RESUMO
Arsenic trioxide (ATO) is an inorganic arsenic derivative that is very effective against acute promyelocytic leukemia. However, organic arsenic derivatives (OAD) have a more favorable toxicity profile than ATO. We herein characterized dipropil-S-glycerol arsenic (GMZ27), a novel OAD. GMZ27 had potent antiproliferative activity against human acute myeloid leukemia (AML) cell lines that was higher than that of ATO. In contrast to ATO, GMZ27 only marginally induced maturation of leukemia cells and had no effect on the cell cycle. The anti-leukemia activity of GMZ27 against AML cells was independent of the presence of the PML-RARα fusion protein. GMZ27 dissipates mitochondrial transmembrane potential, and induces cleavage of caspase 9 and activation of caspase 3 without altering the expression levels of (BCL-2), BAX and BCL-xl. GMZ27 induces the formation of intracellular superoxide, a reactive oxygen species (ROS) which plays a major role in the antileukemia activity of this OAD. In addition to ROS generation, GMZ27 concomitantly reduces intracellular glutathione which markedly weakens the cellular antioxidant capacity, thus enhancing the detrimental intracellular effects of ROS production. These results indicate that GMZ27 induces apoptosis in AML cells in a PML-RARα-independent fashion, through the induction of ROS production. This activity provides the rationale for the testing of GMZ27 in patients with AML.
Assuntos
Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Arsenicais/farmacologia , Leucemia Mielomonocítica Aguda/tratamento farmacológico , Leucemia Promielocítica Aguda/tratamento farmacológico , Proteínas de Fusão Oncogênica/biossíntese , Animais , Apoptose/fisiologia , Trióxido de Arsênio , Caspase 9/metabolismo , Ciclo Celular/efeitos dos fármacos , Processos de Crescimento Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Relação Dose-Resposta a Droga , Ativação Enzimática/efeitos dos fármacos , Feminino , Células HL-60 , Humanos , Leucemia Mielomonocítica Aguda/metabolismo , Leucemia Mielomonocítica Aguda/patologia , Leucemia Promielocítica Aguda/metabolismo , Leucemia Promielocítica Aguda/patologia , Camundongos , Óxidos/farmacologia , Oxigênio/metabolismoRESUMO
Arsenic trioxide (ATO) is an inorganic arsenic derivative that is highly effective against PML-RARalpha-positive leukemia but much less against other hematological malignancies. We synthesized an organic arsenic derivative (OAD), S-dimethylarsino-thiosuccinic acid (MER1), which offers a superior toxicity profile and comparable in vitro activity relative to ATO. In Swiss Webster mice, maximally-tolerated cumulative dose of MER1 when given i.v. for 5 days was 100 mg/kg/d. We demonstrated that MER1 induced apoptosis and dose- and time-dependent inhibition of survival and growth in a panel of myeloid leukemia cell lines. Unlike ATO, this activity was independent of PML-RARalpha status and was not associated with induction of myeloid maturation. In NB4 and HL60 cells, MER1 and ATO induced caspase activation and dissipation of mitochondrial transmembrane potential. At the same time, MER1 induced generation of reactive oxygen species (ROS) and cell cycle arrest in G2/M phase and proved to be more potent than ATO at inducing apoptosis. ROS generation and intracellular glutathione levels were key modulators of MER1-induced cytotoxicity as evidenced by abrogation of apoptosis in myeloid leukemia cell lines pretreated with the disulfide bond-reducing agent dithiothreitol or the radical scavenger N-acetyl-L-cysteine. Collectively, these data indicate that MER1 induces apoptosis in PML-RARalpha-positive and -negative myeloid leukemia cells by enhancing oxidative stress. This agent, therefore, combines low in vivo toxicity with formidable in vitro pro-apoptotic ROS-mediated activity, and may represent a novel OAD suitable for clinical development against a variety of hematological malignancies.
