Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 11 de 11
Filtrar
Mais filtros










Base de dados
Intervalo de ano de publicação
1.
Pharmacol Res ; 153: 104660, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31982489

RESUMO

Multidrug resistance (MDR) represents an obstacle in anti-cancer therapy. MDR is caused by multiple mechanisms, involving ATP-binding cassette (ABC) transporters such as P-glycoprotein (P-gp), which reduces intracellular drug levels to sub-therapeutic concentrations. Therefore, sensitizing agents retaining effectiveness against apoptosis- or drug-resistant cancers are desired for the treatment of MDR cancers. The sarcoplasmic/endoplasmic reticulum Ca2+ ATPase (SERCA) pump is an emerging target to overcome MDR, because of its continuous expression and because the calcium transport function is crucial to the survival of tumor cells. Previous studies showed that SERCA inhibitors exhibit anti-cancer effects in Bax-Bak-deficient, apoptosis-resistant and MDR cancers, whereas specific P-gp inhibitors reverse the MDR phenotype of cancer cells by blocking efflux of chemotherapeutic agents. Here, we unraveled SERCA and P-gp as double targets of the triterpenoid, celastrol to reverse MDR. Celastrol inhibited both SERCA and P-gp to stimulate calcium-mediated autophagy and ATP depletion, thereby induced collateral sensitivity in MDR cancer cells. In vivo studies further confirmed that celastrol suppressed tumor growth and metastasis by SERCA-mediated calcium mobilization. To the best of our knowledge, our findings demonstrate collateral sensitivity in MDR cancer cells by simultaneous inhibition of SERCA and P-gp for the first time.

2.
Acta Pharm Sin B ; 9(5): 1021-1034, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31649851

RESUMO

Polo-like kinase (PLK1) has been identified as a potential target for cancer treatment. Although a number of small molecules have been investigated as PLK1 inhibitors, many of which showed limited selectivity. PLK1 harbors a regulatory domain, the Polo box domain (PBD), which has a key regulatory function for kinase activity and substrate recognition. We report on 3-bromomethyl-benzofuran-2-carboxylic acid ethyl ester (designated: MCC1019) as selective PLK1 inhibitor targeting PLK1 PBD. Cytotoxicity and fluorescence polarization-based screening were applied to a library of 1162 drug-like compounds to identify potential inhibitors of PLK1 PBD. The activity of compound MC1019 against the PLK1 PBD was confirmed using fluorescence polarization and microscale thermophoresis. This compound exerted specificity towards PLK1 over PLK2 and PLK3. MCC1019 showed cytotoxic activity in a panel of different cancer cell lines. Mechanistic investigations in A549 lung adenocarcinoma cells revealed that MCC1019 induced cell growth inhibition through inactivation of AKT signaling pathway, it also induced prolonged mitotic arrest-a phenomenon known as mitotic catastrophe, which is followed by immediate cell death via apoptosis and necroptosis. MCC1019 significantly inhibited tumor growth in vivo in a murine lung cancer model without affecting body weight or vital organ size, and reduced the growth of metastatic lesions in the lung. We propose MCC1019 as promising anti-cancer drug candidate.

