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1.
Biochem Biophys Res Commun ; 478(2): 710-5, 2016 09 16.
Article in English | MEDLINE | ID: mdl-27498029

ABSTRACT

Calotropin (M11), an active compound isolated from Asclepias curasavica L., was found to exert strong inhibitory and pro-apoptotic activity specifically against cisplatin-induced resistant non-small cell lung cancer (NSCLC) cells (A549/CDDP). Molecular mechanism study revealed that M11 induced cell cycle arrest at the G2/M phase through down-regulating cyclins, CDK1, CDK2 and up-regulating p53 and p21. Furthermore, M11 accelerated apoptosis through the mitochondrial apoptotic pathway which was accompanied by increase Bax/Bcl-2 ratio, decrease in mitochondrial membrane potential, increase in reactive oxygen species production, activations of caspases 3 and 9 as well as cleavage of poly ADP-ribose polymerase (PARP). The activation and phosphorylation of JNK was also found to be involved in M11-induced apoptosis, and SP610025 (specific JNK inhibitor) partially prevented apoptosis induced by M11. In contrast, all of the effects that M11 induce cell cycle arrest and apoptosis in A549/CDDP cells were not significant in A549 cells. Drugs with higher sensitivity against resistant tumor cells than the parent cells are rather rare. Results of this study supported the potential application of M11 on the non-small lung cancer (NSCLC) with cisplatin resistance.


Subject(s)
Antineoplastic Agents, Phytogenic/pharmacology , Apoptosis/drug effects , Asclepias/chemistry , Cardenolides/pharmacology , Drug Resistance, Neoplasm/drug effects , G2 Phase Cell Cycle Checkpoints/drug effects , Gene Expression Regulation, Neoplastic/drug effects , A549 Cells , Antineoplastic Agents, Phytogenic/isolation & purification , Apoptosis/genetics , CDC2 Protein Kinase , Cardenolides/isolation & purification , Caspase 3/genetics , Caspase 3/metabolism , Caspase 9/genetics , Caspase 9/metabolism , Cisplatin/pharmacology , Cyclin-Dependent Kinase 2/antagonists & inhibitors , Cyclin-Dependent Kinase 2/genetics , Cyclin-Dependent Kinase 2/metabolism , Cyclin-Dependent Kinase Inhibitor p21/agonists , Cyclin-Dependent Kinase Inhibitor p21/genetics , Cyclin-Dependent Kinase Inhibitor p21/metabolism , Cyclin-Dependent Kinases/antagonists & inhibitors , Cyclin-Dependent Kinases/genetics , Cyclin-Dependent Kinases/metabolism , Drug Resistance, Neoplasm/genetics , Humans , MAP Kinase Kinase 4/genetics , MAP Kinase Kinase 4/metabolism , Membrane Potential, Mitochondrial/drug effects , Mitochondria/drug effects , Mitochondria/metabolism , Plant Extracts/chemistry , Poly(ADP-ribose) Polymerases/genetics , Poly(ADP-ribose) Polymerases/metabolism , Proteolysis , Proto-Oncogene Proteins c-bcl-2/agonists , Proto-Oncogene Proteins c-bcl-2/genetics , Proto-Oncogene Proteins c-bcl-2/metabolism , Reactive Oxygen Species/metabolism , Signal Transduction , Tumor Suppressor Protein p53/agonists , Tumor Suppressor Protein p53/genetics , Tumor Suppressor Protein p53/metabolism , bcl-2-Associated X Protein/agonists , bcl-2-Associated X Protein/genetics , bcl-2-Associated X Protein/metabolism
2.
Free Radic Biol Med ; 95: 230-42, 2016 06.
Article in English | MEDLINE | ID: mdl-27021965

ABSTRACT

Resveratrol gains a great interest for its strong antioxidant properties, while the molecular mechanisms underlie the beneficial effects on psychosocial stress remain controversial. In this study, we demonstrated that resveratrol protected peritoneal macrophages and RAW 264.7 cells from stress-induced decrease in the total cell count, phagocytic capability, reactive oxygen species generation, monodansylcadaverine and mitochondrial membrane potential in stressed mice. Resveratrol promoted stress-induced autophagy in both models. Modulation of autophagy by rapamycin or 3-methyladenine regulated the protective effect of resveratrol, suggesting a role of autophagy in the protective mechanisms of resveratrol. The comparison studies revealed that distinct mechanisms were implicated in the protective effect of resveratrol and other antioxidants (vitamin C and edaravone). Resveratrol promoted autophagy via upregulating SIRT3 expression and phosphorylation of AMP-activated protein kinase (AMPK). Knockdown of SIRT3 resulted in decreased autophagy and abolished protective effect of resveratrol. SIRT1 was also involved in the protective mechanism of resveratrol, although its effect on autophagy was unnoticeable. Pharmacological manipulation of autophagy modulated the effects of resveratrol on SIRT3 and AMPK, revealing the engagement of a positive feedback loop. In sharp contrast, vitamin C and edaravone effectively protected macrophages from stress-induced cytotoxicity, accompanied by downregulated SIRT3 expression and AMPK phosphorylation, and decreased level of autophagy response. Taken together, we conclude that a SIRT3/AMPK/autophagy network orchestrates in the protective effect of resveratrol in macrophages.


