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Br J Pharmacol ; 177(2): 372-387, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31621893


BACKGROUND AND PURPOSE: This study investigates the antifibrotic activities and potential mechanisms of costunolide (COS), a natural sesquiterpene compound. EXPERIMENTAL APPROACH: Rats subjected to bile duct ligation and mice challenged with CCl4 were used to study the antifibrotic effects of COS in vivo. Mouse primary hepatic stellate cells (pHSCs) and human HSC line LX-2 also served as an in vitro liver fibrosis models. The expression of fibrogenic genes and signaling proteins in the neurogenic locus notch homologue protein 3 (Notch3)-hairy/enhancer of split-1 (HES1) pathway was examined using western blot and/or real-time PCR. Notch3 degradation was analysed using immunofluorescence and coimmunoprecipitation. KEY RESULTS: In animals, COS administration attenuated hepatic histopathological injury and collagen accumulation and reduced the expression of fibrogenic genes. COS time- and dose-dependently suppressed the levels of fibrotic markers in LX-2 cells and mouse pHSCs. Mechanistic studies showed COS destabilized Notch3 and subsequently inhibited the Notch3-HES1 pathway, thus inhibiting HSC activation. Furthermore, COS blocked the WW domain-containing protein 2 (WWP2)/protein phosphatase 1G (PPM1G) interaction and enhanced the effect of WWP2 on Notch3 degradation. CONCLUSIONS AND IMPLICATIONS: COS exerted potent antifibrotic effects in vitro and in vivo by disrupting the WWP2/PPM1G complex, promoting Notch3 degradation and inhibiting the Notch3/HES1 pathway. This indicates that COS may be a potential therapeutic candidate for the treatment of liver fibrosis.

Biomed Pharmacother ; 120: 109478, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31568987


Resistance to chemotherapeutic agents is a major cause of treatment failure in patients with oral cancer. Proton pump inhibitors (PPIs), essentially H+-K+-ATPase inhibitors which are currently used in the treatment of acid related diseases, have demonstrated promising antitumor and chemo-sensitizing efficacy. The main purpose of the present study was to investigate whether pantoprazole (PPZ, one of PPIs) could increase the sensitivity of chemoresistant oral epidermoid carcinoma cells (KB/V) to vincristine (VCR) and elucidate the underlying action mechanism. Results showed that combination treatment of PPZ and VCR synergistically inhibited the proliferation of KB/V cells in vitro and in vivo. Furthermore, administration of PPZ and VCR not only induce apoptosis and G2/M phase arrest in KB/V cells but also suppress the migration and invasion of KB/V cells. The mechanism underlying synergistic anti-tumor effect of PPZ and VCR was related to the inhibition of the function and expression of P-glycoprotein (P-gp) and the down-regulation of EGFR/MAPK and PI3K/Akt/mTOR signaling pathways in KB/V cells. Additionally, we observed that PPZ treatment induced an increase in lysosomal pH and inhibited the activity of lysosomal enzyme acid phosphatase in KB/V cells, which could functionally reduce the sequestration of VCR in lysosomes and sensitized KB/V cells to VCR. In conclusion, our study demonstrated that PPZ could be included in new combined therapy of human oral cancer (especially on VCR-resistant therapy) together with VCR.

Chem Biol Interact ; 280: 70-76, 2018 Jan 25.
Artigo em Inglês | MEDLINE | ID: mdl-29223570


Hepatocellular carcinoma (HCC) chemoresistance, which is regarded as a kind of stress management reaction to chemotherapy drugs, severely hinders the therapy outcomes of HCC treatment. Stress management is generally achieved by activating certain signal pathways and chemical factors, among which, nuclear factor-E2-related factor2 (Nrf2) is a key factor in HCC chemoresistance formation. Nrf2 is a nuclear factor that coordinates the induction and expression of a battery of genes encoding cytoprotective proteins when participating in the Nrf2antioxidant response element (Nrf2/ARE) pathway, which is one of the most important intracellular antioxidant stress pathways. This review summarizes the recent understanding of the involvement of Nrf2 in the chemoresistance of liver cancer, its target proteins, expression regulation and potential Nrf2 inhibitors that sensitize chemotherapy drugs in HCC.