3.
Br J Pharmacol ; 176(16): 2922-2944, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31124139

RESUMO

BACKGROUND AND PURPOSE: Celastrol exhibits anti-arthritic effects in rheumatoid arthritis (RA), but the role of celastrol-mediated Ca2+ mobilization in treatment of RA remains undefined. Here, we describe a regulatory role for celastrol-induced Ca2+ signalling in synovial fibroblasts of RA patients and adjuvant-induced arthritis (AIA) in rats. EXPERIMENTAL APPROACH: We used computational docking, Ca2+ dynamics and functional assays to study the sarcoplasmic/endoplasmic reticulum Ca2+ ATPase pump (SERCA). In rheumatoid arthritis synovial fibroblasts (RASFs)/rheumatoid arthritis fibroblast-like synoviocytes (RAFLS), mechanisms of Ca2+ -mediated autophagy were analysed by histological, immunohistochemical and flow cytometric techniques. Anti-arthritic effects of celastrol, autophagy induction, and growth rate of synovial fibroblasts in AIA rats were monitored by microCT and immunofluorescence staining. mRNA from joint tissues of AIA rats was isolated for transcriptional analysis of inflammatory genes, using siRNA methods to study calmodulin, calpains, and calcineurin. KEY RESULTS: Celastrol inhibited SERCA to induce autophagy-dependent cytotoxicity in RASFs/RAFLS via Ca2+ /calmodulin-dependent kinase kinase-ß-AMP-activated protein kinase-mTOR pathway and repressed arthritis symptoms in AIA rats. BAPTA/AM hampered the in vitro and in vivo effectiveness of celastrol. Inflammatory- and autoimmunity-associated genes down-regulated by celastrol in joint tissues of AIA rat were restored by BAPTA/AM. Knockdown of calmodulin, calpains, and calcineurin in RAFLS confirmed the role of Ca2+ in celastrol-regulated gene expression. CONCLUSION AND IMPLICATIONS: Celastrol triggered Ca2+ signalling to induce autophagic cell death in RASFs/RAFLS and ameliorated arthritis in AIA rats mediated by calcium-dependent/-binding proteins facilitating the exploitation of anti-arthritic drugs based on manipulation of Ca2+ signalling.

4.
Phytomedicine ; 53: 319-331, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30190231

RESUMO

BACKGROUND: Practices of biopiracy to use genetic resources and indigenous knowledge by Western companies without benefit-sharing of those, who generated the traditional knowledge, can be understood as form of neocolonialism. HYPOTHESIS: The One-World Medicine concept attempts to merge the best of traditional medicine from developing countries and conventional Western medicine for the sake of patients around the globe. STUDY DESIGN: Based on literature searches in several databases, a concept paper has been written. Legislative initiatives of the United Nations culminated in the Nagoya protocol aim to protect traditional knowledge and regulate benefit-sharing with indigenous communities. The European community adopted the Nagoya protocol, and the corresponding regulations will be implemented into national legislation among the member states. Despite pleasing progress, infrastructural problems of the health care systems in developing countries still remain. Current approaches to secure primary health care offer only fragmentary solutions at best. Conventional medicine from industrialized countries cannot be afforded by the impoverished population in the Third World. Confronted with exploding costs, even health systems in Western countries are endangered to burst. Complementary and alternative medicine (CAM) is popular among the general public in industrialized countries, although the efficacy is not sufficiently proven according to the standards of evidence-based medicine. CAM is often available without prescription as over-the-counter products with non-calculated risks concerning erroneous self-medication and safety/toxicity issues. The concept of integrative medicine attempts to combine holistic CAM approaches with evidence-based principles of conventional medicine. CONCLUSION: To realize the concept of One-World Medicine, a number of standards have to be set to assure safety, efficacy and applicability of traditional medicine, e.g. sustainable production and quality control of herbal products, performance of placebo-controlled, double-blind, randomized clinical trials, phytovigilance, as well as education of health professionals and patients.


Assuntos
Cooperação Internacional , Medicina Tradicional , Plantas Medicinais , Roubo , Biodiversidade , Colonialismo , Terapias Complementares , Países em Desenvolvimento , Método Duplo-Cego , União Europeia , Medicina Baseada em Evidências , Humanos , Medicina Tradicional/normas , Naturopatia , Patentes como Assunto , Controle de Qualidade , Automedicação
5.
Front Pharmacol ; 9: 143, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29535630

