RESUMEN

Allantoin is a nitrogen metabolite with significant potential to mediate plant defense responses under salinity. However, the impact of allantoin on ions homeostasis and ROS metabolism has yet to be established in plants under Cr toxicity. In the current study, chromium (Cr) notably diminished growth, photosynthetic pigments, and nutrient acquisition in two wheat cultivars (Galaxy-2013 and Anaj-2017). Plants subjected to Cr toxicity displayed excessive Cr accumulation. Chromium produced substantial oxidative stress reflected as higher levels of O2•, H2O2, MDA, methylglyoxal (MG) and lipoxygenase activity. Plants manifested marginally raised antioxidant enzyme activities due to Cr stress. Further, reduced glutathione (GSH) levels diminished with a concurrent rise in oxidized glutathione levels (GSSG). Plants exhibited a considerable abridge in GSH:GSSG due to Cr toxicity. Allantoin (200 and 300 mg L1) subsided metal phytotoxic effects by strengthening the activities of antioxidant enzymes and levels of antioxidant compounds. Plants administered allantoin displayed a considerable rise in endogenous H2S and nitric oxide (NO) levels that, in turn, lessened oxidative injury in Cr-stressed plants. Allantoin diminished membrane damage and improved nutrient acquisition under Cr stress. Allantoin markedly regulated the uptake and distribution of Cr in wheat plants, abridging the degree of metal phytotoxic effect.

Asunto(s)

Antioxidantes , Cromo , Antioxidantes/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Triticum/metabolismo , Alantoína , Metabolismo Secundario , Disulfuro de Glutatión/metabolismo , Peróxido de Hidrógeno/metabolismo , Estrés Oxidativo , Homeostasis , Nutrientes

RESUMEN

The endophytic fungal community in the marine ecosystem has been demonstrated to be relevant source of novel and pharmacologically active secondary metabolites. The current study focused on the evaluation of cytotoxic and apoptosis induction potential in the culture extracts of endophytic fungi associated with Sargassum muticum, a marine brown alga. The cytotoxicity of the four marine endophytes, Aspergillus sp., Nigrospora sphaerica, Talaromyces purpureogenus, and Talaromyces stipitatus, was evaluated by the MTT assay on HeLa cells. Further, several physicochemical parameters, including growth curve, culture media, and organic solvents, were optimized for enhanced cytotoxic activity of the selected extract. The Aspergillus sp. ethyl acetate extract (ASE) showed maximum cytotoxicity on multiple cancer cell lines. Chemical investigation of the metabolites by gas chromatography-mass spectroscopy (GC-MS) showed the presence of several compounds, including quinoline, indole, 2,4-bis(1,1-dimethylethyl) phenol, and hexadecenoic acid, known to be cytotoxic in ASE. The ASE was then tested for cytotoxicity in vitro on a panel of six human cancer cell lines, namely, HeLa (cervical adenocarcinoma), MCF-7 (breast adenocarcinoma), Hep G2 (hepatocellular carcinoma), A-549 (lung carcinoma), A-431 (skin/epidermis carcinoma), and LN-229 (glioblastoma). HeLa cells were most vulnerable to ASE treatment with an IC50 value of 24 ± 2 µg/ml. The mechanism of cytotoxicity exhibited by the ASE was further investigated on Hela cells. The results showed that the ASE was capable of inducing apoptosis in HeLa cells through production of reactive oxygen species, depolarization of mitochondrial membrane, and activation of the caspase-3 pathway, which shows a possible activation of the intrinsic apoptosis pathway. It also arrested the HeLa cells at the G2/M phase of the cell cycle, eventually leading to apoptosis. Through this study, we add to the knowledge about the marine algae associated with fungal endophytes and report its potential for purifying specific compounds responsible for cytotoxicity.

RESUMEN

Plakortinic acids C (3) and D (4), two unprecedented peroxide-polyketides with 7,8-dioxatricyclo[4.2.2.02,5]dec-9-ene scaffold, as well as known biogenetically related congeners, plakortinic acids A (1) and B (2), were isolated from a two-sponge association of Plakortis symbiotica-Xestospongia deweerdtae. Upon chemical derivatization, the structures and relative configurations of 3 and 4 were characterized by analysis of HRESIMS and NMR spectroscopic data, molecular modeling studies, and chiroptical comparisons with known natural products and published values of [α]D of related synthetic analogs. A mixture of methyl ester derivatives 5 and 6 displayed negligible cytotoxicity against a panel of 60 cell lines of various human cancers at a concentration of 10 µM.

