RESUMO
Gastric cancer is one of the leading causes of cancer mortality in the world. Curcumin is a natural product with multiple pharmacological activities, while its clinical application has been limited by the poor chemical stability. We have previously designed a series of curcumin derivatives with high stability and anticancer potentials. The present study aims to identify the anti-cancer effects and mechanisms of WZ26, an analog of curcumin, in gastric cancer cells. In vitro, WZ26 showed higher chemical stability and much stronger anti-proliferative effects than curcumin, accompanied by dose-dependent induction of cell cycle arrest and apoptosis in gastric cancer cells. Mechanistically, the novel compound WZ26 induced ROS production, resulting in the activation of JNK-mitochondrial and ER stress apoptotic pathways. Blockage of ROS production totally reversed WZ26-induced JNK activation, Bcl-2/Bax decrease, ER stress activation, and final cell apoptosis in SGC-7901 cells. WZ26 also exhibited potent anti-tumor effects in human gastric cancer cell xenograft models. WZ26 could be considered as a potential chemotherapeutic agent for the treatment of advanced gastric cancer. In addition, this study also demonstrated that ROS production could be act as a vital candidate pathway for inducing tumor cell apoptosis by targeting mitochondrial and ER stress-related death pathway. © 2015 Wiley Periodicals, Inc.
Assuntos
Antineoplásicos/administração & dosagem , Curcumina/análogos & derivados , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Bibliotecas de Moléculas Pequenas/administração & dosagem , Neoplasias Gástricas/metabolismo , Animais , Antineoplásicos/farmacologia , Apoptose , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Camundongos , Bibliotecas de Moléculas Pequenas/farmacologia , Neoplasias Gástricas/tratamento farmacológico , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Obesity and increased free fatty acid (FFA) level are tightly linked, leading to the development of cardiovascular disorders. Curcumin is a natural product from Curcuma longa with multiple bioactivities and is known to have cardioprotective effects in several cellular and animal models. The current study was designed to evaluate the cardioprotective effects of curcumin and demonstrate the underlying mechanism in FFA-induced cardiac injury. Using cell culture studies and high fat in vivo model, we explored the mechanistic basis of anti-inflammatory and antioxidant activities of curcumin. We observed that palmitate (PA) treatment in cardiac derived H9C2 cells induced a marked increase in reactive oxygen species, inflammation, apoptosis and hypertrophy. All of these changes were effectively suppressed by curcumin treatment. In addition, oral administration of curcumin at 50mg/kg completely suppressed high fat diet-induced oxidative stress, inflammation, apoptosis, fibrosis, hypertrophy and tissue remodeling in mice. The beneficial actions of curcumin are closely associated with its ability to increase Nrf2 expression and inhibit NF-κB activation. Thus, both in vitro and in vivo studies showed a promising role of curcumin as a cardioprotective agent against palmitate and high fat diet mediated cardiac dysfunction. We indicated the regulatory roles of Nrf2 and NF-κB in obesity-induced heart injury, and suggested that they may be important therapeutic targets in the treatment of obesity-related disorders.
Assuntos
Cardiotônicos/uso terapêutico , Curcumina/farmacologia , Ácidos Graxos não Esterificados/efeitos adversos , Miocárdio/metabolismo , Miocárdio/patologia , Fator 2 Relacionado a NF-E2/metabolismo , NF-kappa B/metabolismo , Animais , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/uso terapêutico , Apoptose/efeitos dos fármacos , Peso Corporal/efeitos dos fármacos , Cardiomegalia/complicações , Cardiomegalia/tratamento farmacológico , Cardiomegalia/patologia , Cardiotônicos/farmacologia , Linhagem Celular , Curcumina/administração & dosagem , Curcumina/uso terapêutico , Dieta Hiperlipídica , Fibrose , Masculino , Camundongos Endogâmicos C57BL , Estresse Oxidativo/efeitos dos fármacos , Palmitatos/efeitos adversos , Ratos , Espécies Reativas de Oxigênio/metabolismoRESUMO
Inflammation plays a central role in the development and progression of diabetic nephropathy (DN). Researches on novel anti-inflammatory agents may offer new opportunities for the treatment of DN. We previously found a chalcone derivative L6H21 could inhibit LPS-induced cytokine release from macrophages. The aim of this study was to investigate whether L6H21 could ameliorate the high glucose-mediated inflammation in NRK-52E cells and attenuate the inflammation-mediated renal injury. According to the results, L6H21 showed a great inhibitory effect on the expression of pro-inflammatory cytokines, cell adhesion molecules, chemokines, and macrophage adhesion via down-regulation of NF-κB/MAPKs activity in high glucose-stimulated renal NRK-52E cells. Further, in vivo oral administration with L6H21 at a dosage of 20 mg/kg/2 days showed a decreased expression of pro-inflammatory cytokines, cell adhesion molecules, which subsequently contributed to the inhibition on renal macrophage infiltration, the reduction of serum creatinine and BUN levels, and the improvement on the fibrosis and pathological changes in the renal tissues of diabetic mice. These findings provided that chalcone derived L6H21 may be a promising anti-inflammatory agent and have the potential in the therapy of diabetic nephropathy, and importantly, MAPK/NF-κB signaling system may be a novel therapeutic target for human DN in the future.
Assuntos
Anti-Inflamatórios/farmacologia , Chalconas/farmacologia , Nefropatias Diabéticas/tratamento farmacológico , Glucose/toxicidade , Inflamação/induzido quimicamente , Infiltração de Neutrófilos/efeitos dos fármacos , Animais , Adesão Celular/efeitos dos fármacos , Células Cultivadas , Citocinas/antagonistas & inibidores , Citocinas/biossíntese , Diabetes Mellitus Experimental/complicações , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Experimental/patologia , Nefropatias Diabéticas/patologia , Rim/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , NF-kappa B/antagonistas & inibidores , Fator de Necrose Tumoral alfa/metabolismoRESUMO
BACKGROUND: Prostate cancer is the most commonly diagnosed malignancy among men. The Discovery of new agents for the treatment of prostate cancer is urgently needed. Compound WZ35, a novel analog of the natural product curcumin, exhibited good anti-prostate cancer activity, with an IC50 of 2.2 µM in PC-3 cells. However, the underlying mechanism of WZ35 against prostate cancer cells is still unclear. METHODS: Human prostate cancer PC-3 cells and DU145 cells were treated with WZ35 for further proliferation, apoptosis, cell cycle, and mechanism analyses. NAC and CHOP siRNA were used to validate the role of ROS and ER stress, respectively, in the anti-cancer actions of WZ35. RESULTS: Our results show that WZ35 exhibited much higher cell growth inhibition than curcumin by inducing ER stress-dependent cell apoptosis in human prostate cells. The reduction of CHOP expression by siRNA partially abrogated WZ35-induced cell apoptosis. WZ35 also dose-dependently induced cell cycle arrest in the G2/M phase. Furthermore, we found that WZ35 treatment for 30 min significantly induced reactive oxygen species (ROS) production in PC-3 cells. Co-treatment with the ROS scavenger NAC completely abrogated the induction of WZ35 on cell apoptosis, ER stress activation, and cell cycle arrest, indicating an upstream role of ROS generation in mediating the anti-cancer effect of WZ35. CONCLUSIONS: Taken together, this work presents the novel anticancer candidate WZ35 for the treatment of prostate cancer, and importantly, reveals that increased ROS generation might be an effective strategy in human prostate cancer treatment.
Assuntos
Antineoplásicos/farmacologia , Antioxidantes/farmacologia , Curcumina/farmacologia , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Pontos de Checagem da Fase G2 do Ciclo Celular/efeitos dos fármacos , Neoplasias da Próstata/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Curcumina/análogos & derivados , Expressão Gênica , Humanos , Masculino , Neoplasias da Próstata/genética , Fator de Transcrição CHOP/genética , Fator de Transcrição CHOP/metabolismoRESUMO
Colon cancer is characterized by its fast progression and poor prognosis, and novel agents of treating colon cancer are urgently needed. WZ35, a synthetic curcumin derivative, has been reported to exhibit promising antitumor activity. Here, we investigated the in vitro and in vivo activities of WZ35 and explored the underlying mechanisms in colon cancer cell lines. WZ35 treatment significantly decreased the cell viability associated with G2/M cell cycle arrest and apoptosis induction in colon cancer cell lines. We also show that WZ35 is highly effective in inhibiting tumor growth in a CT26 xenograft mouse model. Mechanistically, WZ35 treatment significantly induced reactive oxygen species (ROS) generation and endoplasmic reticulum (ER) stress in CT26 cells. Abrogation of ROS production by N-acetylcysteine (NAC) co-treatment almost totally reversed the WZ35-induced cell apoptosis and ER stress activation. Inhibition of p-PERK by GSK2606414 can significantly reverse WZ35-induced cell apoptosis in CT26 cells. Taken together, the curcumin derivative WZ35 exhibited anti-tumor effects in colon cancer cells both in vitro and in vivo, via a ROS-ER stress-mediated mechanism. These findings indicate that activating ROS generation could be an important strategy for the treatment of colon cancers.
