RESUMO
The anti-leukemia mechanisms of Morinda citrifolia L. leaf extract were investigated on human Jurkat leukemia cells and in leukemia-induced BALB/c mice. The leukemia-induced mice were fed daily with the extract (100 or 200 mg/kg BW) and compared to ATRA (All-trans-retinoic-acid; 5 mg/kg BW). After 4 weeks' treatment, the extract (standardized to epicatechin and scopoletin), arrested Jurkat cell-cycle at the G0/G1 phase and activated the caspase-3 and caspase-8 (death-receptor extrinsic pathways). The extract dose-dependently reduced the blood and bone marrow myeloblasts levels of leukemia-induced mice; upregulated cancer suppressor genes CSF3, SOCS1, PTEN and TRP53; increased anti-inflammatory IL10 and IL4; downregulated anti-apoptotic or proliferation genes; decreased the pro-inflammatory NF-κß; suppressed pro-angiogenesis VEGFA mRNA expressions, and restored the homeostatic immune or leukocytes levels. The extract directly ameliorated leukemia via cancer cells apoptosis, suppressed inflammation and angiogenesis; and mitigated bone marrow myeloblasts imbalance, without any observable toxicity on the animals. PRACTICAL APPLICATIONS: The scopoletin (coumarin) and epicatechin (flavonoid)-rich Morinda citrifolia (Noni) leaves may be used as functional food ingredient, vegetables, or dietary supplements to treat and suppress leukemia progression by directly killing the cancer cells and preventing new cancer cells development and bone marrow myeloblast imbalance in the bone marrow, without being toxic to normal cells. The M. citrifolia leaf extract suppressed inflammation, and potential metastasis by inhibiting new cancer-related blood vessel formation.
Assuntos
Inibidores da Angiogênese/administração & dosagem , Anti-Inflamatórios/administração & dosagem , Catequina/administração & dosagem , Medicamentos de Ervas Chinesas/administração & dosagem , Leucemia/tratamento farmacológico , Morinda/química , Escopoletina/administração & dosagem , Animais , Apoptose/efeitos dos fármacos , Humanos , Interleucina-10/genética , Interleucina-10/imunologia , Interleucina-4/genética , Interleucina-4/imunologia , Leucemia/genética , Leucemia/imunologia , Leucemia/fisiopatologia , Masculino , Camundongos , Camundongos Endogâmicos BALB CRESUMO
Drug resistance and the severe side effects of chemotherapy necessitate the development of novel anticancer drugs. Natural products are a valuable source for drug development. Scopoletin is a coumarin compound, which can be found in several Artemisia species and other plant genera. Microarray-based RNA expression profiling of the NCI cell line panel showed that cellular response of scopoletin did not correlate to the expression of ATP-binding cassette (ABC) transporters as classical drug resistance mechanisms (ABCB1, ABCB5, ABCC1, ABCG2). This was also true for the expression of the oncogene EGFR and the mutational status of the tumor suppressor gene, TP53. However, mutations in the RAS oncogenes and the slow proliferative activity in terms of cell doubling times significantly correlated with scopoletin resistance. COMPARE and hierarchical cluster analyses of transcriptome-wide mRNA expression resulted in a set of 40 genes, which all harbored binding motifs in their promoter sequences for the transcription factor, NF-κB, which is known to be associated with drug resistance. RAS mutations, slow proliferative activity, and NF-κB may hamper its effectiveness. By in silico molecular docking studies, we found that scopoletin bound to NF-κB and its regulator IκB. Scopoletin activated NF-κB in a SEAP-driven NF-κB reporter cell line, indicating that NF-κB might be a resistance factor for scopoletin. In conclusion, scopoletin might serve as lead compound for drug development because of its favorable activity against tumor cells with ABC-transporter expression, although NF-κB activation may be considered as resistance factor for this compound. Further investigations are warranted to explore the full therapeutic potential of this natural product.