RESUMO

Arsenic trioxide is a traditional remedy in Chinese Medicine since ages. Nowadays, it is clinically used to treat acute promyelocytic leukemia (APL) by targeting PML/RARA. However, the drug's activity is broader and the mechanisms of action in other tumor types remain unclear. In this study, we investigated molecular modes of action by classical and network pharmacological approaches. CEM/ADR5000 resistance leukemic cells were similar sensitive to As2O3 as their wild-type counterpart CCRF-CEM (resistance ratio: 1.88). Drug-resistant U87.MG ΔEGFR glioblastoma cells harboring mutated epidermal growth factor receptor were even more sensitive (collateral sensitive) than wild-type U87.MG cells (resistance ratio: 0.33). HCT-116 colon carcinoma p53-/- knockout cells were 7.16-fold resistant toward As2O3 compared to wild-type cells. Forty genes determining cellular responsiveness to As2O3 were identified by microarray and COMPARE analyses in 58 cell lines of the NCI panel. Hierarchical cluster analysis-based heat mapping revealed significant differences between As2O3 sensitive cell lines and resistant cell lines with p-value: 1.86 × 10-5. The genes were subjected to Galaxy Cistrome gene promoter transcription factor analysis to predict the binding of transcription factors. We have exemplarily chosen NF-kB and AP-1, and indeed As2O3 dose-dependently inhibited the promoter activity of these two transcription factors in reporter cell lines. Furthermore, the genes identified here and those published in the literature were assembled and subjected to Ingenuity Pathway Analysis for comprehensive network pharmacological approaches that included all known factors of resistance of tumor cells to As2O3. In addition to pathways related to the anticancer effects of As2O3, several neurological pathways were identified. As arsenic is well-known to exert neurotoxicity, these pathways might account for neurological side effects. In conclusion, the activity of As2O3 is not restricted to acute promyelocytic leukemia. In addition to PML/RARA, numerous other genes belonging to diverse functional classes may also contribute to its cytotoxicity. Network pharmacology is suited to unravel the multifactorial modes of action of As2O3.

6.
Biochem Pharmacol ; 146: 63-73, 2017 12 15.
Artigo em Inglês | MEDLINE | ID: mdl-29061340

RESUMO

Multidrug resistance (MDR) represents a serious problem in cancer treatment. One strategy to overcome this obstacle is to identify agents that are selectively lethal to MDR cells. The aim of this study was to discover novel compounds against MDR leukemia and to determine the molecular mechanisms behind collateral sensitivity. A library of 1162 compounds was tested against parental, drug-sensitive CCRF-CEM cells using the resazurin assay. A total of 302 compounds showed reasonable activity (less than 50% cell viability). Eleven out of 30 lawsone derivatives revealed considerable collateral sensitivity in MDR P-glycoprotein (Pgp)-overexpressing CEM/ADR5000 cells. They reduced ß-catenin activity in a Wnt/ß-catenin reporter cell line. Their activities significantly correlated with apolar desolvation (R = 0.819). Compound (1) (3-hydroxy-1,4-dioxo-N-phenyl-naphthalene-2-carboxamide) was the most active compound and dose-dependently down-regulated protein expression of ß-catenin, c-MYC, Pgp and Frizzled 7. By molecular docking, we predicted that compound (1) bound to the palmitoyl-binding groove of the cysteine-rich domain of Frizzled-7 and Frizzled-8. Compound (1) neither stimulated ATPase activity of Pgp nor reactive oxygen species generation, both of which have been previously described as possible mechanisms of collateral sensitivity. Instead, we found that Wnt/ß-catenin signaling was selectively inhibited in CEM/ADR5000 cells, but not in CCRF-CEM cells. In conclusion, we found for the first time that the inhibition of Wnt/ß-catenin signaling may represent a novel molecular mechanism of collateral sensitivity in MDR cells. Wnt/ß-catenin signaling, therefore, represents a potential therapeutic target for the selective killing of Pgp-mediated MDR.