Assuntos
Antineoplásicos/farmacologia , Arsenicais/farmacologia , Leucemia Mieloide/tratamento farmacológico , Proteínas de Fusão Oncogênica/metabolismo , Succinatos/farmacologia , Animais , Antineoplásicos/administração & dosagem , Apoptose/efeitos dos fármacos , Trióxido de Arsênio , Arsenicais/administração & dosagem , Caspases/efeitos dos fármacos , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Dose Máxima Tolerável , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Camundongos , Óxidos/farmacologia , Espécies Reativas de Oxigênio/metabolismo , Succinatos/administração & dosagemRESUMO
A new class of platinum(II) coordination complexes and their dye tagged conjugates has been synthesized from N-substituted diaminocyclohexane ligands. The in vitro anticancer activities of the platinum compounds have been validated against the breast cancer cell-line MCF-7 and the normal cell-line MCF-10A via sulforhodamine B and colony formation assay. The platinum compounds and the corresponding metal-free ligands exhibited higher drug efficiencies than cisplatin and oxaliplatin against MCF-7 cells. Cellular uptake and DNA-bound Pt were demonstrated by atomic absorption spectroscopy. The platinum complexes displayed increased cellular accumulation and DNA binding as compared with cisplatin. Real-time reverse transcription polymerase chain reaction assay was employed to investigate drug effects on mRNA expression in MCF-7 cells. The results indicated that the study compounds are effective in regulating cyclin D1, Bcl-2, and p53 genes; yet, oxaliplatin is less effective in manipulating those genes. The luminescent probe that was integrated into the platinum complexes made it possible to monitor cellular drug distribution using optical imaging. Targeting of tumor cell nuclei by the study compounds was confirmed by confocal microscopy. Taken together, these new platinum(II)-based antitumor agents are different from marketed platinum drugs in several critical aspects and could have potential in cancer therapy.
Assuntos
Antineoplásicos/toxicidade , Corantes Fluorescentes/química , Compostos Organoplatínicos/química , Antineoplásicos/síntese química , Antineoplásicos/química , Linhagem Celular Tumoral , Cisplatino/toxicidade , Ciclina D1/genética , Ciclina D1/metabolismo , DNA/metabolismo , Regulação da Expressão Gênica , Humanos , Microscopia Confocal , Compostos Organoplatínicos/síntese química , Compostos Organoplatínicos/toxicidade , Oxaliplatina , Proteínas Proto-Oncogênicas c-bcl-2/genética , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismoRESUMO
The inorganic arsenic derivative arsenic trioxide (ATO) has proven to be highly efficacious in patients with acute promyelocytic leukemia (APL) and has been associated with complete cytogenetic response in most treated patients diagnosed with this disease. This is due to ATO's direct effect on PML-RARalpha oncoprotein patognomonic for APL. ATO has shown moderate activity against certain other hematologic and solid organ malignancies but is also associated with significant toxicities, especially when used at higher doses. The development of orally bioavailable organic arsenic derivatives (OAD) offering improved toxicity profiles and better efficacy may expand the use of arsenic derivatives in hematologic malignancies and solid tumors. The favorable in vivo carcinostatic activity of S-dimethylarsino-thioglucose, the first OAD synthesized in murine leukemia models by our group in 1975, set the stage for our efforts to develop OADs. Unfortunately, the program remained dormant for almost two decades. The success of ATO in APL in the late 1990s re-ignited the interest in the use of OADs in cancer chemotherapy. This review describes the chemical development of OADs and summarizes the clinical development of a promising lead compound, Darinaparsin (ZIO-101; SGLU; S-dimethylarsino-glutathione), for the treatment of a variety of cancers.