RESUMEN

INTRODUCTION: Miuraenamides belong to natural marine compounds with interesting biological properties. MATERIALS AND METHODS: Miuraenamides initiate polymerization of monomeric actin and therefore show high cytotoxicity by influencing the cytoskeleton. New derivatives of the miuraenamides have been synthesized containing an N-methylated amide bond instead of the more easily hydrolysable ester in the natural products. RESULTS: Incorporation of an aromatic side chain onto the C-terminal amino acid of the tripeptide fragment also led to highly active new miuraenamides. CONCLUSION: In this study, we showed that the ester bond of the natural product miuraenamide can be replaced by an N-methyl amide. The yields in the cyclization step were high and generally much better than with the corresponding esters. On the other hand, the biological activity of the new amide analogs was lower compared to the natural products, but the activity could significantly be increased by incorporation of a p-nitrophenyl group at the C-terminus of the peptide fragment.

Asunto(s)

Ésteres , Péptidos Cíclicos , Amidas , Ciclización

RESUMEN

Electrospray ionization mass spectrometry (ESI MS) is a powerful investigative tool to analyze the reactions of metallodrugs with proteins and peptides and characterize the resulting adducts. Here, we have applied this type of approach to four experimental anticancer gold(III) compounds for which extensive biological and mechanistic data had previously been gathered, namely, Auoxo6, Au2phen, AuL12, and Aubipyc. These gold(III) compounds were reacted with two representative proteins, i.e., human serum albumin (HSA) and human carbonic anhydrase I (hCA I), and with the C-terminal dodecapeptide of thioredoxin reductase. ESI MS analysis allowed us to elucidate the nature of the resulting metal-protein adducts from which the main features of the occurring metallodrug-protein reactions can be inferred. In selected cases, MS data were integrated and supported by independent 1HNMR and UV-Vis absorption measurements to gain an overall description of the occurring processes. From data analysis, it emerges that most of the investigated gold(III) complexes, endowed with an appreciable oxidizing character, undergo quite facile reduction to gold(I); the resulting gold(I) species tightly associate with the above proteins/peptides with a remarkable selectivity for free cysteine residues. In contrast, in the case of the less-oxidizing Aubipyc complex, the gold(III) oxidation state is conserved, and a gold(III) fragment still containing the original ligand is found to be associated with the target proteins. It is notable that the C-terminal dodecapeptide of thioredoxin reductase containing the characteristic -Gly-Cys-Sec-Gly metal-binding motif is able in all cases to trigger gold(III)-to-gold(I) reduction. Our investigation allowed us to identify in detail the nature of the gold fragments that ultimately bind the protein targets and determine the exact binding stoichiometry; some insight on the reaction kinetics was also gained. Notably, a few clear correlations could be established between the structure of the metal complexes and the nature of the resulting protein adducts. The mechanistic implications of these findings are analyzed and thoroughly discussed. Overall, the present results set the stage to better understand the real target biomolecules of these gold compounds and elucidate at the atomic level their interaction modes with proteins and peptides.

RESUMEN

The use of preparations derived from frog skins for curative purposes antedates research history and is perpetuated in current medicine. The skins of anuran's (frogs and toads) are a rich source of compounds with a great importance in the search of antibiotics, analgesics, immunomodulators, enzymatic inhibitors and antitumoral agents applying to human health. Nowadays, cancer is the second most common cause of mortality with more than 8.2 million of deaths worldwide per year. Acute monocytic leukemia is the subtype M5 of acute myeloid leukemia (AML) a cancer type with reduced survival rates in patients. The monocyte to macrophage differentiation plays an essential role increasing the expansion of AML cell lines. Herein we studied the cytotoxic and antiproliferative activities of eleven amphibian species of three families belonging to Argentinean zones, against THP-1 monocytes and THP-1 macrophages acute monocytic leukemia cell lines. The evaluated species showed pronounced deleterious effects on acute monocytic leukemia THP-1 cell lines, reducing cell proliferation and inducing apoptosis, autophagy and in some cases cell aggregation. Being this work of great importance for the study of new natural anti-cancer compounds.

