial Cells/metabolism , Oxidative Stress , Retinal Pigment Epithelium/metabolism , Adaptor Proteins, Signal Transducing/genetics , Adaptor Proteins, Signal Transducing/metabolism , Adult , Amiloride/analogs & derivatives , Amiloride/pharmacology , Apoptosis , Autophagy , Biological Transport, Active , Caspases/genetics , Caspases/metabolism , Cell Count , Cell Line , Cell Survival , Epithelial Cells/cytology , Epithelial Cells/drug effects , Etoposide/pharmacology , Gene Expression , Humans , Reactive Oxygen Species/agonists , Reactive Oxygen Species/metabolism , Retinal Pigment Epithelium/cytology , Retinal Pigment Epithelium/drug effects , Sequestosome-1 Protein , Signal Transduction , Sodium-Hydrogen Exchangers/antagonists & inhibitors , Sodium-Hydrogen Exchangers/metabolism , Topoisomerase Inhibitors/pharmacology
13.
Curr Pharm Biotechnol ; 14(5): 524-36, 2013.
Article in English | MEDLINE | ID: mdl-22429135

ABSTRACT

Poly(ADP-ribose) polymerases (PARPs) and poly(ADP-ribosylation) play essential roles in several biological processes, among which neoplastic transformation and telomere maintenance. In this paper, we review the poly(ADP-ribosylation) process together with the highly appealing use of PARP inhibitors for the treatment of cancer. In addition, we report our results concerning poly(ADP-ribosylation) in a cellular model system for neoplastic transformation developed in our laboratory. Here we show that PARP-1 and PARP-2 expression increases during neoplastic transformation, together with the basal levels of poly(ADP-ribosylation). Furthermore, we demonstrate a greater effect of the PARP inhibitor 3-aminobenzamide (3AB) on cellular viability in neoplastically transformed cells compared to normal fibroblasts and we show that prolonged 3AB administration to tumorigenic cells causes a decrease in telomere length. Taken together, our data support an active involvement of poly(ADP-ribosylation) in neoplastic transformation and telomere length maintenance and confirm the relevant role of poly(ADP-ribosylation) inhibition for the treatment of cancer.


Subject(s)
Cell Transformation, Neoplastic/drug effects , Cell Transformation, Neoplastic/metabolism , Poly(ADP-ribose) Polymerase Inhibitors , Poly(ADP-ribose) Polymerases/metabolism , Animals , Benzamides/pharmacology , Benzamides/therapeutic use , Humans , Neoplasms/drug therapy , Neoplasms/metabolism , Telomere/drug effects , Telomere/metabolism
14.
Cells ; 2(2): 294-305, 2013 May 08.
Article in English | MEDLINE | ID: mdl-24709702

ABSTRACT

An apoptotic program leading to controlled cell dismantling implies perturbations of nuclear dynamics, as well as changes affecting the organelle structure and distribution. In human cancer cells driven to apoptosis by different stimuli, we have recently investigated the morphological properties of several organelles, including mitochondria, lysosomes, endoplasmic reticulum and Golgi apparatus. In this review, we will discuss the body of evidence in the literature suggesting that organelles are generally relocated and/or degraded during apoptosis, irrespectively of the apoptogenic stimulus and cell type.

15.
PLoS One ; 7(11): e48556, 2012.
Article in English | MEDLINE | ID: mdl-23139792

ABSTRACT

In this work, we show that vertical, high aspect-ratio (HAR) photonic crystals (PhCs), consisting of periodic arrays of 5 µm wide gaps with depth of 50 µm separated by 3 µm thick silicon walls, fabricated by electrochemical micromachining, can be used as three-dimensional microincubators, allowing cell lines to be selectively grown into the gaps. Silicon micromachined dice incorporating regions with different surface profiles, namely flat silicon and deeply etched PhC, were used as microincubators for culturing adherent cell lines with different morphology and adhesion properties. We extensively investigated and compared the proliferative behavior on HAR PhCs of eight human cell models, with different origins, such as the epithelial (SW613-B3; HeLa; SW480; HCT116; HT29) and the mesenchymal (MRC-5V1; CF; HT1080). We also verified the contribution of cell sedimentation into the silicon gaps. Fluorescence microscopy analysis highlights that only cell lines that exhibit, in the tested culture condition, the behavior typical of the mesenchymal phenotype are able to penetrate into the gaps of the PhC, extending their body deeply in the narrow gaps between adjacent silicon walls, and to grow adherent to the vertical surfaces of silicon. Results reported in this work, confirmed in various experiments, strongly support our statement that such three-dimensional microstructures have selection capabilities with regard to the cell lines that can actively populate the narrow gaps. Cells with a mesenchymal phenotype could be exploited in the next future as bioreceptors, in combination with HAR PhC optical transducers, e.g., for label-free optical detection of cellular activities involving changes in cell adhesion and/or morphology (e.g., apoptosis) in a three-dimensional microenvironment.