Assuntos
Antineoplásicos/química , Antineoplásicos/farmacologia , Arsenicais/química , Arsenicais/farmacologia , Glutationa/análogos & derivados , Animais , Antineoplásicos/uso terapêutico , Antineoplásicos/toxicidade , Arsenicais/uso terapêutico , Ensaios de Seleção de Medicamentos Antitumorais , Glutationa/química , Glutationa/farmacologia , Glutationa/uso terapêutico , Glutationa/toxicidade , Humanos , Leucemia Mieloide Aguda/tratamento farmacológico , CamundongosRESUMO
We report a new series of Herceptin-platinum(II) binding complexes, Her-nLPt(II) (Her denotes Herceptin; L denotes diamino ligands and L=L1-L4; n=1, 5, or 10). Solution chemistry studies have shown that these complexes are stable under physiological conditions (pH 7.4 in PBS). The platinum(II) compound L1Pt(II)Cl(2) inhibits the growth of a panel of human cancer cell lines at sub-micromolar concentrations. Remarkable cancer-cell-specific cytotoxicity was observed with Her-nL1Pt(II) (n=1, 5, 10) toward Her2/neu-overexpressing cancer cells (SK-BR-3 and SK-OV-3) over normal fibroblast cells. Annexin V apoptosis assays in SK-BR-3 and low-Her2/neu-expressing MCF-7 breast cancer cells further confirmed the critical role of Herceptin with this cancer-cell-specific agent. It was also found that the L1Pt(II)Cl(2) complex is an efficient regulator of the apoptotic genes Bcl-2 in the treated SK-BR-3 cells. Also, enhanced regulatory effects were observed in Her-10L1Pt(II). Taken together, this study suggests a new approach for the development of mAb-platinum(II)-based targeting agents for the treatment of human cancers.
Assuntos
Anticorpos Monoclonais/química , Anticorpos Monoclonais/farmacologia , Antineoplásicos/química , Antineoplásicos/farmacologia , Compostos Organoplatínicos/química , Compostos Organoplatínicos/farmacologia , Anticorpos Monoclonais Humanizados , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Conformação Molecular , Receptor ErbB-2/antagonistas & inibidores , Reprodutibilidade dos Testes , Estereoisomerismo , TrastuzumabRESUMO
A set of 12 enantiomeric diamine-based small molecules was synthesized and screened for anticancer activity against five human cancer cell lines: NCI-H460, A549, MCF-7, SK-BR-3, and T-47D. The salicyl diamino compounds (1-6) were found to induce inhibition of the growth of cancer cells at submicromolar concentrations. The lead compound, N,N'-bis-salicyl-(1R,2R)-diaminocyclohexane (1) displayed single-reagent anticancer activity with an IC(50) value equal to or less than 2.0 microM in H460 and A-549 cancer cells. SRB and colony formation assays indicated that compound 1 shows greater cytotoxic activity toward MCF-7 cells than MCF-10A cells. Real-time RT-PCR analysis demonstrated that compound 1, is an extremely efficient regulator of antiapoptotic genes, Bcl-xL, Bcl-2, and the cell cycle related gene, cyclin D1. This study provides a new insight into the development of novel small molecules in the treatment of human breast cancers.
Assuntos
Antineoplásicos/química , Diaminas/química , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Diaminas/farmacologia , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Espectroscopia de Ressonância Magnética , RNA Mensageiro/antagonistas & inibidores , RNA Mensageiro/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Espectrometria de Massas por Ionização por Electrospray , EstereoisomerismoRESUMO
Some new S-dialkylarsenic compounds, S-dialkylarsino-3-mercapto-1,2-propanediol (3a-3d) and their derivatives (4a,4b), have been synthesized. They were screened at the National Cancer Institute (NCI) for their anticancer activity against a panel of about 60 human tumor cell lines. Most of them display anticancer activity having GI(50) and LC(50) values at low concentrations and are sensitive to leukemia, renal cancer and prostate cancer cell lines and in which the compound 3c is the most active.
