RESUMO
OBJECTIVES: Acridone alkaloids from Citrus and their derivatives show various kinds of biological activity. However, the anticancer activities of dimeric acridone alkaloids with unique structures and the molecular mechanism of these effects are poorly understood. METHODS: We investigated the cytotoxicity effects of dimeric acridone alkaloids isolated from Marsh grapefruit on human myeloid leukaemia HL-60 cells. KEY FINDINGS: Of the six dimeric acridone alkaloids tested, citbismine-E, the most potent, dose- and time-dependently decreased HL-60 cell viability by inducing apoptosis. The treatment of HL-60 cells with citbismine-E yielded a significant increase in levels of intracellular reactive oxygen species (ROS). Citbismine-E lowered the mitochondrial membrane potential and increased the activities of caspase-9 and -3. In addition, citbismine-E-induced apoptosis, decrease in mitochondrial membrane potential and caspase activation were significantly alleviated by pretreatment of the cells with antioxidant N-acetylcysteine (NAC). Citbismine-E induced intrinsic caspase-dependent apoptosis through ROS-mediated c-Jun N-terminal kinase activation. Citbismine-E-induced production of oxidative stress biomarkers, malondialdehyde and 8-hydroxy-2'-deoxyguanosine was also attenuated by pretreatment with NAC. CONCLUSIONS: Citbismine-E is a powerful cytotoxic agent against HL-60 cells that acts by inducing mitochondrial dysfunction-mediated apoptosis through ROS-dependent JNK activation. Citbismine-E also induced oxidative stress damage via ROS-mediated lipid peroxidation and DNA damage in HL-60 cells.
Assuntos
Acridonas/uso terapêutico , Alcaloides/uso terapêutico , Antineoplásicos Fitogênicos/uso terapêutico , Citrus paradisi , Leucemia/metabolismo , Extratos Vegetais/uso terapêutico , Acridonas/isolamento & purificação , Acridonas/farmacologia , Alcaloides/isolamento & purificação , Alcaloides/farmacologia , Antineoplásicos Fitogênicos/isolamento & purificação , Antineoplásicos Fitogênicos/farmacologia , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/fisiologia , Citotoxinas , Relação Dose-Resposta a Droga , Células HL-60 , Humanos , Leucemia/tratamento farmacológico , Extratos Vegetais/isolamento & purificação , Extratos Vegetais/farmacologiaRESUMO
Nonalcoholic fatty liver disease (NAFLD)/nonalcoholic steatohepatitis (NASH) are global epidemic public health problems with pathogenesis incompletely understood. Hepatocyte excessive apoptosis is a significant symbol for NAFLD/NASH patients, and therefore anti-apoptosis therapy could be used for NAFLD/NASH treatment. Up-regulation of BCL-2 has been found to be closely related with anti-apoptosis. BCL-2 gene promoter region has a C-rich sequence, which can form i-motif structure and play important role in regulating gene transcription. In this study, after extensive screening and evaluation, we found that acridone derivative A22 could up-regulate BCL-2 transcription and translation in vitro and in cells through selective binding to and stabilizing BCL-2 gene promoter i-motif. Our further experiments showed that A22 could reduce hepatocyte apoptosis in NAFLD/NASH model possibly through up-regulating BCL-2 expression. A22 could reduce inflammation, endoplasmic reticulum stress and cirrhosis in high-fat diet-fed mice liver model. Our findings provide a potentially new approach of anti-apoptosis for NAFLD/NASH treatment, and A22 could be further developed as a lead compound for NAFLD/NASH therapy. Our present study first demonstrated that gene promoter i-motif could be targeted for gene up-regulation for extended treatment of other important diseases besides cancer.
Assuntos
Acridonas/uso terapêutico , Genes bcl-2 , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Hepatopatia Gordurosa não Alcoólica/genética , Regulação para Cima/efeitos dos fármacos , Animais , Apoptose , Linhagem Celular Tumoral , Dieta Hiperlipídica , Humanos , Fígado/efeitos dos fármacos , Fígado/patologia , Masculino , Camundongos Endogâmicos C57BL , Hepatopatia Gordurosa não Alcoólica/patologia , Regiões Promotoras Genéticas/efeitos dos fármacosRESUMO
The global impact of malaria remains staggering despite extensive efforts to eradicate the disease. With increasing drug resistance and the absence of a clinically available vaccine, there is an urgent need for novel, affordable, and safe drugs for prevention and treatment of malaria. Previously, we described a novel antimalarial acridone chemotype that is potent against both blood-stage and liver-stage malaria parasites. Here, we describe an optimization process that has produced a second-generation acridone series with significant improvements in efficacy, metabolic stability, pharmacokinetics, and safety profiles. These findings highlight the therapeutic potential of dual-stage targeting acridones as novel drug candidates for further preclinical development.