Asunto(s)

Venenos de Anfibios/farmacología , Anuros/fisiología , Citotoxinas/farmacología , Animales , Proliferación Celular/efectos de los fármacos , Humanos , Leucemia Monocítica Aguda , Piel

RESUMEN

Abnormal blood vessels and hypoxic and necrotic regions are common features of solid tumors and related to the malignant phenotype and therapy resistance. Certain obligate or facultative anaerobic bacteria exhibit inherent ability to colonize and proliferate within solid tumors in vivo. Escherichia coli Nissle 1917 (EcN), a non-pathogenic probiotic in European markets, has been known to proliferate selectively in the interface between the viable and necrotic regions of solid tumors. The objective of this study was to establish a tumor-targeting therapy system using the genetically engineered EcN for targeted delivery of cytotoxic compounds, including colibactin, glidobactin and luminmide. Biosynthetic gene clusters of these cytotoxic compounds were introduced into EcN and the corresponding compounds were detected in the resultant recombinant EcN strains. The recombinant EcN showed significant cytotoxic activity in vitro and in vivo as well, and significantly suppressed the tumor growth. Together, this study confirmed efficient tumor-targeting colonization of EcN and demonstrated its potentiality in the tumor-specific delivery of cytotoxic compounds as a new tumor-targeting therapy system.

Asunto(s)

Sistemas de Liberación de Medicamentos , Proteínas de Escherichia coli/farmacología , Escherichia coli/genética , Ingeniería Genética/métodos , Neoplasias/terapia , Animales , Línea Celular Tumoral , Femenino , Humanos , Ratones , Ratones Desnudos , Familia de Multigenes , Péptidos/administración & dosificación , Péptidos Cíclicos/administración & dosificación , Policétidos/administración & dosificación , Probióticos , Proteínas Recombinantes/administración & dosificación

RESUMEN

Cytotoxic compounds like reactive carbonyl compounds such as methylglyoxal (MG), melandialdehyde (MDA), besides the ROS accumulate significantly at higher levels under salinity stress conditions and affect lipids and proteins that inhibit plant growth and productivity. The detoxification of these cytotoxic compounds by overexpression of NADPH-dependent Aldo-ketoreductase (AKR1) enzyme enhances the salinity stress tolerance in tobacco. The PsAKR1 overexpression plants showed higher survival and chlorophyll content and reduced MDA, H2O2, and MG levels under NaCl stress. The transgenic plants showed reduced levels of Na+ levels in both root and shoot due to reduced reactive carbonyl compounds (RCCs) and showed enhanced membrane stability resulted in higher root growth and biomass. The increased levels of antioxidant glutathione and enhanced activity of superoxide dismutase (SOD), ascorbate peroxidase (APX) and glutathione reductase (GR) suggest AKR1 could protect these enzymes from the RCC induced protein carbonylation by detoxification process. The transgenics also showed higher activity of delta 1-pyrroline-5- carboxylate synthase (P5CS) enzyme resulted in increasedproline levels to maintain osmotic homeostasis. The results demonstrates that the AKR1 protects proteins or enzymes that are involved in scavenging of cytotoxic compounds by detoxifying RCCs generated under salinity stress.

Asunto(s)

Nicotiana/enzimología , Oxidorreductasas/metabolismo , Plantas Tolerantes a la Sal/fisiología , Aldehído Deshidrogenasa/metabolismo , Aldehído Reductasa/metabolismo , Aldo-Ceto Reductasas , Antioxidantes/metabolismo , Ascorbato Peroxidasas/metabolismo , Biomasa , Clorofila/metabolismo , Glutatión Reductasa/metabolismo , Peróxido de Hidrógeno/metabolismo , Ornitina-Oxo-Ácido Transaminasa/metabolismo , Presión Osmótica , Oxidorreductasas/biosíntesis , Oxidorreductasas/genética , Fotosíntesis , Plantas Modificadas Genéticamente , Prolina/metabolismo , Piruvaldehído/metabolismo , Salinidad , Estrés Fisiológico/fisiología , Superóxido Dismutasa/metabolismo , Nicotiana/genética , Nicotiana/fisiología