Assuntos
Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Glicerol/análogos & derivados , Glicerol/síntese química , Glicerol/farmacologia , Compostos de Sulfidrila/síntese química , Compostos de Sulfidrila/farmacologia , Linhagem Celular Tumoral , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Indicadores e Reagentes , Dose Letal Mediana , Espectroscopia de Ressonância Magnética , Espectrometria de Massas , Relação Estrutura-AtividadeRESUMO
Various proteins involved in transcriptional regulation possess highly selective DNA-binding domains, known as zinc fingers. However, little is known about small-molecule zinc(II) complexes in the regulation of gene expression and programmed cell death. A new family of zinc(II) complexes is reported, which might be useful against human cancer cells. By using template synthesis and in vitro cell-line screening, a set of zinc(II) complexes has been found to induce apoptosis of cancer cells and display single-reagent in vitro cytotoxicity. The method used to synthesize the molecules resulted in "built-in" luminescent behavior. Confocal optical imaging clearly demonstrated penetration through the cell membrane by these metal complexes. We have discovered that C3, the meso-zinc(II) complex is an extremely efficient regulator of the cell cycle and anti-apoptosis genes bcl-2 and bcl-xL. This study provides a new insight into the development of zinc(II) complexes as potential drugs.
Assuntos
Antineoplásicos/farmacologia , Proteínas Reguladoras de Apoptose/genética , Genes cdc/efeitos dos fármacos , Compostos Organometálicos , Zinco/química , Apoptose , Neoplasias da Mama/tratamento farmacológico , Ciclo Celular , Linhagem Celular Tumoral , Regulação para Baixo/efeitos dos fármacos , Feminino , Humanos , Concentração Inibidora 50 , Estrutura Molecular , Compostos Organometálicos/farmacologia , Proteínas Proto-Oncogênicas c-bcl-2/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-bcl-2/metabolismoRESUMO
The first pi-conjugated macrocyclic diimine and triaza DNA-binding intercalators and their platinum(II) conjugates have been synthesized by direct Schiff base cyclocondensation. The in vitro anticancer activities of compounds 3, 4, and 5 were tested on five cancer cell lines: MCF-7, A549, P388, A2780, and A2780cisR. Ovarian tumors were included specifically to evaluate the new conjugates' ability to circumvent A2780cisR resistance. Antitumor effects of the newly conjugated compounds were compared to those of cisplatin. The data clearly indicate that improved drug efficiencies are achieved as a result of the intercalative moieties. The luminescent probe that was integrated in complexes 8-10 made it possible to monitor drug penetration using optical imaging. Enhanced targeting of tumor nuclei by the study compounds was confirmed by confocal microscopy. This paper describes a new class of platinum-based antitumorals differing from cisplatin in several critical aspects with the potential for significantly improving clinical outcomes in cancer patients.
Assuntos
Antineoplásicos/síntese química , Compostos Aza/síntese química , Quelantes/síntese química , Iminas/síntese química , Substâncias Intercalantes/síntese química , Compostos Organoplatínicos/síntese química , Antineoplásicos/química , Antineoplásicos/farmacologia , Compostos Aza/química , Linhagem Celular Tumoral , Quelantes/química , Cisplatino/farmacologia , Resistencia a Medicamentos Antineoplásicos , Ensaios de Seleção de Medicamentos Antitumorais , Corantes Fluorescentes/química , Fluorometria , Humanos , Iminas/química , Substâncias Intercalantes/química , Substâncias Intercalantes/farmacologia , Microscopia Confocal , Compostos Organoplatínicos/química , Compostos Organoplatínicos/farmacologia , Relação Estrutura-AtividadeRESUMO
Novel chiral Robson-type macrocyclic complexes M(2)-L [where M = Mn(II), Mn(III), Co(II) and Co(III) and L denotes tetra-Schiff base chiral ligands, L1 or L2] have been synthesized by metal template condensation of 2,6-diformyl-4-methyl-phenol, with 1R,2R-diaminocyclohexane (L1) or 1R,2R-diphenylethylenediamine (L2). The dinuclear Co(II) and Co(III) complexes catalyze asymmetric cyclopropanation of styrene with diazoacetate cooperatively and with high enantioselectivity.
