RESUMO
Natural products can overcome the limitations of conventional chemotherapy. Acetyl-11-keto-beta-boswellic acid (AKBA) as a natural product extracted from frankincense, exhibited chemotherapeutic activities in different cancers. However, whether AKBA exerts inhibiting effect of oral squamous cell carcinoma (OSCC) cells growth and the mechanism need to be explored. We attempted to investigate the therapeutic effects of AKBA against OSCC and explore the mechanism involved. Here we attempt to disclose the cell-killing effect of AKBA on OSCC cell lines and try to figure out the specifical pathway. The presence of increase autophagosome and the production of mitochondrial reactive oxygen species were confirmed after the application of AKBA on OSCC cells, and RAB7B inhibition enhanced autophagosome accumulation. Though the increase autophagosome was detected induced by AKBA, autophagic flux was inhibited as the failure fusion of autophagosome and lysosome. Cal27 xenografts were established to verify the role of anti-OSCC cells of AKBA in vivo. Based above findings, we speculate that natural product AKBA suppresses OSCC cells growth via RAB7B-mediated autophagy and may serve as a promising strategy for the therapy of OSCC.
Assuntos
Autofagia , Proliferação de Células , Camundongos Nus , Neoplasias Bucais , Triterpenos , Ensaios Antitumorais Modelo de Xenoenxerto , Proteínas rab de Ligação ao GTP , proteínas de unión al GTP Rab7 , Humanos , Autofagia/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Triterpenos/farmacologia , Animais , Proteínas rab de Ligação ao GTP/metabolismo , Neoplasias Bucais/tratamento farmacológico , Neoplasias Bucais/patologia , Neoplasias Bucais/metabolismo , Linhagem Celular Tumoral , Camundongos , Carcinoma de Células Escamosas/tratamento farmacológico , Carcinoma de Células Escamosas/patologia , Carcinoma de Células Escamosas/metabolismo , Camundongos Endogâmicos BALB C , Espécies Reativas de Oxigênio/metabolismoRESUMO
Background and aim: Pediatric high-grade gliomas (pedHGG) comprise a very poor prognosis. Thus, parents of affected children are increasingly resorting to complementary and alternative medicine (CAM), among those Boswellia extracts. However, nothing is known about the therapeutic effectiveness of their active substances, Boswellic acids (BA) in pedHGG. Thus, we aimed to investigate if the three main Boswellic acids (BA) present in Boswellia plants, alpha-boswellic acid (α-BA), beta-boswellic acid (ß-BA) and 3-acetyl-11-keto-beta-boswellic acid (AKBA) hold any promising potential for treatment of affected pedHGG patients. Experimental procedure: Histone 3 (H3)-wildtype and H3.3K27M-mutant pedHGG cell lines were treated with BA, either alone or in combination with radio-chemotherapy with temozolomide. Cell viability, stemness properties, apoptosis, in ovo tumor growth and the transcriptome was investigated upon BA treatment. Results and conclusion: Interestingly, α-BA and ß-BA treatment promoted certain tumor properties in both pedHGG cells. AKBA treatment reduced cell viability and colony growth accompanied by induction of slight anti-inflammatory effects especially in H3.3K27M-mutant pedHGG cells. However, no effects on apoptosis and in ovo tumor growth were found. In conclusion, besides positive anti-tumor effects of AKBA, tumor promoting effects were observed upon treatment with α-BA and ß-BA. Thus, only pure AKBA formulations may be used to exploit any potential positive effects in pedHGG patients. In conclusion, the use of commercially available supplements with a mixture of different BA cannot be recommended due to detrimental effects of certain BA whereas pure AKBA formulations might hold some potential as therapeutic supplement for treatment of pedHGG patients.