Subject(s)
Cell Culture Techniques/instrumentation , Cell Culture Techniques/methods , Microtechnology/instrumentation , Microtechnology/methods , Photons , Silicon/chemistry , Cell Line , Crystallization , Epithelial Cells/cytology , Humans , Microscopy, Fluorescence
16.
PLoS One ; 7(9): e44935, 2012.
Article in English | MEDLINE | ID: mdl-23028690

ABSTRACT

Multiple Sclerosis (MS) is a chronic disease of the central nervous system, the etiology of which, although not completely known, involves inflammation and autoimmunity. In the present study we aimed at identifying molecular markers of apoptosis, cellular stress and DNA damage in isolated peripheral blood mononuclear cells (PBMCs) of MS patients. The analysis was carried on 19 relapsing-remitting untreated MS patients and 13 healthy individuals. We investigated the emergency-driven synthesis of poly(ADP-ribose) (PAR), the expression level of the constitutive enzyme poly(ADP-ribose) polymerase-1 (PARP-1) and the DNA damage-induced phosphorylation of histone H2AX. PAR accumulation, PARP-1 and phosphorylated H2AX (γH2AX) were detected by immunofluorescence experiments on PBMCs isolated from 19 patients and 13 healthy volunteers. Our results show for the first time a net increased amount in PAR and γH2AX in MS patients compared to healthy individuals. Patients were further subdivided in three groups, according to the neuroimaging (MRI)-based classification of disease phase. Remarkably, we found a positive correlation between the level of γH2AX and MS aggressiveness. In addition, apoptosis in PBMCs was monitored by flow cytometry of both phosphatidylserine exposure (revealed by Annexin V-FITC labeling) and membrane permeability to propidium iodide. Our observations provide the evidence that the number of apoptotic cells was significantly higher in patients compared to healthy individuals, thus suggesting that apoptosis could affect MS lymphocyte function.


Subject(s)
Lymphocytes/metabolism , Multiple Sclerosis/metabolism , Oxidative Stress , Adult , Apoptosis , Biomarkers/metabolism , Case-Control Studies , DNA Breaks, Double-Stranded , Female , Follow-Up Studies , Gadolinium/metabolism , Histones/chemistry , Histones/metabolism , Humans , Lymphocytes/pathology , Male , Multiple Sclerosis/diagnosis , Multiple Sclerosis/genetics , Multiple Sclerosis/pathology , Phosphorylation , Poly(ADP-ribose) Polymerases/metabolism , Serine/metabolism
17.
Cell Biol Int ; 35(9): 883-9, 2011 Sep.
Article in English | MEDLINE | ID: mdl-21375507

ABSTRACT

Sertoli cells play an essential role in the development of a functional testis. ROS (reactive oxygen species) are normally produced by the developing testicular cells and may be dangerous to spermatogenesis. The aim of this study was to investigate the developmental expression of genes involved in antioxidant defense as well as in the DNA damage response in rat Sertoli cells. As revealed by quantitative RT-PCR analysis, the expression pattern of the antioxidant enzymes GST (glutathione-S-transferase), CAT (catalase) and SOD (superoxide dismutase) showed a progressive decrease from birth to puberty. The expression level of the oncosuppressor p53 revealed a net reduction as well. We next focused on PARP-1 [poly(ADP-ribose) polymerase-1], a 'guardian of the genome' that combats stress conditions. At both the mRNA and protein level, PARP-1 expression was low at the early stage of development and increased later on. Maximal PARP-1 expression was preceded by a rise in the transcript level for MTs (metallothioneins), which provide zinc to zinc-dependent enzymes and proteins, including PARP-1. Our results showed an increased expression of PARP-1 during Sertoli cell development, together with a decrease in the expression of antioxidant enzymes. In conclusion, a role of PARP-1 in protecting the testicular differentiation is suggested.