Assuntos
Propano/química , Catálise , Ciclização , Modelos Moleculares , EstereoisomerismoRESUMO
A family of novel chiral "calixsalen" Schiff base macrocycles R,R-H(3)L4, R,R-H(3)L5, containing three chiral diamino moieties were synthesized by an efficient self-assembly and characterized by (1)H and (13)C NMR, mass spectrometry, and X-ray diffraction. The systematic synthesis, structure, and coordination properties of the [2 + 2] and [3 + 3] Robson-type Schiff base macrocyclic mono-, di-, tri-, and tetranuclear metal complexes were explored.
RESUMO
[structure: see text] [structure: see text] New oligomeric chiral macrocyclic ligands have been synthesized using an efficient self-assembly method. High enantioselective cooperativity in the catalytic asymmetric aldol reactions was directly observed using the conceptually novel chiral multinuclear complex catalysts.
RESUMO
PURPOSE: Arsenic trioxide (As(2)O(3)), an inorganic arsenic compound, has recently been approved for the treatment of relapsed or refractory acute promyelocytic leukemia. However, systemic toxicity associated with As(2)O(3) treatment remains a problem. Inorganic arsenic is detoxified in vivo by methylation reactions into organic arsenic compounds that are less toxic. METHODS AND RESULTS: We investigated the antiproliferative and cytotoxic activity of dimethylarsinic acid (DMAA), an organic arsenic derivative and major metabolic by-product of As(2)O(3), against a panel of eight leukemia and multiple myeloma cell lines. As(2)O(3) was tested in comparison. In clonogenic assay, the average concentration of DMAA that suppressed cell colony growth by 50% was 0.5-1 m M, while for As(2)O(3) it was on average 1-2 microM. At those concentrations DMAA and As(2)O(3) had significantly less effect on colony growth of normal progenitor cells. Cytotoxic doses of DMAA and As(2)O(3) in 3-day trypan blue dye exclusion assay experiments were similar to doses effective in clonogenic assay. Assessment of apoptosis by annexin V assay revealed a high rate of apoptosis in all cell lines treated with DMAA and As(2)O(3), but significantly less effect on normal progenitor cells. DMAA, unlike As(2)O(3), had no effect on the maturation of leukemic cells. CONCLUSIONS: DMAA exerts differential antiproliferative and cytotoxic activity against leukemia and multiple myeloma cells, with no significant effect on normal progenitor cells. However, concentrations of DMAA needed to achieve such efficacy are up to 1000 times those of As(2)O(3). Evaluation of novel organic arsenic that would combine the high efficacy of As(2)O(3) and the low toxicity of DMAA is warranted.
Assuntos
Ácido Cacodílico/farmacologia , Herbicidas/farmacologia , Leucemia/patologia , Mieloma Múltiplo/patologia , Morte Celular , Divisão Celular/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Células Tumorais CultivadasRESUMO
The reactions of alpha,beta-unsaturated aldehydes and ketones with bis(dimethylaluminum) selenide, (Me(2)Al)(2)Se, yield the corresponding alpha,beta-unsaturated selenoaldehydes and selenoketones. They are too unstable to be isolated in the monomeric form, but they undergo regioselective [4 + 2] dimerization via a "head-to-head" oriented transition state to afford diselenin derivatives (trans and cis isomers). Theoretical calculations at the density functional theory level show that this selectivity occurs because the "head-to-head" dimerization is thermodynamically favored over the "head-to-tail" by about 14 kcal/mol. Both dimerization reactions have low energy barriers: 1.5 and 2.8 kcal/mol for the former and 0.9 and 1.3 kcal/mol for the latter. In the presence of norbornadiene, these compounds function as 4pi heterodienes (C=C-C=Se) to give the respective cycloadduct products. On the other hand, they act as 2pi dienophiles (C=Se) in the reactions with cyclopentadiene except for selenoacrolein which serves as a 4pi diene and only one C=C bond (2pi) in cyclopentadiene is involved in the reaction. Theoretical calculations have been carried out in order to better understand these observations.