RESUMEN

Using a high-throughput approach, we identified lemur tyrosine kinase 2 (LMTK2) as a novel determinant of cell sensitivity to TRAIL. LMTK2 is a poorly characterized serine/threonine kinase believed to play a role in endosomal membrane trafficking and neuronal physiology, and recently found to be mutated in diverse tumor types. We show that LMTK2 silencing sensitizes immortalized epithelial cells and cancer cells to TRAIL, and this phenomenon is accompanied by changes in the expression of BCL2 family members. In epithelial cells, LMTK2 targeting causes the down-regulation of the BCL2 and BCL-xL anti-apoptotic proteins and the reciprocal up-regulation of the pro-apoptotic protein BIM, while, in cancer cells, LMTK2 knock-down reduces BCL2 without increasing BIM levels. We provide evidence that both BIM and BCL2 proteins are regulated by LMTK2 in a GSK3ß- and PP1A-dependent manner and that their perturbation, together with BCL-xL reduction, determines an increased sensitivity not only to TRAIL, but also to other compounds. Overall, our findings suggest a broad function of LMTK2 in the regulation of the apoptotic pathway and highlight LMTK2 as a novel candidate target to increase the cytotoxic activity of chemotherapeutic compounds.

Asunto(s)

Apoptosis/efectos de los fármacos , Proteínas de la Membrana/fisiología , Proteínas Serina-Treonina Quinasas/fisiología , Proteínas Proto-Oncogénicas c-bcl-2/análisis , Proteína bcl-X/análisis , Proteína 11 Similar a Bcl2/análisis , Línea Celular Tumoral , Receptores ErbB/análisis , Quinasas MAP Reguladas por Señal Extracelular/fisiología , Glucógeno Sintasa Quinasa 3 beta/metabolismo , Humanos , Proteínas de la Membrana/antagonistas & inhibidores , Proteína Fosfatasa 1/fisiología , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , ARN Interferente Pequeño/genética , Ligando Inductor de Apoptosis Relacionado con TNF/farmacología

RESUMEN

Metabolites from marine fungi have hogged the limelight in drug discovery because of their promise as therapeutic agents. A number of metabolites related to marine fungi have been discovered from various sources which are known to possess a range of activities as antibacterial, antiviral and anticancer agents. Although, over a thousand marine fungi based metabolites have already been reported, none of them have reached the market yet which could partly be related to non-comprehensive screening approaches and lack of sustained lead optimization. The origin of these marine fungal metabolites is varied as their habitats have been reported from various sources such as sponge, algae, mangrove derived fungi, and fungi from bottom sediments. The importance of these natural compounds is based on their cytotoxicity and related activities that emanate from the diversity in their chemical structures and functional groups present on them. This review covers the majority of anticancer compounds isolated from marine fungi during 2012-2016 against specific cancer cell lines.

RESUMEN

A novel series of twenty 3-thiocyanato-1H-indoles, carrying diversification at positions N-1, C-2 and C-5 of the heterocyclic core, were synthesized; their antiproliferative activity against four human cancer cell lines (HL60, HEP-2, NCI-H292 and MCF-7) was evaluated, employing doxorubicin as positive control. Indole, N-methylindole and 2-(4-chlorophenyl)-N-methylindole demonstrated to be essentially inactive, whereas several of their congener 3-thiocyanato-1H-indoles displayed good to excellent levels of potency (IC50 ≤ 6 µM), while being non-hemolytic. N-Phenyl-3-thiocyanato-1H-indole and 1-methyl-2-(4-chlorophenyl)-3-thiocyanato-1H-indole showed good to high potency against all the cell lines. On the other side, the N-(4-chlorophenyl)-, 2-(4-chlorophenyl)- and 2-phenyl- 3-thiocyanato-1H-indole derivatives were slightly less active against the test cell lines. Overall, these results suggest that the indole-3-thiocyanate motif can be suitably decorated to afford highly cytotoxic compounds and that the substituted indole can be employed as a useful scaffold toward more potent compounds.