RESUMO
Acetyl-11-keto-beta-boswellic acid (AKBA), a potent anti-inflammatory compound purified from Boswellia species, was investigated in a preclinical study for its potential in preventing and treating non-alcoholic fatty liver disease (NAFLD), the most common chronic inflammatory liver disorder. The study involved thirty-six male Wistar rats, equally divided into prevention and treatment groups. In the prevention group, rats were given a high fructose diet (HFrD) and treated with AKBA for 6 weeks, while in the treatment group, rats were fed HFrD for 6 weeks and then given a normal diet with AKBA for 2 weeks. At the end of the study, various parameters were analyzed including liver tissues and serum levels of insulin, leptin, adiponectin, monocyte chemoattractant protein-1 (MCP-1), transforming growth factor beta (TGF-ß), interferon gamma (INF-Ï), interleukin-6 (IL-6), and tumor necrosis factor alpha (TNF-α). Additionally, the expression levels of genes related to the inflammasome complex and peroxisome proliferator-activated receptor gamma (PPAR-Ï), as well as the levels of phosphorylated and non-phosphorylated AMP-activated protein kinase alpha-1 (AMPK-α1) protein, were measured. The results showed that AKBA improved NAFLD-related serum parameters and inflammatory markers and suppressed PPAR-Ï and inflammasome complex-related genes involved in hepatic steatosis in both groups. Additionally, AKBA prevented the reduction of the active and inactive forms of AMPK-α1 in the prevention group, which is a cellular energy regulator that helps suppress NAFLD progression. In conclusion, AKBA has a beneficial effect on preventing and avoiding the progression of NAFLD by preserving lipid metabolism, improving hepatic steatosis, and suppressing liver inflammation.
Assuntos
Hepatopatia Gordurosa não Alcoólica , Ratos , Masculino , Animais , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Hepatopatia Gordurosa não Alcoólica/metabolismo , Proteínas Quinases Ativadas por AMP/metabolismo , Inflamassomos/metabolismo , Frutose/metabolismo , Frutose/farmacologia , Frutose/uso terapêutico , Metabolismo dos Lipídeos , Receptores Ativados por Proliferador de Peroxissomo/metabolismo , Ratos Wistar , Fígado/metabolismo , Dieta , Inflamação/metabolismoRESUMO
Multiple sclerosis (MS) is a severe immune-mediated neurological disease characterized by neuroinflammation, demyelination, and axonal degeneration in the central nervous system (CNS). This is frequently linked to motor abnormalities and cognitive impairments. The pathophysiological hallmarks of MS include inflammatory demyelination, axonal injury, white matter degeneration, and the development of CNS lesions that result in severe neuronal degeneration. Several studies suggested downregulation of nuclear factor erythroid-2-related factor-2 (Nrf2)/Heme oxygenase-1 (HO-1) signaling is a causative factor for MS pathogenesis. Acetyl-11-keto-ß-boswellic acid (AKBA) is an active pentacyclictriterpenoid obtained from Boswellia serrata, possessing antioxidant and anti-inflammatory properties. The present study explores the protective potential of AKBA on behavioral, molecular, neurochemical, and gross pathological abnormalitiesandhistopathological alterations by H&E and LFB staining techniques in an experimental model of multiple sclerosis, emphasizing the increase inNrf2/HO-1 levels in the brain. Moreover, we also examine the effect of AKBA on the intensity of myelin basic protein (MBP) in CSF and rat brain homogenate. Specific apoptotic markers (Bcl-2, Bax, andcaspase-3) were also estimated in rat brain homogenate. Neuro behavioralabnormalities in rats were examined using an actophotometer, rotarod test, beam crossing task (BCT),and Morris water maze (MWM). AKBA 50 mg/kg and 100 mg/kg were given orally from day 8 to 35 to alleviate MS symptoms in the EB-injected rats. Furthermore, cellular, molecular, neurotransmitter, neuroinflammatory cytokine, and oxidative stress markers in rat whole brain homogenate, blood plasma, and cerebral spinal fluid were investigated. This study shows that AKBA upregulates the level of antioxidant proteins such as Nrf2 and HO-1 in the rat brain. AKBA restores altered neurochemical levels, potentially preventing gross pathological abnormalities during MS progression.
