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J Exp Clin Cancer Res ; 37(1): 151, 2018 Jul 13.
Artigo em Inglês | MEDLINE | ID: mdl-30005681


BACKGROUND: Colorectal cancer (CRC) is one of the most prevalent malignancies in the world and developed drug resistance has represented one of the most challenging tasks for management. The current therapeutic regimens may select and enrich cancer stem-like cells (CSCs) resulting in the increased resistance against treatment, metastatic potential and mortality. Regorafenib is a multi-kinase inhibitor, an FDA-approved last-of-line treatment for patients with chemo-refractory metastatic CRC. However, regorafenib's potential effects on CSCs have not been fully elucidated. METHODS: Here, we developed two 5-FU resistant CRC cell lines, HCT-116R and DLD-1R and showed the increased CSCs characteristics such as increased side-population cells, tumor sphere formation and expression of stemness markers. These cell lines and CSCs properties were used for evaluating the potential of regorafenib in suppressing CSCs. RESULTS: We showed that regorafenib treatment decreased the stemness phenotypes including tumor sphere formation, and side-population, of both HCT-116R and DLD-1R cells. Additionally, regorafenib suppressed the cell viability in both cell lines synergistically with 5-FU. In vivo, the combination of regorafenib and 5-FU significantly suppressed the tumorigenesis and stemness markers of 5-FU resistant DLD-1R. Mechanistically, regorafenib-mediated effects were associated with the induction of tumor suppressor miR-34a and suppression of WNT/ß-catenin signaling. Our findings demonstrated that regorafenib treatment was associated with the increased level of miR-34a, resulting in reversing drug resistance and cancer-initiating cell phenotypes by degrading WNT/ß-catenin in CRC. CONCLUSION: Regorafenib might be a potential drug for colon cancer stem-like cells and it should be investigated in future clinical trials.

Neoplasias do Colo/tratamento farmacológico , Neoplasias do Colo/genética , MicroRNAs/metabolismo , Células-Tronco Neoplásicas/metabolismo , Compostos de Fenilureia/uso terapêutico , Piridinas/uso terapêutico , Carcinogênese , Linhagem Celular Tumoral , Resistencia a Medicamentos Antineoplásicos , Humanos , Compostos de Fenilureia/farmacologia , Piridinas/farmacologia , Transdução de Sinais
Sci Rep ; 8(1): 1621, 2018 01 26.
Artigo em Inglês | MEDLINE | ID: mdl-29374219


Trichostatin A (TSA) possess histone deacetylase (HDAC) inhibitory potential, can reverse the deactivation of tumor suppressor genes and inhibit tumor cell proliferation. We evaluated the effect of TSA on HDAC expression, tumor cell proliferation, and cancer stem cells (CSCs) activities in pancreatic ductal adenocarnoma (PDAC) cells. The PDAC cell lines MiaPaCa-2 and PANC-1 were distinctly sensitive to TSA, with enhanced apoptosis, compared to SAHA. TSA or SAHA inhibited vimentin, HDACs 1, 7 and 8, upregulated E-cadherin mRNA and protein levels in the PDAC cells, and time-dependently downregulated Oct-4, Sox-2, and Nanog, as well as inhibited PDAC tumorsphere formation. TSA also induces accumulation of acetylated histones, while increasing histone 3 lysine 4 or 9 dimethylation levels in PDAC cells and enhancing the epigenetic activity of SAHA. The anti-CSCs effect of TSA was like that obtained by silencing HDAC-1 or 7 using siRNA, and enhances Gemcitabine activity. Our study highlights the molecular targetability of HDACs 1, 7, and 8, confirm their PDAC-CSCs maintaining role, and demonstrate that compared to SAHA, TSA modulates the epigenetically- mediated oncogenic activity of PDAC-CSCs, and potentiate Gemcitabine therapeutic activity, making a case for further exploration of TSA activity alone or in combination with Gemcitabine in PDAC therapy.

Antimetabólitos Antineoplásicos/metabolismo , Desoxicitidina/análogos & derivados , Inibidores de Histona Desacetilases/metabolismo , Histona Desacetilases/metabolismo , Ácidos Hidroxâmicos/metabolismo , Células-Tronco Neoplásicas/efeitos dos fármacos , Neoplasias Pancreáticas/patologia , Apoptose , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Desoxicitidina/metabolismo , Humanos , Células-Tronco Neoplásicas/fisiologia
Phytochemistry ; 145: 40-47, 2018 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-29080411


Six previously undescribed diterpenoids, named euphorantins S-T and euphorneroids A-D, including ingol and ent-atisane types, along with eleven known diterpenoids, were isolated from Euphorbia neriifolia. Their structures were elucidated on the basis of extensive NMR analysis and high resolution mass spectrometry. Euphorneroid D and ent-3-oxoatisan-16α,17-acetonide exhibited moderate anti-HIV-1 activities, with EC50 values of 34 µM (SI = 2.3) and 24 µM (SI = 1.9), respectively.

Fármacos Anti-HIV/farmacologia , Diterpenos/farmacologia , Euphorbia/química , HIV-1/efeitos dos fármacos , Casca de Planta/química , Caules de Planta/química , Fármacos Anti-HIV/química , Fármacos Anti-HIV/isolamento & purificação , Linhagem Celular , Diterpenos/química , Diterpenos/isolamento & purificação , Relação Dose-Resposta a Droga , Humanos , Testes de Sensibilidade Microbiana , Estrutura Molecular , Relação Estrutura-Atividade
Planta Med ; 83(17): 1368-1373, 2017 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-28662527


Three new compounds (1 - 3), including a sesterterpenoid, aspterpenacid C (1), with an unusual 5/3/7/6/5 pentacyclic skeleton, together with seven known ones (4 - 10), were isolated from the ethanol extract of the traditional Chinese medicinal plant Swertia bimaculata. Their structures were elucidated on the basis of the methods of spectroscopic NMR, MS, and computational chemistry. The structure of 1 was further confirmed by single-crystal X-ray diffraction analysis. Compounds 1 - 10 were tested for activities on the inhibition of nitric oxide production and HIV-1 replication in vitro. Compound 1 exhibited moderate activity in inhibiting nitric oxide production (IC50 = 16.1 µM) and HIV-1 replication (EC50 = 1.35 µM).

Fármacos Anti-HIV/isolamento & purificação , Fármacos Anti-HIV/farmacologia , Anti-Inflamatórios/isolamento & purificação , Anti-Inflamatórios/farmacologia , Medicamentos de Ervas Chinesas/farmacologia , HIV-1/efeitos dos fármacos , Swertia/química , Animais , Fármacos Anti-HIV/química , Anti-Inflamatórios/química , China , Medicamentos de Ervas Chinesas/química , Camundongos , Estrutura Molecular , Óxido Nítrico/antagonistas & inibidores , Células RAW 264.7 , Replicação Viral/efeitos dos fármacos