Asunto(s)

Antineoplásicos/síntesis química , Antineoplásicos/farmacología , Indoles/síntesis química , Indoles/farmacología , Antineoplásicos/química , Antineoplásicos/toxicidad , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Técnicas de Química Sintética , Ensayos de Selección de Medicamentos Antitumorales , Hemólisis/efectos de los fármacos , Humanos , Indoles/química , Indoles/toxicidad

RESUMEN

In a search of small molecules active against apoptosis-resistant cancer cells, a series of isatin-based heterocyclic compounds were synthesized and found to inhibit proliferation of cancer cell lines resistant to apoptosis. The synthesis of these compounds involved a condensation of commercially available, active methylene heterocycles with isatin proceeding in moderate to excellent yields. The heterocyclic scaffolds prepared in the current investigation appear to be a useful starting point for the development of agents to fight cancers with apoptosis resistance, and thus, associated with dismal prognoses.

Asunto(s)

Antineoplásicos/química , Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Isatina/análogos & derivados , Isatina/farmacología , Neoplasias/patología , Antineoplásicos/síntesis química , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Isatina/síntesis química , Isatina/química , Estructura Molecular , Relación Estructura-Actividad

RESUMEN

Marine sessile organisms often inhabit rocky substrata, which are crowded by other sessile organisms. They acquire living space via growth interactions and/or by allelopathy. They are known to secrete toxic compounds having multiple roles. These compounds have been explored for their possible applications in cancer chemotherapy, because of their ability to kill rapidly dividing cells of competitor organisms. As compared to the therapeutic applications of these compounds, their possible ecological role in competition for space has received little attention. To select the potential candidate organisms for the isolation of lead cytotoxic molecules, it is important to understand their chemical ecology with special emphasis on their allelopathic interactions with their competitors. Knowledge of the ecological role of allelopathic compounds will contribute significantly to an understanding of their natural variability and help us to plan effective and sustainable wild harvests to obtain novel cytotoxic chemicals. This review highlights the significance of studying allelopathic interactions of marine invertebrates in the discovery of cytotoxic compounds, by selecting sponge as a model organism.

Asunto(s)

Descubrimiento de Drogas , Feromonas/química , Feromonas/metabolismo , Poríferos/química , Poríferos/fisiología , Animales , Organismos Acuáticos/química , Organismos Acuáticos/fisiología , Descubrimiento de Drogas/métodos , Humanos

RESUMEN

We here report an investigation of the interactions with tubulin of two types of molecules of a hybrid structural type consisting in a combretastatin A-4 moiety and a simplified pironetin fragment. The cytotoxicities of the molecules on two reference tumoral cell lines were measured. In addition, the effects of the compounds on the cell cycle and on microtubule assembly were observed. The dynamics of microtubule polymerization was investigated by means of immunofluorescence assays. It was thus established that at least some of the compounds under study exert their cytotoxic action by means of interaction with tubulin.

Asunto(s)

Diseño de Fármacos , Fragmentos de Péptidos/metabolismo , Pironas/metabolismo , Estilbenos/metabolismo , Moduladores de Tubulina/metabolismo , Tubulina (Proteína)/metabolismo , Sitios de Unión , Ciclo Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Células HT29 , Humanos , Concentración 50 Inhibidora , Microtúbulos/efectos de los fármacos , Microtúbulos/metabolismo , Fragmentos de Péptidos/química , Fragmentos de Péptidos/farmacología , Polimerizacion , Unión Proteica , Conformación Proteica , Pironas/química , Pironas/farmacología , Estilbenos/química , Estilbenos/farmacología , Relación Estructura-Actividad , Tubulina (Proteína)/química , Tubulina (Proteína)/efectos de los fármacos , Moduladores de Tubulina/química , Moduladores de Tubulina/farmacología