Assuntos
Esclerose Múltipla , Fator 2 Relacionado a NF-E2 , Animais , Antioxidantes/farmacologia , Etídio , Heme Oxigenase-1/genética , Modelos Teóricos , Esclerose Múltipla/tratamento farmacológico , Esclerose Múltipla/genética , Fator 2 Relacionado a NF-E2/genética , Fator 2 Relacionado a NF-E2/metabolismo , Neuroproteção , Ratos , TriterpenosRESUMO
BACKGROUND: Boswellia serrate is an ancient and highly valued ayurvedic herb. Its extracts have been used in medicine for centuries to treat a wide variety of chronic inflammatory diseases. However, the mechanism by which B. serrata hydro alcoholic extract inhibited pro-inflammatory cytokines in zebrafish (Danio rerio) larvae with LPS-induced inflammation remained unknown. METHODS: LC-MS analysis was used to investigate the extract's phytochemical components. To determine the toxicity of B. serrata extract, cytotoxicity and embryo toxicity tests were performed. The in-vivo zebrafish larvae model was used to evaluate the antioxidant and anti-inflammatory activity of B. serrata extract. RESULTS: According to an in silico study using molecular docking and ADMET, the compounds acetyl-11-keto-boswellic and 11-keto-beta-boswellic acid present in the extract had higher binding affinity for the inflammatory specific receptor, and it is predicted to be an orally active molecule. In both in-vitro L6 cells and in-vivo zebrafish larvae, 160 µg/mL concentration of extract caused a high rate of lethality. The extract was found to have a protective effect against LPS-induced inflammation at concentrations ranged between 10 and 80 µg/mL. In zebrafish larvae, 80 µg/mL of treatment significantly lowered the level of intracellular ROS, apoptosis, lipid peroxidation, and nitric oxide. Similarly, zebrafish larvae treated with B. serrata extract (80 µg/mL) showed an increased anti-inflammatory activity by lowering inflammatory specific gene expression (iNOS, TNF-α, COX-2, and IL-1). CONCLUSIONS: Overall, our findings suggest that B. serrata can act as a potent redox scavenger against LPS-induced inflammation in zebrafish larvae and an inhibitor of specific inflammatory genes.
Assuntos
Boswellia , Triterpenos , Animais , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/uso terapêutico , Boswellia/química , Citocinas/uso terapêutico , Inflamação/induzido quimicamente , Inflamação/tratamento farmacológico , Larva , Lipopolissacarídeos/toxicidade , Simulação de Acoplamento Molecular , Extratos Vegetais/química , Triterpenos/química , Peixe-ZebraRESUMO
BACKGROUND: Globally, head and neck cancer is the sixth most common cancer. Despite the advancement in treatment, drug resistance remains a major cause for setback. In an earlier work, the authors reported that Boswellia dalzielii (Hutch) stem bark exhibited dose-dependent cytotoxicity in head and neck cancer cells, AW8507. Therefore, the cell death induction effect of Boswellia dalzielii stem bark chloroform extract in head and neck cancer cell line, AW8507, and its derived constituent on cell cycle and apoptosis proteins was further investigated. METHODS: The cell death induction activity of the Boswellia dalzielii stem bark chloroform fraction (CLBD) in AW8507 was determined using Annexin V-FITC/PI staining in flow cytometry. High-performance liquid chromatography-mass spectrometry was employed for compounds analysis of the CLBD, and reverse virtual screening was used to identify the mechanism of action of the compound, acetyl-11-keto-beta-boswellic acid, that was elucidated in the Boswellia dalzielii chloroform fraction. RESULTS: The data obtained showed that Boswellia dalzielii stem bark Chloroform extract increased the percentage of cells presenting for early apoptosis from 4.14 to 10.10% in AW8507 cells. High-performance liquid chromatography-mass spectrometry analysis of the chloroform fraction identified acetyl-11-keto-beta-boswellic acid. Reverse virtual screening on selected proteins showed that acetyl-11-keto-beta-boswellic acid is a multi-protein target compound. It binds preferably to phosphorylated-cyclin dependent kinase 1 (p-CDK1) (binding score = - 9.2 kcal/mol), blocking the activation of cyclin B-CDK1 needed for cell cycle progression at G2/M phase of the cell cycle. Acetyl-11-keto-beta-boswellic acid also binds more tightly with αß tubulin (binding score = 8.9 kcal/mol) than with the standard drug, docetaxel (binding score = 8.3 kcal/mol). CONCLUSIONS: The results obtained confirmed the culpability of Boswellia dalzielii-derived acetyl-11-keto-beta-boswellic acid in the obstruction of the cell cycle progression in head and neck cancer cell line, AW8507; and the induction of apoptosis earlier reported for Boswellia dalzielii (Hutch) stem bark. Additional in vitro and/or in vivo studies would be required to validate in silico observations.