Assuntos
Antineoplásicos/farmacologia , Naftoquinonas/química , Naftoquinonas/farmacologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Proteínas Wnt/metabolismo , beta Catenina/metabolismo , Antineoplásicos/administração & dosagem , Antineoplásicos/química , Linhagem Celular Tumoral , Relação Dose-Resposta a Droga , Resistencia a Medicamentos Antineoplásicos , Humanos , Estrutura Molecular , Espécies Reativas de Oxigênio , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/fisiologia , beta Catenina/genética
7.
Oncotarget ; 8(21): 35103-35115, 2017 May 23.
Artigo em Inglês | MEDLINE | ID: mdl-28402272

RESUMO

Ginkgolic acids (GA), a group of alkyl phenols found in crude extracts of Ginkgo biloba leaves, are known to have anticancer activity, but their mode of action is not well understood. Our aim in this study was to investigate the anti-migratory activity of seven GA against breast cancer cells and to determine the molecular mechanism behind this activity. All seven GA and their mixture inhibited wound healing in MCF-7 and MDA-MB 231 breast cancer cells. None of the compounds nor the mixture showed cytotoxicity towards the two cell lines, if tested by the resazurin assay. C13:0 inhibited NF-κB activity in the HEK Blue Null 1 reporter cell line. Furthermore, C13:0 inhibited degradation of nuclear factor of κ-light polypeptide gene enhancer in B-cells inhibitor α (IκBα). Sumoylation assay revealed that GA inhibited sumoylation of NF-κB essential modulator (NEMO). Molecular docking on SUMO-activating enzyme E1 showed that the seven GA bound to the active adenylation site with high calculated affinities ranging from -10.28 to -12.27 kcal/mol. Quantitative RT-PCR using C15:0, C13:0 and the mixture showed a significant down-regulation of urokinase plasminogen activator (uPA), plasminogen activator inhibitor-1 (PAI-1), C-X-C chemokine receptor type 4 (CXCR4) and matrix metalloproteinase 9 (MMP-9). We conclude that GA revealed considerable anti-migratory activity at non-cytotoxic concentrations, indicating anti-metastatic activity with low toxicity. This effect can be explained by the inhibition of NEMO sumoylation leading to inhibition of IκBα degradation and consequently a reduction of NF-κB activity, leading to the down-regulation of metastasis related genes including uPA, PAI-1, CXCR4, and MMP-9.


Assuntos
Neoplasias da Mama/metabolismo , Quinase I-kappa B/metabolismo , NF-kappa B/metabolismo , Salicilatos/farmacologia , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Quinase I-kappa B/química , Células MCF-7 , Metaloproteinase 9 da Matriz/genética , Modelos Moleculares , Simulação de Acoplamento Molecular , Inibidor 1 de Ativador de Plasminogênio/genética , Receptores CXCR4/genética , Salicilatos/química , Transdução de Sinais/efeitos dos fármacos , Sumoilação/efeitos dos fármacos , Ativador de Plasminogênio Tipo Uroquinase/genética
8.
Front Pharmacol ; 8: 110, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28344555

RESUMO

Multidrug resistance, a major problem that leads to failure of anticancer chemotherapy, requires the development of new drugs. Repurposing of established drugs is a promising approach for overcoming this problem. An example of such drugs is niclosamide, a known anthelmintic that is now known to be cytotoxic and cytostatic against cancer cells. In this study, niclosamide showed varying activity against different cancer cell lines. It revealed better activity against hematological cancer cell lines CCRF-CEM, CEM/ADR5000, and RPMI-8226 compared to the solid tumor cell lines MDA-MB-231, A549, and HT-29. The multidrug resistant CEM/ADR5000 cells were similar sensitive as their sensitive counterpart CCRF-CEM (resistance ration: 1.24). Furthermore, niclosamide caused elevations in reactive oxygen species and glutathione (GSH) levels in leukemia cells. GSH synthetase (GS) was predicted as a target of niclosamide. Molecular docking showed that niclosamide probably binds to the ATP-binding site of GS with a binding energy of -9.40 kcal/mol. Using microscale thermophoresis, the binding affinity between niclosamide and recombinant human GS was measured (binding constant: 5.64 µM). COMPARE analyses of the NCI microarray database for 60 cell lines showed that several genes, including those involved in lipid metabolism, correlated with cellular responsiveness to niclosamide. Hierarchical cluster analysis showed five major branches with significant differences between sensitive and resistant cell lines (p = 8.66 × 105). Niclosamide significantly decreased nuclear factor of activated T-cells (NFAT) activity as predicted by promoter binding motif analysis. In conclusion, niclosamide was more active against hematological malignancies compared to solid tumors. The drug was particularly active against the multidrug-resistant CEM/ADR5000 leukemia cells. Inhibition of GSH synthesis and NFAT signaling were identified as relevant mechanisms for the anticancer activity of niclosamide. Gene expression profiling predicted the sensitivity or resistance of cancer cells to niclosamide.