Assuntos
Acridonas/química , Antimaláricos/química , Acridonas/farmacocinética , Acridonas/farmacologia , Acridonas/uso terapêutico , Administração Oral , Animais , Antimaláricos/farmacocinética , Antimaláricos/farmacologia , Antimaláricos/uso terapêutico , Sobrevivência Celular/efeitos dos fármacos , Modelos Animais de Doenças , Feminino , Meia-Vida , Células Hep G2 , Humanos , Estágios do Ciclo de Vida/efeitos dos fármacos , Malária/tratamento farmacológico , Malária/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Plasmodium falciparum/efeitos dos fármacos , Plasmodium falciparum/isolamento & purificação , Relação Estrutura-AtividadeRESUMO
A potent Nonsterodial Anti-inflammatory Drug (NSAID) candidates has been conceived and built by an assembly of a hydrophilic, fluorescent and COX-2 inhibiting units in the same molecule. The isatinimino-acridinedione core (TM-7) was achieved in a simple three step synthetic procedure viz (i) a multicomponent reaction between dimedone, aldehyde and amine to furnish the nitroacridinedione (4), (ii) reduction step and (iii) schiff's-base condensation with isatin. The excellent anti-inflammatory pharmacological efficiency of the drug was established by in vivo biological experiments. Accordingly, it was found that the treatment with the synthesized isatinimino analogues (dosage: 30â¯mg/kg) inhibited protein expression of cyclooxygenase-2 (COX-2), inducible nitric oxide synthase (iNOS), and nuclear factor kappa B (NF-κB) as well as production of prostaglandin E2 (PGE2), nitric oxide (NO), tumor necrosis factor-alpha (TNF-α), interleukin-1beta (IL-1ß), and interleukin-6 (IL-6) levels induced by carrageenan. Further, a comparative molecular modeling analysis of TM-7 carried out with the crystal structure of aspirin acetylated human COX-2 suggested effectively binding and efficient accommodation inside the active site's gorge.
Assuntos
Acridonas/uso terapêutico , Anti-Inflamatórios não Esteroides/uso terapêutico , Inibidores de Ciclo-Oxigenase 2/uso terapêutico , Inflamação/tratamento farmacológico , Isatina/análogos & derivados , Isatina/uso terapêutico , Acridonas/síntese química , Acridonas/metabolismo , Animais , Anti-Inflamatórios não Esteroides/síntese química , Anti-Inflamatórios não Esteroides/metabolismo , Domínio Catalítico , Ciclo-Oxigenase 2/química , Ciclo-Oxigenase 2/metabolismo , Inibidores de Ciclo-Oxigenase 2/síntese química , Inibidores de Ciclo-Oxigenase 2/metabolismo , Citocinas/metabolismo , Edema/tratamento farmacológico , Humanos , Indometacina/uso terapêutico , Isatina/metabolismo , Masculino , Simulação de Acoplamento Molecular , NF-kappa B/metabolismo , Óxido Nítrico Sintase Tipo II/metabolismo , Ligação Proteica , Ratos Wistar , Transdução de Sinais/efeitos dos fármacosRESUMO
Malaria remains one of the deadliest diseases in the world today. Novel chemoprophylactic and chemotherapeutic antimalarials are needed to support the renewed eradication agenda. We have discovered a novel antimalarial acridone chemotype with dual-stage activity against both liver-stage and blood-stage malaria. Several lead compounds generated from structural optimization of a large library of novel acridones exhibit efficacy in the following systems: (1) picomolar inhibition of in vitro Plasmodium falciparum blood-stage growth against multidrug-resistant parasites; (2) curative efficacy after oral administration in an erythrocytic Plasmodium yoelii murine malaria model; (3) prevention of in vitro Plasmodium berghei sporozoite-induced development in human hepatocytes; and (4) protection of in vivo P. berghei sporozoite-induced infection in mice. This study offers the first account of liver-stage antimalarial activity in an acridone chemotype. Details of the design, chemistry, structure-activity relationships, safety, metabolic/pharmacokinetic studies, and mechanistic investigation are presented herein.
