13 research outputs found
Marine drugs for cancer: surfacing biotechnological innovations from the oceans
This review will discuss the contributions of marine natural molecules, a source only recently found to have pharmaceutical prospects, to the development of anticancer drugs. Of the seven clinically utilized compounds with a marine origin, four are used for the treatment of cancer. The development of these drugs has afforded valuable knowledge and crucial insights to meet the most common challenges in this endeavor, such as toxicity and supply. In this context, the development of these compounds will be discussed herein to illustrate, with successful examples provided by cytarabine, trabectedin, eribulin and brentuximab vedotin, the steps involved in this process as well as the scientific advances and technological innovation potential associated with developing a new drug from marine resources
Marine drugs for cancer: surfacing biotechnological innovations from the oceans
This review will discuss the contributions of marine natural molecules, a source only recently found to have pharmaceutical prospects, to the development of anticancer drugs. Of the seven clinically utilized compounds with a marine origin, four are used for the treatment of cancer. The development of these drugs has afforded valuable knowledge and crucial insights to meet the most common challenges in this endeavor, such as toxicity and supply. In this context, the development of these compounds will be discussed herein to illustrate, with successful examples provided by cytarabine, trabectedin, eribulin and brentuximab vedotin, the steps involved in this process as well as the scientific advances and technological innovation potential associated with developing a new drug from marine resources
Chromomycin A2 Induces Autophagy in Melanoma Cells
The present study highlights the biological effects of chromomycin A2 toward metastatic melanoma cells in culture. Besides chromomycin A2, chromomycin A3 and demethylchromomycin A2 were also identified from the extract derived from Streptomyces sp., recovered from Paracuru Beach, located in the northeast region of Brazil. the cytotoxic activity of chromomycin A2 was evaluated across a panel of human tumor cell lines, which found IC50 values in the nM-range for exposures of 48 and 72 h. MALME-3M, a metastatic melanoma cell line, showed the highest sensitivity to chromomycin A2 after 48h incubation, and was chosen as a model to investigate this potent cytotoxic effect. Treatment with chromomycin A2 at 30 nM reduced cell proliferation, but had no significant effect upon cell viability. Additionally, chromomycin A2 induced accumulation of cells in G(0)/G(1) phase of the cell cycle, with consequent reduction of S and G(2)/M and unbalanced expression of cyclins. Chromomycin A2 treated cells depicted several cellular fragments resembling autophagosomes and increased expression of proteins LC3-A and LC3-B. Moreover, exposure to chromomycin A2 also induced the appearance of acidic vacuolar organelles in treated cells. These features combined are suggestive of the induction of autophagy promoted by chromomycin A2, a feature not previously described for chromomycins.Conselho Nacional de Desenvolvimento CientĂfico e TecnolĂłgico (CNPq)Fundacao Cearense de Apoio ao Desenvolvimento Cientifico e Tecnologico (FUNCAP-Programa Areas Estrategicas)Univ Fed Ceara, Inst Marine Sci, BR-60165081 Fortaleza, Ceara, BrazilUniv Fed Ceara, Dept Physiol & Pharmacol, BR-60430270 Fortaleza, Ceara, BrazilUniversidade Federal de SĂŁo Paulo, Dept Marine Sci, BR-11030400 SĂŁo Paulo, BrazilUniv Fed Ceara, Dept Organ & Inorgan Chem, BR-60021970 Fortaleza, Ceara, BrazilFdn MEDINA, Ctr Excelencia Invest Medicamentos Innovadores An, Granada 18016, SpainUniversidade Federal de SĂŁo Paulo, Dept Marine Sci, BR-11030400 SĂŁo Paulo, BrazilWeb of Scienc
Cytotoxic lipidic α-amino acids from the zoanthid Protopalythoa variabilis from the Northeastern coast of Brazil
Two lipidic α-amino acids 1a and 1b were isolated from the zoanthid Protopalythoa variabilis using a bioguided fractionation for cytotoxic activity. The structures of the metabolites were determined by spectroscopic methods, including NMR (nuclear magnetic resonance) ÂčH e 13C, IR (infrared) and high resolution mass spectrometry (positive mode). The cytotoxic activity of the crude extract, as well as of the mixture of 1a and 1b were measured in vitro using the MTT assay for four human tumor cell lines. This finding has important biological and chemical implications for this type of compound. This is the first report of lipidic α-amino acids from natural sources, as well as of their cytotoxic activity.Dois α-aminoĂĄcidos lipĂdicos 1a e 1b foram isolados do zoantĂdeo Protopalythoa variabilis atravĂ©s de fracionamento guiado pela atividade citotĂłxica. As estruturas foram determinadas por diferentes mĂ©todos espectroscĂłpicos, tais como, RMN (ressonĂąncia magnĂ©tica nuclear) ÂčH e 13C, IV (infravermelho) e espectrometria de massa de alta resolução (modo positivo). A atividade citotĂłxica dos extratos, das fraçÔes e 1a/1b foi avaliada in vitro atravĂ©s do teste do MTT contra quatro linhagens de cĂ©lulas tumorais. Este achado tem implicaçÔes biolĂłgicas e quĂmicas importantes para essa classe de compostos. Este Ă© o primeiro relato de α-aminoĂĄcidos lipĂdicos a partir de uma fonte natural, bem como de sua atividade citotĂłxica.CNPqFINEPInstitute Claude Bernar
Structure Elucidation and Anticancer Activity of 7-Oxostaurosporine Derivatives from the Brazilian Endemic Tunicate Eudistoma vannamei
The present study reports the identification of two new staurosporine derivatives, 2-hydroxy-7-oxostaurosporine (1) and 3-hydroxy-7-oxostaurosporine (2), obtained from mid-polar fractions of an aqueous methanol extract of the tunicate Eudistoma vannamei, endemic to the northeast coast of Brazil. The mixture of 1 and 2 displayed IC50 values in the nM range and was up to 14 times more cytotoxic than staurosporine across a panel of tumor cell lines, as evaluated using the MTT assay.CNPqCAPESInCBFAPES
Study of anticancer potential of compounds obtainded from the zoanthid Protopalythoa variabilis duerden, 1898 (cnidaria, anthozoa) from the cearĂ coast.