9.
Phytomedicine ; 23(2): 166-73, 2016 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-26926178

RESUMO

BACKGROUND: Biopiracy mainly focuses on the use of biological resources and/or knowledge of indigenous tribes or communities without allowing them to share the revenues generated out of economic exploitation or other non-monetary incentives associated with the resource/knowledge. METHODS: Based on collaborations of scientists from five continents, we have created a communication platform to discuss not only scientific topics, but also more general issues with social relevance. This platform was termed 'PhytCancer -Phytotherapy to Fight Cancer' (www.phyt-cancer.uni-mainz.de). As a starting point, we have chosen the topic "biopiracy", since we feel this is of pragmatic significance for scientists working with medicinal plants. RESULTS: It was argued that the patenting of herbs or natural products by pharmaceutical corporations disregarded the ownership of the knowledge possessed by the indigenous communities on how these substances worked. Despite numerous court decisions in U.S.A. and Europe, several international treaties, (e.g. from United Nations, World Health Organization, World Trade Organization, the African Unity and others), sharing of a rational set of benefits amongst producers (mainly pharmaceutical companies) and indigenous communities is yet a distant reality. In this paper, we present an overview of the legal frameworks, discuss some exemplary cases of biopiracy and bioprospecting as excellent forms of utilization of natural resources. CONCLUSIONS: We suggest certain perspectives, by which we as scientists, may contribute towards prevention of biopiracy and also to foster the fair utilization of natural resources. We discuss ways, in which the interests of indigenous people especially from developing countries can be secured.


Assuntos
Produtos Biológicos , Bioprospecção/ética , Indústria Farmacêutica/ética , Etnofarmacologia , Propriedade , Plantas Medicinais , Roubo , Países em Desenvolvimento , Cooperação Internacional , Patentes como Assunto
10.
J Ethnopharmacol ; 179: 177-96, 2016 Feb 17.
Artigo em Inglês | MEDLINE | ID: mdl-26721219