RESUMEN

Calicheamicin is a DNA-damaging agent that, following intracellular activation, binds to DNA in the minor groove and introduces double-strand DNA breaks, leading to G2/M arrest and subsequent cell death. Importantly, the mechanism of action of calicheamicin is fundamentally different from the tubulin-binding class of cytotoxics targeting the mitotic spindle, which represent the most common class of payloads for antibody-drug conjugates (ADCs) currently undergoing clinical development. Spindle poisons that target tubulin, including auristatins and maytansines, are most effective against rapidly proliferating cells. In contrast, calicheamicin induces DNA double-strand breaks and apoptosis independent of cell cycle progression. Such properties may be advantageous when targeting malignant cells that are not markedly different in their proliferation status compared to normal cells. Here we review calicheamicin conjugates, with a particular focus on the preclinical- and clinical development of inotuzumab ozogamicin, targeting the CD22 antigen expressed on a large variety of hematologic malignancies. In pre-clinical experiments, inotuzumab ozogamicin potently induced tumor regressions in models of non-Hodgkin's lymphoma (NHL), either alone or in combination with the anti-CD20 antibody Rituximab. Promising anti-tumor responses were observed in early stage clinical trials, where inotuzumab ozogamicin was administered either as single agent or in combination with Rituximab. Consistent with the cell cycle independent mechanism of action of the calicheamicin payload, high rates of complete responses were observed in less aggressive forms of lymphomas, including follicular lymphoma (FL) and relapsed, diffuse large B-cell lymphoma (DLBCL). Inotuzumab ozogamicin is currently being tested in phase III clinical trials in acute lymphocytic leukemia (ALL). Particular focus is dedicated to reviewing the pre-clinical and clinical data generated with this compound in NHL and to outline future focus areas for pre-clinical- and clinical research of inotuzumab ozogamicin, and the calicheamicin class of antibody-drug conjugates more generally.

Asunto(s)

Anticuerpos Monoclonales Humanizados/uso terapéutico , Neoplasias Hematológicas/terapia , Inmunoconjugados/uso terapéutico , Inmunoterapia/métodos , Lectina 2 Similar a Ig de Unión al Ácido Siálico/inmunología , Anticuerpos Monoclonales Humanizados/inmunología , Proliferación Celular/efectos de los fármacos , Proliferación Celular/genética , Roturas del ADN de Doble Cadena/efectos de los fármacos , Ensayos de Selección de Medicamentos Antitumorales , Neoplasias Hematológicas/genética , Neoplasias Hematológicas/inmunología , Humanos , Inmunoconjugados/inmunología , Inotuzumab Ozogamicina , Linfoma no Hodgkin/genética , Linfoma no Hodgkin/inmunología , Linfoma no Hodgkin/terapia

RESUMEN

We here report the synthesis and biological evaluation of several combretastatin A-4 derivatives alkylated at the phenol hydroxyl group. Some of these derivatives contain an (E)-arylalkene fragment reminiscent of that present in some natural stilbenes like resveratrol. The cytotoxicities towards one human healthy kidney embryonic and two tumoral cell lines were determined. In addition, the ability of these compounds to inhibit the production of the vascular endothelial growth factor (VEGF) was measured. Finally, the expression of genes controlling the production of telomerase was measured. Some of the compounds were found to have an activity comparable or higher than that of combretastatin A-4 in at least one of the aforementioned biological properties. The compounds with the (E)-arylalkene fragment were in general terms more active than the simple O-alkyl derivatives. However, no clear structure/activity correlations were perceived when comparing the observed compound activities across the three biological properties. This points out the existence of marked differences between the mechanisms responsible for their cytotoxicity.

Asunto(s)

Inhibidores de la Angiogénesis/química , Inhibidores de la Angiogénesis/farmacología , Antineoplásicos/química , Antineoplásicos/farmacología , Bibencilos/química , Bibencilos/farmacología , Telomerasa/antagonistas & inhibidores , Inhibidores de la Angiogénesis/síntesis química , Bibencilos/síntesis química , Línea Celular , Línea Celular Tumoral , Ensayos de Selección de Medicamentos Antitumorales , Regulación de la Expresión Génica/efectos de los fármacos , Humanos , Telomerasa/genética , Factor A de Crecimiento Endotelial Vascular/antagonistas & inhibidores , Factor A de Crecimiento Endotelial Vascular/metabolismo