Conselho Nacional de Desenvolvimento CientĂfico e TecnolĂgicoO cĂncer Ă um dos principais problemas mundiais de saĂde e uma das causas mais importantes de morbidade e mortalidade em crianĂas e adultos. Apesar do sucesso no tratamento de diversos tipos de tumor, ainda nĂo se chegou ao fĂrmaco ideal e as terapias existentes nem sempre alcanĂam resultados satisfatĂrios alĂm de induzir muitos efeitos colaterais. A pesquisa em produtos naturais marinhos (PNM), embora recente, tem revelado uma enorme diversidade de estruturas quĂmicas, muitas vezes inĂditas e com potente atividade biolĂgica. MolĂculas citotĂxicas, com potencial aplicaĂĂo na quimioterapia do cĂncer, sĂo freqĂentemente isoladas dos organismos marinhos e dos quatro fĂrmacos oriundos de PNM comercializados atualmente, dois sĂo utilizados na quimioterapia do cĂncer. AlĂm dos metabĂlitos secundĂrios, o estudo de polissacarĂdeos modificadores da resposta biolĂgica para imunoterapia adjuvante tambĂm vem surgindo como uma Ărea bastante promissora. Os cnidĂrios juntamente com esponjas, ascĂdias, moluscos e algas compĂem o grupo de representantes marinhos quimicamente mais prolĂficos. O zoantĂdeo Protopalythoa variabilis (Cnidaria, Anthozoa) Ă encontrado no litoral do mundo inteiro, porĂm o seu potencial farmacolĂgico nunca foi investigado anteriormente. O potencial antitumoral de substĂncias obtidas do P. variabilis encontrado no litoral cearense foi avaliado neste trabalho. O fracionamento guiado pela citotoxicidade de 4 linhagens de cĂlulas tumorais (HL-60, leucemia; HCT-8, cĂlon; SF-295, sistema nervoso central e MDA-MB-435, melanoma) do extrato hidroalcoĂlico bruto (EHB) rendeu uma mistura de alfa-aminoĂcidos lipĂdicos (1a/1b) inĂditos a partir da fraĂĂo hexano e 5 fraĂĂes (AcOEt-P-1-5) contendo sinais compatĂveis com esterĂides da fraĂĂo acetato de etila. Os 1a/1b apresentaram uma mĂdia de concentraĂĂo inibitĂria mĂdia (CI50) nas linhagens testadas de 85 ng/mL, enquanto a AcOEt-P-4, mais ativa dentre as derivadas da AcOEt exibiu uma mĂdia de CI50 de 117,5 ng/mL. Essa foi a primeira vez que alfa-aminoĂcidos lipĂdicos foram obtidos de uma fonte natural e tambĂm que o potencial citotĂxico de compostos dessa classe Ă demonstrado. O estudo da citotoxicidade dos 1a/1b e da AcOEt-P-4, na linhagem leucĂmica HL-60, revelou que estas amostras devem sua atividade Ă induĂĂo de apoptose com via intrĂnseca desempenhando um importante papel. A partir do resĂduo do EHB do P. variabilis, foram obtidos polissacarĂdeos sulfatados ligados a proteĂnas (PPV). O PPV nĂo apresentou citotoxicidade contra as cĂlulas tumorais in vitro, porĂm induziu 50% de inibiĂĂo do crescimento tumoral em camundongos transplantados com a linhagem B-16 (melanoma). As anĂlises dos parĂmetros bioquĂmicos, hematolĂgicos e histopatolĂgicos indicaram que o PPV nĂo apresentou toxicidade nos animais e aumentou a proliferaĂĂo de monĂcitos. Estudos adicionais com macrĂfagos peritoneais in vitro confirmaram que o PPV Ă um modificador da resposta biolĂgica. A ativaĂĂo dos macrĂfagos pelo PPV induziu a produĂĂo de Ăxico nĂtrico, e das citocinas IL-1 e IL-6, mas nĂo TNF-alfa. O presente trabalho mostrou que a espĂcie P. variabilis Ă uma rica e profĂcua fonte de compostos com potencial antitumoral a ser explorada, possuindo tanto metabĂlitos citotĂxicos capazes de induzir apoptose em cĂlulas tumorais diretamente, quanto macromolĂculas imunomoduladoras com atividade antitumoral in vivo.Cancer is one of the biggest health problems in all over the world and causes a great amount of death of children and adults. Despite success of several cancer therapies, the ideal anticancer drug is not available yet and the numerous side effects are a limiting point. The natural products research, although recent, has shown often a variety of new chemical structures and potent biological activities. Cytotoxic compounds with possible cancer chemotherapy application are commonly isolated from marine organisms. Two within four marketed drugs from marine sources are used for cancer chemotherapy. Besides small weight molecules, the polysaccharides biological response modifiers also have showing to be a promising field as adjuvant in traditional