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Plants from Kenyan flora are traditionally used against many ailments, including cancer and related diseases. Cancer is characterized as a condition with complex signs and symptoms. Recently there are recommendations that ethnopharmacological usages such as immune and skin disorders, inflammatory, infectious, parasitic and viral diseases should be taken into account when selecting plants that treat cancer. AIM: The present study was aimed at investigating the cytotoxicity of a plethora of 145 plant parts from 91 medicinal plants, most of which are used in the management of cancer and related diseases by different communities in Kenya, against CCRF-CEM leukemia cell line. MATERIALS AND METHODS: Extracts from different plant parts (leaves, stems, stem bark, roots, root barks, aerial parts and whole herb) were obtained by cold percolation using different solvent systems, such as (1:1v/v) dichloromethane (CH2Cl2) and n-hexane (1), methanol (MeOH) and CH2Cl2 (2); neat MeOH (3), 5% H2O in MeOH (4) and with ethanol (EtOH, 5); their cytotoxicities were determined using the resazurin reduction assay against CCRF-CEM cells. RESULTS: At a single concentration of 10µg/mL, 12 out of 145 extracts exhibited more than 50% cell inhibition. These include samples from the root bark of Erythrina sacleuxii (extracted with 50% n-hexane-CH2Cl2), the leaves of Albizia gummifera, and Strychnos usambarensis, the stem bark of Zanthoxylum gilletii, Bridelia micrantha, Croton sylvaticus, and Albizia schimperiana; the root bark of Erythrina burttii and E. sacleuxii (extracted with 50% CH2Cl2-MeOH), the stem bark of B. micrantha and Z. gilletii (extracted using 5% MeOH-H2O) and from the berries of Solanum aculeastrum (extracted with neat EtOH). The EtOH extract of the berries of S. aculeastrum and A. schimperiana stem bark extract displayed the highest cytotoxicity towards leukemia CCRF-CEM cells, with IC50 values of 1.36 and 2.97µg/mL, respectively. Other extracts having good activities included the extracts of the stem barks of Z. gilletii and B. micrantha and leaves of S. usambarensis with IC50 values of 9.04, 9.43 and 11.09µg/mL, respectively. CONCLUSIONS: The results of this study provided information related to the possible use of some Kenyam medicinal plants, and mostly S. aculeastrum, A. schimperiana, C. sylvaticus, Z. gilletii, B. micrantha and S. usambarensis in the treatment of leukemia. The reported data helped to authenticate the claimed traditional use of these plants. However, most plants are used in combination as traditional herbal concoctions. Hence, the cytotoxicity of corresponding plant combinations should be tested in vitro to authenticate the traditional medical practitioners actual practices.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Inibidores do Crescimento/farmacologia , Leucemia/patologia , Extratos Vegetais/farmacologia , Plantas Medicinais , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Humanos , Quênia
11.
Anticancer Res ; 35(4): 2105-12, 2015 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-25862866

RESUMO

BACKGROUND: Resistance to chemotherapy is a main problem in cancer. The search for new effective compounds that can increase sensitivity of resistant cells to existing chemotherapeutics is an urgent need. In previous studies, it has been demonstrated that steroid derivatives showed promising results concerning their capacity to modulate resistance of multidrug-resistant cell lines. MATERIALS AND METHODS: Steroid derivatives were studied for their growth-inhibitory effect, cytotoxicity, reversal of multidrug resistance, apoptosis induction, and interaction with doxorubicin on multidrug resistant human ATP-binding cassette, sub-family B, member 1 (ABCB1) gene-transfected mouse T-lymphoma cell line, and human PC-3 and LNCaP prostate cancer cell lines in vitro. The steroidal interaction with P-glycoprotein (ABCB1) was investigated by molecular docking. RESULTS: Both the activity of steroid derivatives on inhibition of the ABCB1 pump and their interaction with doxorubicin are dependent on the substituent groups of the investigated steroidal structures. Even though the investigated steroid derivatives were found to have limited antiproliferative effect on the three different cancer cell lines, in combination with doxorubicin, most of them acted as good potentiators. The binding energies from molecular docking ranged from -6.43 to -9.88 kcal/mol. The predicted inhibition constants ranged from 0.1 to 10.1 µM. A significant negative correlation was found between binding energy and fluorescence activity ratio (R=-0.5, p=0.015). CONCLUSION: The effective compounds can be candidates of model molecules for possible application in the treatment of multidrug resistant cancer in rational drug design.


Assuntos
Doxorrubicina/administração & dosagem , Resistencia a Medicamentos Antineoplásicos/genética , Linfoma de Células T/tratamento farmacológico , Neoplasias da Próstata/tratamento farmacológico , Subfamília B de Transportador de Cassetes de Ligação de ATP/antagonistas & inibidores , Subfamília B de Transportador de Cassetes de Ligação de ATP/metabolismo , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Animais , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Resistência a Múltiplos Medicamentos/genética , Humanos , Técnicas In Vitro , Linfoma de Células T/genética , Linfoma de Células T/patologia , Masculino , Camundongos , Neoplasias da Próstata/genética , Neoplasias da Próstata/patologia
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA