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1.
Redox Biol ; 11: 254-262, 2017 04.
Artigo em Inglês | MEDLINE | ID: mdl-28012440

RESUMO

Artesunate, an anti-malarial drug, has been repurposed as an anticancer drug due to its induction of cell death via reactive oxygen species (ROS) production. However, the molecular mechanisms regulating cancer cell death and the resistance of cells to artesunate remain unclear. We investigated the molecular mechanisms behind the antitumor effects of artesunate and an approach to overcome artesunate resistance in head and neck cancer (HNC). The effects of artesunate and trigonelline were tested in different HNC cell lines, including three cisplatin-resistant HNC cell lines. The effects of these drugs as well as the inhibition of Keap1, Nrf2, and HO-1 were assessed by cell viability, cell death, glutathione (GSH) and ROS production, protein expression, and mouse tumor xenograft models. Artesunate selectively killed HNC cells but not normal cells. The artesunate sensitivity was relatively low in cisplatin-resistant HNC cells. Artesunate induced ferroptosis in HNC cells by decreasing cellular GSH levels and increasing lipid ROS levels. This effect was blocked by co-incubation with ferrostatin-1 and a trolox pretreatment. Artesunate activated the Nrf2-antioxidant response element (ARE) pathway in HNC cells, which contributed to ferroptosis resistance. The silencing of Keap1, a negative regulator of Nrf2, decreased artesunate sensitivity in HNC cells. Nrf2 genetic silencing or trigonelline reversed the ferroptosis resistance of Keap1-silenced and cisplatin-resistant HNC cells to artesunate in vitro and in vivo. Nrf2-ARE pathway activation contributes to the artesunate resistance of HNC cells, and inhibition of this pathway abolishes ferroptosis-resistant HNC. CONDENSED ABSTRACT: Our results show the effectiveness and molecular mechanism of artesunate treatment on head and neck cancer (HNC). Artesunate selectively killed HNC cells but not normal cells by inducing an iron-dependent, ROS-accumulated ferroptosis. However, this effect may be suboptimal in some cisplatin-resistant HNCs because of Nrf2-antioxidant response element (ARE) pathway activation. Inhibition of the Nrf2-ARE pathway increased artesunate sensitivity and reversed the ferroptosis resistance in resistant HNC cells.


Assuntos
Alcaloides/farmacologia , Antineoplásicos/farmacologia , Artemisininas/farmacologia , Regulação Neoplásica da Expressão Gênica , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Fator 2 Relacionado a NF-E2/antagonistas & inibidores , Animais , Antimaláricos/farmacologia , Apoptose , Artemisininas/antagonistas & inibidores , Artesunato , Cromanos/farmacologia , Cisplatino/farmacologia , Cicloexilaminas/farmacologia , Reposicionamento de Medicamentos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/genética , Neoplasias de Cabeça e Pescoço/genética , Neoplasias de Cabeça e Pescoço/metabolismo , Neoplasias de Cabeça e Pescoço/patologia , Heme Oxigenase-1/genética , Heme Oxigenase-1/metabolismo , Humanos , Ferro/metabolismo , Proteína 1 Associada a ECH Semelhante a Kelch/genética , Proteína 1 Associada a ECH Semelhante a Kelch/metabolismo , Masculino , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Fator 2 Relacionado a NF-E2/genética , Fator 2 Relacionado a NF-E2/metabolismo , Fenilenodiaminas/farmacologia , Espécies Reativas de Oxigênio/agonistas , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais , Ensaios Antitumorais Modelo de Xenoenxerto
2.
PLoS One ; 10(3): e0120426, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25799586

RESUMO

Despite recent advances in the therapy of non-small cell lung cancer (NSCLC), the chemotherapy efficacy against NSCLC is still unsatisfactory. Previous studies show the herbal antimalarial drug dihydroartemisinin (DHA) displays cytotoxic to multiple human tumors. Here, we showed that DHA decreased cell viability and colony formation, induced apoptosis in A549 and PC-9 cells. Additionally, we first revealed DHA inhibited glucose uptake in NSCLC cells. Moreover, glycolytic metabolism was attenuated by DHA, including inhibition of ATP and lactate production. Consequently, we demonstrated that the phosphorylated forms of both S6 ribosomal protein and mechanistic target of rapamycin (mTOR), and GLUT1 levels were abrogated by DHA treatment in NSCLC cells. Furthermore, the upregulation of mTOR activation by high expressed Rheb increased the level of glycolytic metabolism and cell viability inhibited by DHA. These results suggested that DHA-suppressed glycolytic metabolism might be associated with mTOR activation and GLUT1 expression. Besides, we showed GLUT1 overexpression significantly attenuated DHA-triggered NSCLC cells apoptosis. Notably, DHA synergized with 2-Deoxy-D-glucose (2DG, a glycolysis inhibitor) to reduce cell viability and increase cell apoptosis in A549 and PC-9 cells. However, the combination of the two compounds displayed minimal toxicity to WI-38 cells, a normal lung fibroblast cell line. More importantly, 2DG synergistically potentiated DHA-induced activation of caspase-9, -8 and -3, as well as the levels of both cytochrome c and AIF of cytoplasm. However, 2DG failed to increase the reactive oxygen species (ROS) levels elicited by DHA. Overall, the data shown above indicated DHA plus 2DG induced apoptosis was involved in both extrinsic and intrinsic apoptosis pathways in NSCLC cells.


Assuntos
Apoptose/efeitos dos fármacos , Artemisininas/farmacologia , Carcinoma Pulmonar de Células não Pequenas/patologia , Glucose/metabolismo , Glicólise/efeitos dos fármacos , Neoplasias Pulmonares/patologia , Trifosfato de Adenosina/biossíntese , Artemisininas/antagonistas & inibidores , Transporte Biológico/efeitos dos fármacos , Caspase 8/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Desoxiglucose/farmacologia , Sinergismo Farmacológico , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Glucose/farmacologia , Transportador de Glucose Tipo 1/metabolismo , Humanos , Transdução de Sinais/efeitos dos fármacos , Serina-Treonina Quinases TOR/metabolismo
3.
PLoS One ; 8(12): e81783, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-24349127

RESUMO

We reported previously that Artemisinin (ART), a widely used anti-malarial drug, is an inhibitor of in vitro HCV subgenomic replicon replication. We here demonstrate that ART exerts its antiviral activity also in hepatoma cells infected with full length infectious HCV JFH-1. We identified a number of ART analogues that are up to 10-fold more potent and selective as in vitro inhibitors of HCV replication than ART. The iron donor Hemin only marginally potentiates the anti-HCV activity of ART in HCV-infected cultures. Carbon-centered radicals have been shown to be critical for the anti-malarial activity of ART. We demonstrate that carbon-centered radicals-trapping (the so-called TEMPO) compounds only marginally affect the anti-HCV activity of ART. This provides evidence that carbon-centered radicals are not the main effectors of the anti-HCV activity of the Artemisinin. ART and analogues may possibly exert their anti-HCV activity by the induction of reactive oxygen species (ROS). The combined anti-HCV activity of ART or its analogues with L-N-Acetylcysteine (L-NAC) [a molecule that inhibits ROS generation] was studied. L-NAC significantly reduced the in vitro anti-HCV activity of ART and derivatives. Taken together, the in vitro anti-HCV activity of ART and analogues can, at least in part, be explained by the induction of ROS; carbon-centered radicals may not be important in the anti-HCV effect of these molecules.


Assuntos
Antivirais/farmacologia , Artemisininas/farmacologia , Hepacivirus/efeitos dos fármacos , RNA Viral/antagonistas & inibidores , Replicação Viral/efeitos dos fármacos , Acetilcisteína/farmacologia , Antimaláricos/farmacologia , Antioxidantes/farmacologia , Artemisininas/antagonistas & inibidores , Linhagem Celular Tumoral , Óxidos N-Cíclicos/farmacologia , Reposicionamento de Medicamentos , Hemina/farmacologia , Hepacivirus/crescimento & desenvolvimento , Hepacivirus/metabolismo , Hepatócitos/efeitos dos fármacos , Hepatócitos/virologia , Humanos , RNA Viral/metabolismo , Espécies Reativas de Oxigênio/antagonistas & inibidores , Espécies Reativas de Oxigênio/metabolismo , Relação Estrutura-Atividade
4.
Zhongguo Zhong Yao Za Zhi ; 38(19): 3363-7, 2013 Oct.
Artigo em Chinês | MEDLINE | ID: mdl-24422409

RESUMO

OBJECTIVE: The study aimed to develop the assay of chrysosplenetin (CHR), a metabolic inhibitor of artemisinin by UPLC-MS/MS in rat plasma and investigate the pharmacokinetics parameters of CHR. METHOD: The plasma samples were precipitated by acetonitrile to remove the proteins. Separation was carried out on a Shim-pack XR-ODS C,18(2. 0 mm x 100 mm, 2. 2 micromp.m) column using a mobile phase containing methanol-0. 1% formic acid (87:13) using by diazepam as internal standard. Mass spectrometer with electrospray ionization (ESI) operated in the positive ion mode was used for analysis. Total analysis time was 2 min. RESULT: The assay was linear in the range 5-5 000 microg L-1 (r =0. 999 3) with recoveries in the range from 69. 0% to 81.2% and satisfied inter-, intra- precision and accuracy. CHR after oral administration is not easy to absorb with double or multimodal peak phenomenon. The t1/2 of CHR after intravenous injection was very short and that of low, medium, and high dosage was (17. 01 +/- 8. 06) , (24. 62 +/- 4. 59), (28. 46+/- 4. 63) min, respectively. CONCLUSION: The developed method was special, rapid, and sensitive for determination of CHR pharmacokinetics. [Key words] UPLC-MS/MS; chrysosplenetin; pharmacokinetics; plasma; rat


Assuntos
Artemisininas/antagonistas & inibidores , Cromatografia Líquida de Alta Pressão/métodos , Flavonoides/sangue , Espectrometria de Massas por Ionização por Electrospray/métodos , Animais , Feminino , Flavonoides/farmacologia , Masculino , Ratos , Reprodutibilidade dos Testes , Espectrometria de Massas em Tandem
5.
Exp Parasitol ; 127(1): 222-7, 2011 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-20736008

RESUMO

The effect of 16 alpha-acetoxy-26-hydroxycholest-4-ene-3,22-dione (SN-1) isolated from Solanum nudum Dunal (a Solanaceae traditionally used for treating fever in Colombia) on Plasmodium falciparum erythrocyte stages and its in vitro antiplasmodial activity when combined with the following conventional drugs was studied: chloroquine (CQ), amodiaquine (AQ), desethylamodiaquine (desethyl-AQ), quinine (QN), artemisinin (AR), atovaquone (ATV) and quinine (QN). It was found that SN-1 targeted trophozoites and had a synergistic effect when combined with CQ and QN; however, it had an antagonist effect when used with the other combinations.


Assuntos
Antimaláricos/farmacologia , Fitosteróis/farmacologia , Plasmodium falciparum/efeitos dos fármacos , Solanum/química , Amodiaquina/análogos & derivados , Amodiaquina/antagonistas & inibidores , Amodiaquina/farmacologia , Antimaláricos/antagonistas & inibidores , Artemisininas/antagonistas & inibidores , Artemisininas/farmacologia , Atovaquona/antagonistas & inibidores , Atovaquona/farmacologia , Cloroquina/farmacologia , Sinergismo Farmacológico , Eritrócitos/parasitologia , Citometria de Fluxo , Humanos , Quinina/farmacologia , Trofozoítos/efeitos dos fármacos
6.
Parasitol Int ; 56(3): 221-6, 2007 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-17544319

RESUMO

The anti-oxidant drug N-acetylcysteine (NAC) has been proposed as adjunctive treatment in severe falciparum malaria. However, this might inhibit the anti-malarial drug action of the artemisinins, which are thought to exert their parasitocidal action through oxidative damage. We studied the interaction between NAC and artesunate as well as quinine in an in vitro drug sensitivity assay. Combination with NAC reduced the parasitocidal effect of artesunate only within the first 6 h of incubation, whereas no interaction was observed with quinine. Pre-incubation of P. falciparum with NAC resulted in a similar inhibitory effect on the anti-malarial activity of artesunate, whereas no inhibition was observed when NAC was added 2 h after parasite exposure to artesunate. Assessment of parasite maturation inhibition by the standard Giemsa's staining was in accordance with the use of a vital staining. The results herein caution the use of adjunctive treatment for malaria infection. Combination of antagonistic drugs may lead to adverse effects.


Assuntos
Acetilcisteína/farmacologia , Antimaláricos/antagonistas & inibidores , Antioxidantes/farmacologia , Artemisininas/antagonistas & inibidores , Plasmodium falciparum/efeitos dos fármacos , Sesquiterpenos/antagonistas & inibidores , Animais , Antimaláricos/farmacologia , Artemisininas/farmacologia , Artesunato , Interações Medicamentosas , Humanos , Testes de Sensibilidade Parasitária , Quinina/farmacologia , Sesquiterpenos/farmacologia
7.
Biochem Pharmacol ; 74(1): 153-60, 2007 Jun 30.
Artigo em Inglês | MEDLINE | ID: mdl-17498668

RESUMO

Artemisinin loses its antimalarial activity on prolonged exposure to erythrocytes, especially alpha-thalassemic erythrocytes. In this report, we show that the major artemisinin-inactivating factor in cytosol of normal erythrocytes was heat-labile but a heat-stable factor from alpha-thalassemic cells also played a significant role in reducing artemisinin effectiveness, which was shown to be heme released from hemoglobin (Hb). Studies of fractionated lysate from genetically normal erythrocytes revealed that the protein fraction with molecular weight greater than 100 kDa was capable of reducing artemisinin effectiveness more readily than lower molecular weight fraction. Catalase and Hb A, but not selenoprotein glutathione peroxidase, were capable of reducing artemisinin effectiveness. Hemin (ferriprotoporphyrin IX) also reduced artemisinin effectiveness in a concentration- and time-dependent manner. It is concluded that heme and heme-containing proteins in erythrocyte are largely responsible for reducing artemisinin effectiveness and may contribute to resistance of Plasmodium falciparum infecting alpha-thalassemic erythrocytes observed in vitro.


Assuntos
Antimaláricos/metabolismo , Artemisininas/metabolismo , Eritrócitos/metabolismo , Hemina/metabolismo , Sesquiterpenos/metabolismo , Animais , Antimaláricos/antagonistas & inibidores , Antimaláricos/farmacologia , Artemisininas/antagonistas & inibidores , Artemisininas/farmacologia , Catalase/metabolismo , Catalase/farmacologia , Fracionamento Químico , Citosol/química , Citosol/metabolismo , Antagonismo de Drogas , Resistência a Medicamentos/efeitos dos fármacos , Hemina/farmacologia , Hemoglobina A/metabolismo , Hemoglobina A/farmacologia , Humanos , Técnicas In Vitro , Plasmodium falciparum/efeitos dos fármacos , Sesquiterpenos/antagonistas & inibidores , Sesquiterpenos/farmacologia , Talassemia/sangue , Talassemia/metabolismo
8.
Parasitol Int ; 55(3): 195-9, 2006 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-16750932