Carcinoma Hepatocelular/patologia , Neoplasias Hepáticas/patologia , Fator 2 Relacionado a NF-E2/metabolismo , Transportadores de Cassetes de Ligação de ATP/metabolismo , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/metabolismo , Proteínas Culina/metabolismo , Resistencia a Medicamentos Antineoplásicos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Proteína 1 Associada a ECH Semelhante a Kelch/metabolismo , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/metabolismo , Fator 2 Relacionado a NF-E2/antagonistas & inibidores , Fator 2 Relacionado a NF-E2/genética , Transdução de Sinais/efeitos dos fármacos
Int J Biochem Cell Biol ; 93: 1-11, 2017 12.
Artigo em Inglês | MEDLINE | ID: mdl-29074436


Multidrug resistance (MDR) is one of major obstacles to effective chemotherapeutic treatment of cancer. This study showed that DHPAC, 2-(6-ethoxy-3-(3-ethoxyphenylamino) -1-methyl-1,4-dihydroindeno[1,2-c]pyrazol-7-yloxy) acetamide, a novel compound that binds to the same site on microtubules as colchicine, has high anti-tumour activity in vincristine-resistant oral epidermoid carcinoma (KB/V) cells. It found that the presence of DHPAC strongly inhibited KB/V cell growth in vivo and in mice xenograft. The inhibitory effect of DHPAC is much stronger than that by colchicine in these KB/V cells (IC50: 64.4nM and 458.0nM respectively). Treatment of the cells with DHPAC induced cell apoptosis by reducing mitochondrial membrane potential and altered the expression of several apoptosis-related proteins such as Bcl-2, Bax, Caspase-9, Cytochrome c and PARP. DHPAC treatment also caused cell rest in G2/M phase by regulating of the expression of a number of cell cycle-related proteins (e.g. Cyclin B1, Cdc2, Cdc25b, Cdc25c, RSK2). Furthermore, DHPAC presence inhibits PTEN phosphorylation and PTEN/Akt/NF-κB signalling. Thus, DHPAC has potent anti-cancer activity in MDR tumuors and may be a potential therapeutic agent for the treatment of vincristine-resistant human oral epidermoid carcinoma.

Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Carcinoma de Células Escamosas/tratamento farmacológico , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Neoplasias Bucais/tratamento farmacológico , Moduladores de Tubulina/química , Moduladores de Tubulina/farmacologia , Antineoplásicos/química , Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/patologia , Humanos , Células K562 , Células MCF-7 , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Neoplasias Bucais/metabolismo , Neoplasias Bucais/patologia , Proteínas de Neoplasias/metabolismo , Vincristina
Cancer Chemother Pharmacol ; 80(5): 925-937, 2017 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-28861639


Drug repositioning, as a smart way to exploit new molecular targets of a known drug, has been gaining increasing attention in the discovery of anti-cancer drugs. Proton pump inhibitors (PPIs) as benzimidazole derivatives, which are essentially H+-K+-ATPases inhibitors, are commonly used in the treatment of acid-related diseases such as gastric ulcer. In recent years, exploring the new application of PPIs in anti-cancer field has become a hot research topic. Interestingly, cancer cells display an alkaline intracellular pH and an acidic extracellular pH. The extracellular acidity of tumors can be corrected by PPIs that are selectively activated in an acid milieu. It is generally believed that PPIs might provoke disruption of pH homeostasis by targeting V-ATPase on cancer cells, which is the theoretical basis for PPIs to play an anti-cancer role. Numerous studies have shown specialized effects of the PPIs on tumor cell growth, metastasis, chemoresistance, and autophagy. PPIs may really represent new anti-cancer drugs due to better safety and tolerance, the potential selectivity in targeting tumor acidity, and the ability to inhibit mechanism pivotal for cancer homeostasis. In this review, we focus on the new therapeutic applications of PPIs in multiple cancers, explaining the rationale behind this approach and providing practical evidence.

Antineoplásicos/uso terapêutico , Reposicionamento de Medicamentos/métodos , Neoplasias/tratamento farmacológico , Inibidores da Bomba de Prótons/uso terapêutico , Antineoplásicos/farmacologia , Humanos , Neoplasias/patologia , Inibidores da Bomba de Prótons/farmacologia