chemotherapy. Cnidarians together with sponges, ascidians, mollusks and algae form the most promising marine group. The zoanthid Protopalythoa variabilis (Cnidaria, Anthozoa) is found in coastline of whole world, however its pharmacological potential have never been investigated before. The antitumor potential of compounds from P. variabilis from CearĂ coast was evaluated in this work. The chemical fractionation guided by the cytotoxicity on four tumor cell lines (HL-60, leukemia; HCT-8, colon; SF-295, central nervous system and MDA-MB-435, melanoma) from crude hydroalcoholic extract yield two new lipidic -amino acids (1a/1b) in mixture from hexane fraction and five fractions (EtOAc-P-1-5) containing sterols signals from ethyl acetate fraction. 1a/1b showed a mean inhibitory concentration mean (IC50) of 85 ng/mL against cell lines tested, whereas EtOAc-P-4, the most powerful of EtOAc derivatives fractions, showed a mean IC50 of 117.5 ng/mL. This was the first report of lipidic amino acids obtained from natural sources and also the first cytotoxic data for this class of compounds. The cytotoxic investigation of 1a/1b and EtOAc-P-4 on HL-60 cells showed treated-cells dead by apoptosis with critical involvement of intrinsic pathway. Protein-bound sulfated polysaccharides (PPV) with high molecular mass were obtained from residue of the hydroalcoholic extract. PPV did not showed cytotoxicity on tumor cell lines in vitro, however it induced 50% of tumor growth inhibition on melanoma B-16 bearing-mice. No toxic evidences were observed in histopathology analysis as well as in biochemical and hematological parameters, however circulating monocytes increased with PPV treatment. In addition peritoneal macrophages investigated in vitro confirmed that PPV is a biological response modifier. The PPV-induced macrophage activation stimulated the release of nitric oxide and cytokines IL-1 and IL-6, but did not do TNF-. This work showed that P. variabilis is a rich source of antitumor compounds, having both small cytotoxic molecules and polysaccharides biological response modifiers with antitumor activity in vivo
Antileukemic effects of Didemnum psammatodes (Tunicata: Ascidiacea) constituents
Chemical investigation of the methanolic extract of the ascidian Didemnum psammatodes has led to the identification of fourteen known compounds: three methyl esters (methyl myristate, methyl palmitate and methyl stearate), four steroids (cholesterol, campesterol, stigmasterol and beta-sitosterol), two fatty acids (palmitic acid and stearic acid), three glyceryl ethers {(1,2-propanediol, 3-(heptadecyloxy), batyl alcohol and 1,2-propanediol, 3-[(methyloctadecyl)oxy]) and two nucleosides (thymidine and 2`-deoxyguanosine). Their structures were proposed by NMR and comparison with literature data and GC analysis in comparison with authentic sample. The cytotoxic activity of these compounds was evaluated against human leukemia cell line panel using the MTT assay. The mixture of the three methyl esters was the most active group of compounds, showing antiproliferative and cytotoxic effects. Further studies on their mode of action suggest that these activities are connected with inhibition of DNA synthesis and induction of both necrosis and apoptosis. (C) 2007 Elsevier Inc. All rights reserved
Pro-apoptotic activity of lipidic α-amino acids isolated from Protopalythoa variabilis
Lipidic alpha-amino acids (LAAs) have been described as non-natural amino acids with long saturated or unsaturated aliphatic chains. In the continuing prospect to discover anticancer agents from marine sources, we have obtained a mixture of two cytotoxic LAAs (1a and 1b) from the zoanthid Protopalythoa variabilis. The anti-proliferative potential of 14 synthetic LAAs and 1a/1b were evaluated on four tumor cell lines (HCT-8, SF-295, MDA-MB-435, and HL-60). Five of the synthetic LAAs showed high percentage of tumor cell inhibition, while 1a/1b completely inhibited tumor cell growth. Additionally, apoptotic effects of 1a/1b were studied on HL-60 cell line. 1a/1b-treated cells showed apoptosis morphology, loss of mitochondrial potential, and DNA fragmentation. (C) 2010 Elsevier Ltd. All rights reserved