Assuntos
Acridonas/química , Acridonas/farmacologia , Antimaláricos/química , Antimaláricos/farmacologia , Descoberta de Drogas/métodos , Acridonas/uso terapêutico , Animais , Antimaláricos/uso terapêutico , Modelos Animais de Doenças , Células Hep G2 , Humanos , Malária/tratamento farmacológico , Camundongos , Plasmodium/classificação , Plasmodium/efeitos dos fármacos , Especificidade da Espécie , Relação Estrutura-AtividadeRESUMO
OBJECTIVE: To investigate the anti-tumor effect of acridone against breast cancer in vivo and provide a therapeutic agent for treatment of breast cancer. MATERIALS AND METHODS: The nude mice xenografted tumor model was established by MCF-7 cells. The mice were randomly divided into four groups. The mice in each group (n=6) were intraperitoneally injected with 0.1 mg/kg saline (low-dose), 0.5 mg/kg (middle-dose) and 1.0 mg/kg (high-dose) of acridone for 21 days, respectively. At the end of the animal experiment, the weight of tumors was recorded to calculate the tumor inhibition rate. The serum hormone levels in peripheral blood were determined using ELISA. Hematoxylin and eosin (HE) staining was used to analyze the histopathological changes. The expression of ABCG2 protein and mRNA were determined by Western blot and RT-PCR, respectively. RESULTS: The inhibition rates of tumor growth in the high-dose, middle-dose, and low-dose groups were 29.18%, 17.21%, and 4.27%, respectively. Compared with control and low-dose group, the tumors growth rate in high-dose and middle-dose groups were decreased significantly. Histologically, the tumors were inhibited in the growth rate, the tissue structure was broken. Estrogen in all groups with acridone treatment decreased, the progesterone in high-dose and middle-dose groups increased remarkably. The expression of ABCG2 protein and ABCG2 mRNA decreased after treatment with acridone. CONCLUSIONS: We showed that acridone could induce cell apoptosis, inhibited ABCG2 (ATP-binding cassette sub-family G member 2) protein and adjusted hormone level. The results suggested that acridone could serve as a chemotherapeutic agent for treatment of breast cancer in vivo.
Assuntos
Acridonas/farmacologia , Apoptose/efeitos dos fármacos , Neoplasias da Mama/patologia , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/genética , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/metabolismo , Acridonas/uso terapêutico , Animais , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/metabolismo , Estrogênios/metabolismo , Feminino , Humanos , Células MCF-7 , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Progesterona/metabolismo , RNA Mensageiro/metabolismo , Transplante HeterólogoRESUMO
Acridines/acridones, quinolines/quinolones (chromophores) and their derivatives constitute extremely important family of compounds in current medicine. Great significance of the compounds is connected with antimicrobial and antitumor activities. Combining these features together in one drug seems to be long-term benefit, especially in oncology therapy. The attractiveness of the chromophore drugs is still enhanced by elimination their toxicity and improvement not only selectivity, specificity but also bioavailability. The best results are reached by conjugation to natural peptides. This paper highlights significant advance in the study of amino acid or peptide chromophore conjugates that provide highly encouraging data for novel drug development. The structures and clinical significance of amino acid or peptide chromophore conjugates are widely discussed.
Assuntos
Acridinas/uso terapêutico , Acridonas/uso terapêutico , Anti-Infecciosos/uso terapêutico , Antineoplásicos/uso terapêutico , Quinolinas/uso terapêutico , Quinolonas/uso terapêutico , Acridinas/química , Acridonas/química , Aminoácidos/química , Aminoácidos/uso terapêutico , Animais , Doenças Transmissíveis/tratamento farmacológico , Humanos , Neoplasias/tratamento farmacológico , Peptídeos/química , Peptídeos/uso terapêutico , Quinolinas/química , Quinolonas/química , Resultado do TratamentoRESUMO
Multidrug resistance (MDR) remains a primary hindrance to curative cancer therapy. Thus, introduction of novel strategies to overcome MDR is of paramount therapeutic significance. Sequestration of chemotherapeutics in lysosomes is an established mechanism of drug resistance. Here, we show that MDR cells display a marked increase in lysosome number. We further demonstrate that imidazoacridinones (IAs), which are cytotoxic fluorochromes, undergo a dramatic compartmentalization in lysosomes because of their hydrophobic weak base nature. We hence developed a novel photoactivation-based pharmacological Trojan horse approach to target and eradicate MDR cancer cells based on photo-rupture of IA-loaded lysosomes and tumor cell lysis via formation of reactive oxygen species. Illumination of IA-loaded cells resulted in lysosomal photodestruction and restoration of parental cell drug sensitivity. Lysosomal photodestruction of MDR cells overexpressing the key MDR efflux transporters ABCG2, ABCB1 or ABCC1 resulted in 10- to 52-fold lower IC(50) values of various IAs, thereby restoring parental cell sensitivity. Finally, in vivo application of this photodynamic therapy strategy after i.v. injection of IAs in human ovarian tumor xenografts in the chorioallantoic membrane model revealed selective destruction of tumors and their associated vasculature. These findings identify lysosomal sequestration of IAs as an Achilles heel of MDR cells that can be harnessed to eradicate MDR tumor cells via lysosomal photodestruction.