Subject(s)
Gene Expression Regulation, Developmental , Poly(ADP-ribose) Polymerases/metabolism , Sertoli Cells/metabolism , Animals , Antioxidants , Catalase/genetics , Catalase/metabolism , Cell Differentiation , Glutathione Transferase/genetics , Glutathione Transferase/metabolism , Male , Poly (ADP-Ribose) Polymerase-1 , Poly(ADP-ribose) Polymerases/genetics , RNA, Messenger/metabolism , Rats , Rats, Wistar , Sertoli Cells/cytology , Superoxide Dismutase/genetics , Superoxide Dismutase/metabolism
18.
Oncol Lett ; 1(1): 109-112, 2010 Jan.
Article in English | MEDLINE | ID: mdl-22966266

ABSTRACT

Drugs that are able to modulate the microtubule dynamics either by inhibiting tubulin polymerization or by blocking microtubule disassembly are of great interest in anti-cancer therapy; a number of them are currently applied in clinical development. Tubulin polymerization inhibitors, including arylthioindoles, are characterized by the presence of an indole nucleus and have been obtained from natural sources or prepared by semi-synthesis. We characterized the effect of 5-bromo-3-[(3,4,5-trimetoxyphenyl)thio]-1H-indole (RS 2518) on the metabolism of human cell lines derived from solid tumors. We found that this new compound impairs cell adhesion, arrests the cells in the G(2)/M cell cycle phase and inhibits cell proliferation, thus leading to apoptosis. The described effects of RS 2518 on cancer cells have led to its selection as a lead compound for further studies. Some analogues have been developed and tested on a panel of cancer cell lines.

19.
Ann N Y Acad Sci ; 1171: 32-7, 2009 Aug.
Article in English | MEDLINE | ID: mdl-19723035

ABSTRACT

A large complex of proteins, called CENPs, are associated with centromeric DNA. Some of them exhibit a cell cycle-related expression (e.g., CENP-E and -F) and are required for the transition from interphase to mitosis, whereas constitutive proteins (e.g., CENP-A, -B, -C, -G, and -H) reside permanently at the centromere and are essential for the correct kinetochore assembly. Poly(ADP-ribose) polymerase-1 (PARP-1), which plays an active role in many basic processes, was described as a possible regulator of CENPs. By multicolor immunofluorescence we therefore analyzed the distribution of PARP-1 and its interaction with CENP-B, -E, and -F during mitosis and apoptosis.


Subject(s)
Apoptosis/physiology , Centromere Protein B/metabolism , Chromosomal Proteins, Non-Histone/metabolism , Mitosis/physiology , Poly(ADP-ribose) Polymerases/metabolism , Antibiotics, Antineoplastic/pharmacology , Antineoplastic Agents, Phytogenic/pharmacology , Apoptosis/drug effects , Cell Nucleus/metabolism , Cytoplasm/metabolism , Dactinomycin/pharmacology , Etoposide/pharmacology , Fluorescent Antibody Technique , HeLa Cells , Humans , Immunohistochemistry , Microfilament Proteins/metabolism , Microscopy, Confocal , Microscopy, Fluorescence , Poly (ADP-Ribose) Polymerase-1 , Protein Binding
20.
J Med Chem ; 52(23): 7512-27, 2009 Dec 10.
Article in English | MEDLINE | ID: mdl-19601594

ABSTRACT

New arylthioindoles along with the corresponding ketone and methylene compounds were potent tubulin assembly inhibitors. As growth inhibitors of MCF-7 cells, sulfur derivatives were superior or sometimes equivalent to the ketones, while methylene derivatives were substantially less effective. Esters 24, 27-29, 36, 39, and 41 showed approximately 50% of inhibition on human HeLa and HCT116/chr3 cells at 0.5 microM, and these compounds inhibited the growth of HEK, M14, and U937 cells with IC(50)'s in the 78-220 nM range. While murine macrophage J744.1 cell growth was significantly less affected (20% at higher concentrations), four other nontransformed cell lines remained sensitive to these esters. The effect of drug treatment on cell morphology was examined by time-lapse microscopy. In a protocol set up to evaluate toxicity on the Saccharomyces cerevisiae BY4741 wild type strain, compounds 24 and 54 strongly reduced cell growth, and 29, 36, and 39 also showed significant inhibition.


Subject(s)
Indoles/chemistry , Indoles/pharmacology , Models, Molecular , Protein Multimerization/drug effects , Sulfur/chemistry , Tubulin/metabolism , Cell Line, Tumor , Cell Proliferation/drug effects , Colchicine/metabolism , Humans , Indoles/chemical synthesis , Indoles/metabolism , Inhibitory Concentration 50 , Protein Structure, Quaternary , Structure-Activity Relationship , Tubulin/chemistry
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