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1.
Front Pharmacol ; 10: 1437, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31849679

RESUMO

The Warburg effect is a peculiar feature of cancer's metabolism, which is an attractive therapeutic target that could aim tumor cells while sparing normal tissue. Matrine is an alkaloid extracted from the herb root of a traditional Chinese medicine, Sophora flavescens Ait. Matrine has been reported to have selective cytotoxicity toward cancer cells but with elusive mechanisms. Here, we reported that matrine was able to reverse the Warburg effect (inhibiting glucose uptake and lactate production) and suppress the growth of human colon cancer cells in vitro and in vivo. Mechanistically, we revealed that matrine significantly decreased the messenger RNA (mRNA) and protein expression of HIF-1α, a critical transcription factor in reprogramming cancer metabolism toward the Warburg effect. As a result, the expression levels of GLUT1, HK2, and LDHA, the downstream targets of HIF-1α in regulating glucose metabolism, were dramatically inhibited by matrine. Moreover, this inhibitory effect of matrine was significantly attenuated when HIF-1α was knocked down or exogenous overexpressed in colon cancer cells. Together, our results revealed that matrine inhibits colon cancer cell growth via suppression of HIF-1α expression and its downstream regulation of Warburg effect. Matrine could be further developed as an antitumor agent targeting the HIF-1α-mediated Warburg effect for colon cancer treatment.

2.
Nanomedicine ; 14(7): 2179-2189, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-30048816

RESUMO

Nanotransducer-mediated photothermal therapy (PTT) has emerged as an attractive therapy modality against cancer, but its efficacy is often limited by the amount of nanoparticles delivered to tumors. Previous studies showed a vasculature modulation treatment, which dilates or prunes tumor blood vessels, may enhance tumor uptake of nanoparticles. However, exploiting these approaches for improved PTT has seldom been studied. In this study, we investigated the impact of mild hyperthermia or anti-angiogenesis therapy on PTT. Briefly, we gave tumor-bearing balb/c mice low doses of sunitinib or submerged tumors in a 42 °C water bath. Next, we injected PEGylated reduced graphene oxide (RGO-PEG) and irradiated the tumors to induce PTT. We then followed up the treatment with multi-parameter MRI. Contrary to expectation, both vessel modulation strategies led to diminished PTT efficacy. Our results show that vessel modulation does not warrant improved PTT, and should be carefully gauged when used in combination with PTT.


Assuntos
Inibidores da Angiogênese/administração & dosagem , Neoplasias da Mama/terapia , Hipertermia Induzida , Imageamento por Ressonância Magnética/métodos , Neovascularização Patológica/terapia , Fototerapia , Sunitinibe/administração & dosagem , Inibidores da Angiogênese/química , Inibidores da Angiogênese/farmacologia , Animais , Apoptose , Neoplasias da Mama/irrigação sanguínea , Neoplasias da Mama/patologia , Proliferação de Células , Terapia Combinada , Feminino , Grafite/química , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Nanopartículas/administração & dosagem , Nanopartículas/química , Neovascularização Patológica/patologia , Sunitinibe/química , Sunitinibe/farmacologia , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto
3.
Pharm Res ; 35(4): 80, 2018 Mar 02.
Artigo em Inglês | MEDLINE | ID: mdl-29500548

RESUMO

PURPOSE: Synthetic oligodeoxynucleotides (ODN) containing unmethylated CpG motifs were found to be able to target cells that express Toll-like receptor 9 to modulate innate and adaptive immune reactions. But their in vivo application in immunotherapy against cancer has not been successful. We attempted in this study to examine polyethylene-glycol (PEG) conjugated CpG ODNs and investigated their mechanism of immune modulation in anti-cancer therapy. METHODS: CpG-PEG conjugates with different PEG lengths were synthesized. In vitro activity as well as in vivo pharmacokinetics and pharmacodynamics properties were evaluated. RESULTS: CpG-PEG20Ks were found to be able to persist longer in circulation and activate various downstream effector cells. After intravenous injection, they resulted in higher levels of IL-12p70 in the circulation and lower M-MDSC infiltrates in the tumor microenvironment. Such activities were different from those of CpG ODNs without PEGylation, suggesting different PK-PD profiles systemically and locally. CONCLUSIONS: Our data support the development of CpG-PEGs as a new therapeutic agent that can be systemically administered to modulate immune responses and the microenvironment in tumor tissues.


Assuntos
Imunidade Adaptativa/efeitos dos fármacos , Composição de Medicamentos/métodos , Neoplasias/tratamento farmacológico , Oligodesoxirribonucleotídeos/farmacologia , Animais , Linhagem Celular Tumoral/transplante , Células Cultivadas , Células Dendríticas , Modelos Animais de Doenças , Avaliação Pré-Clínica de Medicamentos , Feminino , Humanos , Injeções Intravenosas , Interleucina-12/imunologia , Interleucina-12/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Neoplasias/imunologia , Oligodesoxirribonucleotídeos/química , Oligodesoxirribonucleotídeos/uso terapêutico , Ovalbumina/imunologia , Polietilenoglicóis/química , Cultura Primária de Células , Microambiente Tumoral/efeitos dos fármacos , Microambiente Tumoral/imunologia
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