RESUMO

Chlorpheniramine, a histamine H1 receptor antagonist, was assayed for in vitro antimalarial activity against multidrug-resistant Plasmodium falciparum K1 strain and chloroquine-resistant P. falciparum T9/94 clone, by measuring the 3H-hypoxanthine incorporation. Chlorphenirame inhibited P. falciparum K1 and T9/94 growth with IC50 values of 136.0+/-40.2 microM and 102.0+/-22.6 microM respectively. A combination of antimalarial drug and chlorpheniramine was tested against resistant P. falciparum in vitro. Isobologram analysis showed that chlorpheniramine exerts marked synergistic action on chloroquine against P. falciparum K1 and T9/94. Chlorpheniramine also potentiated antimalarial action of mefloquine, quinine or pyronaridine against both of the resistant strains of P. falciparum. However, chlorpheniramine antagonism with artesunate was obtained in both P. falciparum K1 and T9/94. The results in this study indicate that antihistaminic drugs may be promising candidates for potentiating antimalarial drug action against drug resistant malarial parasites.


Assuntos
Antimaláricos/farmacologia , Artemisininas/farmacologia , Clorfeniramina/farmacologia , Antagonistas dos Receptores Histamínicos H1/farmacologia , Plasmodium falciparum/efeitos dos fármacos , Sesquiterpenos/farmacologia , Animais , Artemisininas/antagonistas & inibidores , Artesunato , Resistência a Múltiplos Medicamentos , Sinergismo Farmacológico , Humanos , Concentração Inibidora 50 , Malária Falciparum/parasitologia , Testes de Sensibilidade Parasitária , Sesquiterpenos/antagonistas & inibidores , Tailândia
9.
Nature ; 424(6951): 957-61, 2003 Aug 21.
Artigo em Inglês | MEDLINE | ID: mdl-12931192

RESUMO

Artemisinins are extracted from sweet wormwood (Artemisia annua) and are the most potent antimalarials available, rapidly killing all asexual stages of Plasmodium falciparum. Artemisinins are sesquiterpene lactones widely used to treat multidrug-resistant malaria, a disease that annually claims 1 million lives. Despite extensive clinical and laboratory experience their molecular target is not yet identified. Activated artemisinins form adducts with a variety of biological macromolecules, including haem, translationally controlled tumour protein (TCTP) and other higher-molecular-weight proteins. Here we show that artemisinins, but not quinine or chloroquine, inhibit the SERCA orthologue (PfATP6) of Plasmodium falciparum in Xenopus oocytes with similar potency to thapsigargin (another sesquiterpene lactone and highly specific SERCA inhibitor). As predicted, thapsigargin also antagonizes the parasiticidal activity of artemisinin. Desoxyartemisinin lacks an endoperoxide bridge and is ineffective both as an inhibitor of PfATP6 and as an antimalarial. Chelation of iron by desferrioxamine abrogates the antiparasitic activity of artemisinins and correspondingly attenuates inhibition of PfATP6. Imaging of parasites with BODIPY-thapsigargin labels the cytosolic compartment and is competed by artemisinin. Fluorescent artemisinin labels parasites similarly and irreversibly in an Fe2+-dependent manner. These data provide compelling evidence that artemisinins act by inhibiting PfATP6 outside the food vacuole after activation by iron.


Assuntos
Artemisininas/farmacologia , ATPases Transportadoras de Cálcio/antagonistas & inibidores , Plasmodium falciparum/enzimologia , Animais , Artemisininas/antagonistas & inibidores , ATPases Transportadoras de Cálcio/genética , ATPases Transportadoras de Cálcio/metabolismo , Desferroxamina/farmacologia , Glucose/metabolismo , Ferro/metabolismo , Quelantes de Ferro/farmacologia , Oócitos , Plasmodium falciparum/efeitos dos fármacos , ATPases Transportadoras de Cálcio do Retículo Sarcoplasmático , Tapsigargina/farmacologia , Xenopus laevis
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