RESUMO
Gastric cancer is one of the leading causes of cancer mortality in the world, and finding novel agents and strategies for the treatment of advanced gastric cancer is of urgent need. Curcumin is a well-known natural product with anti-cancer ability, but is limited by its poor chemical stability. In this study, an analog of curcumin with high chemical stability, WZ35, was designed and evaluated for its anti-cancer effects and underlying mechanisms against human gastric cancer. WZ35 showed much stronger anti-proliferative effects than curcumin, accompanied by dose-dependent induction of cell cycle arrest and apoptosis in gastric cancer cells. Mechanistically, our data showed that WZ35 induced reactive oxygen species (ROS) production, resulting in the activation of both JNK-mitochondrial and ER stress apoptotic pathways and eventually cell apoptosis in SGC-7901 cells. Blockage of ROS production totally reversed WZ35-induced JNK and ER stress activation as well as cancer cell apoptosis. In vivo, WZ35 showed a significant reduction in SGC-7901 xenograft tumor size in a dose-dependent manner. Taken together, this work provides a novel anticancer candidate for the treatment of gastric cancer, and importantly, reveals that increased ROS generation might be an effective strategy in human gastric cancer treatment.
Assuntos
Curcumina/análogos & derivados , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Neoplasias Gástricas/tratamento farmacológico , Animais , Apoptose/efeitos dos fármacos , Processos de Crescimento Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Curcumina/farmacologia , Estresse do Retículo Endoplasmático/fisiologia , Feminino , Humanos , MAP Quinase Quinase 4/metabolismo , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Neoplasias Gástricas/metabolismo , Neoplasias Gástricas/patologia , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Accumulating evidence suggests that high expression of FGFR1 is closely related to the development of lung cancer especially in non-small cell lung cancers (NSCLC), to which non-ATP competitive inhibitors represent an effective therapeutical approach due to their good specificity. Herein, a series of NDGA analogues with the framework of bisaryl-1,4-dien-3-one as novel FGFR1 inhibitors have been designed and screened. Among them Aea4 and Aea25 showed strong FGFR1`inhibition and high selectivity over other receptor kinases. The kinase inhibitory assay in different ATP concentrations and computer-assistant molecular docking showed that the FGFR1 inhibition mode of both Aea4 and Aea25 was non-ATP-competitive. The in vitro and in vivo study on anticancer efficacy of Aea4 and Aea25 against non-small cell lung cancer involves inhibition of cell proliferation, apoptosis induction and cell cycle arrest with no toxicity. Thus, these two novel non-ATP competitive inhibitors derived from NDGA may have a great therapeutic potential in the treatment of NSCLC. This work also provides a structural lead for the design of new non-ATP-competitive FGFR1 inhibitors.
Assuntos
Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Apoptose , Linhagem Celular Tumoral , Proliferação de Células , Humanos , Técnicas In VitroRESUMO
Curcumin and its analogues have been reported to exert anti-cancer activity against a variety of tumors. Here, we reported A501, a new curcumin analogue. The effect of A501 on cell viability was detected by MTT assay, the result showed that A501 had a better inhibiting effect on the four non-small cell lung cancer (NSCLC) cells than that of curcumin. Moreover, Colony forming experiment showed A501 significant restrained cell proliferation. Flow cytometry displayed A501 can cause G2/M arrest and induce apoptosis. Western blotting showed that A501 decreased the expression of cyclinB1, cdc-2, bcl-2, while increased the expression of p53, cleaved caspase-3 and bax. In conclusion, curcumin analogues A501 played antitumor activity by inhibiting cell proliferation and inducing apoptosis of NSCLC cells. And it was likely to be a promising starting point for the development of curcumin-based anticancer drugs.