Assuntos
Boswellia , Apoptose , Ciclo Celular , Divisão Celular , Clorofórmio , Humanos , Casca de Planta , Extratos Vegetais/farmacologia , TriterpenosRESUMO
OBJECTIVE: Recurrence of ovarian cancer is mainly due to multidrug resistance (MDR). 3-acetyl-11-keto-beta-boswellic acid (AKBA) could reverse the multidrug resistance in human ileocecal adenocarcinoma cells, but whether AKBA could modulate acquired MDR in ovarian cancer needs to be elucidated. METHODS: The current study examined the effect of AKBA on ovarian cancer MDR using a Taxol resistant human ovarian cancer cell line A2780/Taxol. Cell proliferation, migration and invasion, the intracellular accumulation of Rhodamine 123 and expression of MDR proteins were studiedin vitro. Furthermore, the effect of AKBA on oncogenicity of A2780/Taxol cells in nude mice xenograft model was studied. RESULTS: The results showed that apart from its cytostatic and apoptosis-induction effect, AKBA could restrain A2780/Taxol cell migration and invasion. In addition, AKBA improved the sensitivity of A2780/Taxol cells to Taxol apparently, and the reversal of MDR by AKBA was evident by increasing intracellular Rhodamine 123 in cells. Furthermore, the anti-cancer potential of AKBA was evidenced as that AKBA treatment significantly slowed tumor growth and decreased the expression of P-gp, LRP, BCRP and MRP. CONCLUSION: Above results indicated that AKBA might be a potential compound to reverse MDR in human ovarian cancer.
Assuntos
Subfamília B de Transportador de Cassetes de Ligação de ATP/metabolismo , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/metabolismo , Paclitaxel/uso terapêutico , Triterpenos/farmacologia , Animais , Apoptose/efeitos dos fármacos , Carcinogênese/efeitos dos fármacos , Carcinogênese/metabolismo , Carcinogênese/patologia , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Regulação para Baixo/efeitos dos fármacos , Feminino , Humanos , Camundongos Endogâmicos BALB C , Camundongos Nus , Invasividade Neoplásica , Neoplasias Ovarianas/patologia , Triterpenos/químicaRESUMO
Boswellia serrata and Boswellia sacra (syn. B. carteri) are important medicinal plants widely used for their content of bioactive lipophilic triterpenes. The qualitative and quantitative determination of boswellic acids (BAs) is important for their use in dietary supplements aimed to provide a support for osteoarthritic and inflammatory diseases. We used High Performance Liquid Chromatography (HPLC)-Diode Array Detector (DAD) coupled to ElectroSpray Ionization and tandem Mass Spectrometry (ESI-MS/MS) for the qualitative and quantitative determination of BAs extracted from the gum resins of B. sacra and B. serrata. Limit of detection (LOD), limit of quantification (LOQ), and Matrix Effect were assessed in order to validate quantitative data. Here we show that the BAs quantitative determination was 491.20 g·kg-1 d. wt (49%) in B. sacra and 295.25 g·kg-1 d. wt (30%) in B. serrata. Lower percentages of BAs content were obtained when BAs were expressed on the gum resin weight (29% and 16% for B. sacra and B. serrata, respectively). The content of Acetyl-11-Keto-ß-Boswellic Acid (AKBA) was higher in B. sacra (70.81 g·kg-1 d. wt; 7%) than in B. serrata (7.35 g·kg-1 d. wt; 0.7%). Our results show that any claim of BAs content in either B. sacra or B. serrata gum resins equal to or higher than 70% or AKBA contents of 30% are simply unrealistic or based on a wrong quantitative determination.