Assuntos
Resistencia a Medicamentos Antineoplásicos/genética , NF-kappa B/biossíntese , Neoplasias/tratamento farmacológico , Extratos Vegetais/administração & dosagem , Escopoletina/administração & dosagem , Transportadores de Cassetes de Ligação de ATP/biossíntese , Transportadores de Cassetes de Ligação de ATP/genética , Artemisia/química , Linhagem Celular Tumoral , Resistência a Múltiplos Medicamentos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Simulação de Acoplamento Molecular , NF-kappa B/genética , Neoplasias/genética , Farmacogenética , Extratos Vegetais/química , Análise Serial de Proteínas , Escopoletina/química , Transdução de Sinais/efeitos dos fármacos , Fator de Transcrição RelA/biossínteseRESUMO
Scopoletin is the main constituent of coumarin found in the stems of Erycibe obtusifolia Benth, a traditional Chinese medicine used in the treatment of rheumatoid arthritis. We have previously demonstrated that scopoletin is able to decrease the serum level of uric acid in hyperuricemic mice induced by potassium oxonate, and attenuate croton oil-induced inflammation. In the present study, we evaluated the anti-arthritic effects of scopoletin in rat adjuvant-induced arthritis by assessing paw swelling, pathology, and synovial angiogenesis. It was found that scopoletin, injected intraperitoneally at doses of 50, 100 mg/kg, reduced both inoculated and non-inoculated paw swelling as well as articular index scores, and elevated the mean body weight of adjuvant-induced arthritic rats. Rats treated with higher dose of scopoletin showed a near-normal histological architecture of the joints and a reduced new blood vessel formation in the synovial tissues. Furthermore, scopoletin downregulated the overexpression of vascular endothelial growth factor, basic fibroblast growth factor and interleukin 6 in the synovial tissues of adjuvant-induced arthritic rats. In conclusion, scopoletin is capable of ameliorating clinical symptoms of rat adjuvant-induced arthritis, by reducing numbers of new blood vessels in the synovium and the production of important endogenous angiogenic inducers. Therefore, this compound may be a potential agent for angiogenesis-related diseases and could serve as a structural base for screening more potent synthetic analogs.
Assuntos
Inibidores da Angiogênese/uso terapêutico , Artrite Experimental/tratamento farmacológico , Convolvulaceae/química , Neovascularização Patológica/prevenção & controle , Escopoletina/uso terapêutico , Membrana Sinovial/efeitos dos fármacos , Inibidores da Angiogênese/administração & dosagem , Inibidores da Angiogênese/isolamento & purificação , Animais , Artrite Experimental/patologia , Imuno-Histoquímica , Masculino , Estrutura Molecular , Neovascularização Patológica/metabolismo , Caules de Planta/química , Ratos , Ratos Sprague-Dawley , Escopoletina/administração & dosagem , Escopoletina/isolamento & purificação , Membrana Sinovial/irrigação sanguínea , Membrana Sinovial/metabolismo , Membrana Sinovial/patologiaRESUMO
ABSTRACT. The purpose of this study was to determine a maximum tolerated dose of noni in cancer patients and whether an optimal quality of life-sustaining dose could be identified as an alternative way to select a dose for subsequent Phase II efficacy trials. Dose levels started at two capsules twice daily (2 g), the suggested dose for the marketed product, and were escalated by 2 g daily in cohorts of at least five patients until a maximum tolerated dose was found. Patients completed subscales of the European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30 quality of life (physical functioning, pain, and fatigue) the brief fatigue inventory (BFI), questionnaires at baseline and at approximately 4-week intervals. Blood and urine were collected at baseline and at approximately 4-week intervals for measurement of scopoletin. Fifty-one patients were enrolled at seven dose levels. The maximum tolerated dose was six capsules four times daily (12 g). Although no dose-limiting toxicity was found, seven of eight patients at the next level (14 g), withdrew due to the challenges of ingesting so many capsules. There were dose-related differences in self-reported physical functioning and pain and fatigue control. Overall, patients taking three or four capsules four times daily experienced better outcomes than patients taking lower or higher doses. Blood and urinary scopoletin concentrations related to noni dose. We concluded that it is feasible to use quality of life measures to select a Phase II dose. Three or four capsules four times daily (6-8 g) is recommended when controlling fatigue, pain, and maintaining physical function are the efficacies of interest. Scopoletin, a bioactive component of noni fruit extract, is measurable in blood and urine following noni ingestion and can be used to study the pharmacokinetics of noni in cancer patients.
Assuntos
Atividades Cotidianas , Ensaios Clínicos Fase II como Assunto , Morinda/química , Neoplasias/complicações , Fitoterapia , Escopoletina/administração & dosagem , Relação Dose-Resposta a Droga , Fadiga/prevenção & controle , Humanos , Neoplasias/tratamento farmacológico , Dor/prevenção & controle , Manejo da Dor , Extratos Vegetais/administração & dosagem , Extratos Vegetais/uso terapêutico , Qualidade de Vida , Escopoletina/metabolismo , Escopoletina/uso terapêutico , Índice de Gravidade de Doença , Inquéritos e QuestionáriosRESUMO
Scopoletin (1-50 microg/ml) inhibited the release of PGE2, TNF-alpha, IL-1beta and IL-6 and suppressed the expression of COX-2 in a concentration-dependent manner. These results suggest that scopoletin might suppress the production of such pro-inflammatory cytokines and exert inhibitory activity on LPS-induced PGE2 production through the depression of COX-2 expression.