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1.
Life Sci ; 318: 121492, 2023 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-36775115

RESUMO

AIMS: Grape seed procyanidin extract (GSE), and milk thistle silymarin extract (MTE) contain structurally distinct polyphenols, and each agent has been shown to exert antineoplastic effects against lung cancer. We hypothesize that combinations of GSE and MTE will additively enhance their anticancer effects against lung cancer. MATERIALS AND METHODS: The anti-proliferative effects of GSE, MTE and combinations were evaluated in lung neoplastic cell lines. A dose range finding (DRF) study to determine safety, bioavailability and bioactivity, followed by human lung cancer xenograft efficacy studies were conducted in female nude mice with once daily gavage of leucoselect phytosome (LP), a standardized GSE, and/or siliphos, a standardized MTE. The roles of tumor suppressors miR-663a and its predicted target FHIT in mediating the additive, anti-proliferative effecs of GSE/MTE were also assessed. KEY FINDINGS: GSE with MTE additively inhibited lung preneoplastic and cancer cell proliferations. Mice tolerated all dosing regimens in the DRF study without signs of clinical toxicity nor histologic abnormalities in the lungs, livers and kidneys. Eight weeks of LP and siliphos additively inhibited lung tumor xenograft growth. Plasma GSE/metabolites and MTE/metabolites showed that the combinations did not decrease systemic bioavailabilities of each agent. GSE and MTE additively upregulated miR-663a and FHIT in lung cancer cell lines; transfection of antisense-miR-663a significantly abrogated the anti-proliferative effects of GSE/MTE, upregulation of FHIT mRNA and protein. LP and siliphos also additively increased miR-663a and FHIT protein in lung tumor xenografts. SIGNIFICANCE: Our findings support clinical translations of combinations of GSE and MTE against lung cancer.


Assuntos
Extrato de Sementes de Uva , Neoplasias Pulmonares , MicroRNAs , Proantocianidinas , Silimarina , Vitis , Humanos , Feminino , Animais , Camundongos , Proantocianidinas/farmacologia , Vitis/metabolismo , Silybum marianum , Camundongos Nus , Extrato de Sementes de Uva/farmacologia , Neoplasias Pulmonares/patologia , MicroRNAs/metabolismo
2.
Cancer Prev Res (Phila) ; 12(8): 557-566, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31138523

RESUMO

Grape seed procyanidin extract (GSE) had been reported to exert antineoplastic properties in preclinical studies. A modified phase I, open-label, dose-escalation clinical study was conducted to evaluate the safety, tolerability, MTD, and potential chemopreventive effects of leucoselect phytosome (LP), a standardized GSE complexed with soy phospholipids to enhance bioavailability, in heavy active and former smokers. Eight subjects ages 46-68 years were enrolled into the study and treated with escalating oral doses of LP for 3 months. Bronchoscopies with bronchoalveolar lavage and bronchial biopsies were performed before and after 3 months of LP treatment. Hematoxylin and eosin stain for histopathology grading and IHC examination for Ki-67 proliferative labeling index (Ki-67 LI) were carried out on serially matched bronchial biopsy samples from each subject to determine responses to treatment. Two subjects were withdrawn due to issues unrelated to the study medication, and a total of 6 subjects completed the full study course. In general, 3 months of LP, reaching the highest dose per study protocol was well tolerated and no dosing adjustment was necessary. Such a treatment regimen significantly decreased bronchial Ki-67 LI by an average of 55% (P = 0.041), with concomitant decreases in serum miR-19a, -19b, and -106b, which were oncomirs previously reported to be downregulated by GSE, including LP, in preclinical studies. In spite of not reaching the original enrollment goal of 20, our findings nonetheless support the continued clinical translation of GSE as an antineoplastic and chemopreventive agent against lung cancer.


Assuntos
Antineoplásicos Fitogênicos/administração & dosagem , Biflavonoides/administração & dosagem , Catequina/administração & dosagem , Extrato de Sementes de Uva/administração & dosagem , Neoplasias Pulmonares/prevenção & controle , Proantocianidinas/administração & dosagem , Administração Oral , Idoso , Antineoplásicos Fitogênicos/efeitos adversos , Antineoplásicos Fitogênicos/química , Apoptose , Biflavonoides/efeitos adversos , Biflavonoides/química , Biópsia , Brônquios/diagnóstico por imagem , Brônquios/efeitos dos fármacos , Brônquios/patologia , Broncoscopia , Catequina/efeitos adversos , Catequina/química , Proliferação de Células , Regulação para Baixo/efeitos dos fármacos , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Extrato de Sementes de Uva/efeitos adversos , Extrato de Sementes de Uva/química , Humanos , Antígeno Ki-67/análise , Antígeno Ki-67/metabolismo , Neoplasias Pulmonares/etiologia , Neoplasias Pulmonares/genética , Masculino , MicroRNAs/sangue , MicroRNAs/metabolismo , Pessoa de Meia-Idade , Proantocianidinas/efeitos adversos , Proantocianidinas/química , Fumar/efeitos adversos , Resultado do Tratamento
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