Assuntos
Boswellia/química , Triterpenos/análise , Triterpenos/isolamento & purificação , Boswellia/classificação , Cromatografia Líquida de Alta Pressão , Limite de Detecção , Estrutura Molecular , Extratos Vegetais/análise , Espectrometria de Massas por Ionização por Electrospray , Espectrometria de Massas em Tandem , Triterpenos/químicaRESUMO
OBJECTIVES: To evaluate the effect of ritonavir (RTV) co-administration on the bioavailability of an amorphous dispersion of acetyl-11-keto-beta-boswellic acid (AKBA) and to develop a pharmaceutically acceptable AKBA-RTV combination tablet. METHODS: A pharmacokinetic (PK) study in rats was conducted to evaluate the influence of RTV co-administration on the oral bioavailability of an AKBA amorphous dispersion. KinetiSol was utilized to enable production of an improved RTV formulation that facilitated the development of an AKBA-RTV combination tablet. Following in-vitro characterization, the PK performance of the tablets was evaluated in male beagles. KEY FINDINGS: Co-administration of RTV increased oral absorption of AKBA by about fourfold over the AKBA dispersion alone and approximately 24-fold over the pure compound. The improved RTV amorphous dispersion exhibited similar purity and neutral-phase dissolution to Norvir. The AKBA-RTV combination tablets yielded a substantial increase in AKBA's bioavailability in dogs. CONCLUSIONS: Oral absorption of AKBA is substantially limited by intestinal CYP3A activity and poor aqueous solubility. Consequently, AKBA's oral bioavailability is maximized by administration from a supersaturating formulation in conjunction with a CYP3A inhibitor. The AKBA-RTV combination tablet presented herein represents a breakthrough in the oral delivery of the compound facilitating future use as a drug therapy for broad spectrum cancer treatment.
Assuntos
Antineoplásicos Fitogênicos/farmacocinética , Inibidores do Citocromo P-450 CYP3A/farmacocinética , Citocromo P-450 CYP3A/metabolismo , Intestinos/efeitos dos fármacos , Ritonavir/farmacocinética , Triterpenos/farmacocinética , Administração Oral , Animais , Antineoplásicos Fitogênicos/administração & dosagem , Antineoplásicos Fitogênicos/química , Disponibilidade Biológica , Biotransformação , Inibidores do Citocromo P-450 CYP3A/administração & dosagem , Inibidores do Citocromo P-450 CYP3A/química , Cães , Combinação de Medicamentos , Composição de Medicamentos , Intestinos/enzimologia , Masculino , Ritonavir/administração & dosagem , Ritonavir/química , Comprimidos , Tecnologia Farmacêutica/métodos , Triterpenos/administração & dosagem , Triterpenos/químicaRESUMO
BACKGROUND: Acetyl-11-keto-beta-boswellic acid (AKBA) is a derivative of boswellic acid. We have previously reported that AKBA can reduce the number and size of colonic adenomatous polyps in the APC(Min/+) mouse model. In this study, we evaluated the effect of AKBA on human colonic adenocarcinoma growth. Its efficacy and toxicity were compared with those of the non-steroidal anti-inflammatory drug aspirin. METHODS: The inhibition of cancer cell growth was estimated by colorimetric and clonogenic assay. Cell cycle distribution was analyzed by the flow cytometry assay. Annexin V-FITC/PI staining and JC-1 fluorescence probe assays were performed to determine the apoptotic cells. Further experiment was carried out in mice with HT-29 xenografts. AKBA was orally administered for 24days. The HT-29 xenografts were removed for TUNEL staining and western blotting analysis. Blood was obtained for clinical chemical analysis, and samples of organs were sectioned for microscopic assessment. RESULTS: AKBA significantly inhibited human colon adenocarcinoma growth, showing arrest of the cell cycle in G1-phase and induction of apoptosis. AKBA administration in mice effectively delayed the growth of HT-29 xenografts without signs of toxicity. The activity of AKBA was more potent than that of aspirin. Western blotting suggested that this activity may arise from its multiple effects on the activation of apoptotic proteins, suppression of inflammatory cytokines and modulation of EGFR and ATM/P53 signaling pathways in the HT-29 xenografts. CONCLUSIONS: AKBA prevents the growth of colonic adenocarcinoma through modulation of multiple signaling pathways. GENERAL SIGNIFICANCE: AKBA could be a promising agent in the prevention of colonic adenocarcinomas.