Subject(s)
Oxidative Stress/drug effects , Protein Kinases/genetics , Sirtuin 3/genetics , Stilbenes/administration & dosage , Stress, Psychological/drug therapy , AMP-Activated Protein Kinase Kinases , Animals , Antioxidants/administration & dosage , Antipyrine/administration & dosage , Antipyrine/analogs & derivatives , Apoptosis/drug effects , Ascorbic Acid/administration & dosage , Autophagy/drug effects , Edaravone , Gene Expression Regulation/drug effects , Macrophages/drug effects , Membrane Potential, Mitochondrial/drug effects , Mice , RAW 264.7 Cells , Reactive Oxygen Species/metabolism , Resveratrol , Sirolimus/administration & dosage , Stress, Psychological/genetics
3.
Oncotarget ; 7(4): 4122-41, 2016 Jan 26.
Article in English | MEDLINE | ID: mdl-26716641

ABSTRACT

Transforming growth factor-ß1 (TGF-ß1) present in tumor microenvironment acts in a coordinated fashion to either suppress or promote tumor development. However, the molecular mechanisms underlying the effects of TGF-ß1 on tumor microenvironment are not well understood. Our clinical data showed a positive association between TGF-ß1 expression and cancer-associated fibroblasts (CAFs) in tumor microenvironment of breast cancer patients. Thus we employed starved NIH3T3 fibroblasts in vitro and 4T1 cells mixed with NIH3T3 fibroblasts xenograft model in vivo to simulate nutritional deprivation of tumor microenvironment to explore the effects of TGF-ß1. We demonstrated that TGF-ß1 protected NIH3T3 fibroblasts from Star-induced growth inhibition, mitochondrial damage and cell apoptosis. Interestingly, TGF-ß1 induced the formation of CAFs phenotype in starvation (Star)-treated NIH3T3 fibroblasts and xenografted Balb/c mice, which promoted breast cancer tumor growth. In both models, autophagy agonist rapamycin increased TGF-ß1-induced protective effects and formation of CAFs phenotypes, while autophagy inhibitor 3-methyladenine, Atg5 knockdown or TGF-ß type I receptor kinase inhibitor LY-2157299 blocked TGF-ß1 induced these effects. Taken together, our results indicated that TGF-ß/Smad autophagy was involved in TGF-ß1-induced protective effects and formation of CAFs phenotype in tumor microenvironment, which may be used as therapy targets in breast cancer.


Subject(s)
Autophagy , Breast Neoplasms/pathology , Cell Transformation, Neoplastic/pathology , Protective Agents/pharmacology , Transforming Growth Factor beta1/pharmacology , Tumor Microenvironment/drug effects , Animals , Apoptosis/drug effects , Blotting, Western , Breast Neoplasms/drug therapy , Breast Neoplasms/metabolism , Cell Proliferation/drug effects , Cell Transformation, Neoplastic/drug effects , Cell Transformation, Neoplastic/metabolism , Female , Fibroblasts/cytology , Fibroblasts/drug effects , Fibroblasts/metabolism , Gene Expression Regulation, Neoplastic , Humans , Immunoenzyme Techniques , Membrane Potential, Mitochondrial/drug effects , Mice , Mice, Inbred BALB C , NIH 3T3 Cells , Phenotype , RNA, Messenger/genetics , Real-Time Polymerase Chain Reaction , Retrospective Studies , Reverse Transcriptase Polymerase Chain Reaction , Signal Transduction/drug effects , Tumor Cells, Cultured , Xenograft Model Antitumor Assays
4.
Fitoterapia ; 91: 140-147, 2013 Dec.
Article in English | MEDLINE | ID: mdl-24007984

ABSTRACT

Four new xanthones, 3,5,6,8-tetrahydroxyxanthone-1-C-ß-D-glucoside (1), 7-hydroxy-3,4,8-trimethoxyxanthone-1-O-(ß-D-glucoside) (2), 6-hydroxy-3,5-dimethoxyxanthone-1-O-(ß-D-glucoside) (3), 3,4,7,8-tetramethoxyxanthone-1-O-(ß-D-glucoside) (4), together with twenty-one known xanthones (5-25) were isolated from the ethanol aqueous extract of Swertia mussotii. Their structures were elucidated via spectroscopic analyses. Oxygen radical absorbance capacity of all the isolated xanthones was systematically evaluated by ORAC(FL) assay. Results disclose that all the tested xanthones display moderate to excellent antioxidant activity, where 1 is the most active compound and 13 is the least one. A preliminary structure-activity relationship is also discussed.


Subject(s)
Antioxidants/pharmacology , Glucosides/pharmacology , Plant Extracts/pharmacology , Swertia/chemistry , Xanthones/pharmacology , Altitude , Antioxidants/chemistry , Antioxidants/isolation & purification , Glucosides/chemistry , Glucosides/isolation & purification , Molecular Structure , Oxidation-Reduction , Plant Extracts/chemistry , Structure-Activity Relationship , Xanthones/chemistry , Xanthones/isolation & purification
5.
Mol Nutr Food Res ; 57(7): 1145-57, 2013 Jul.
Article in English | MEDLINE | ID: mdl-23505001

ABSTRACT

SCOPE: Resveratrol, a powerful natural compound for human health, is widely reported for its immunity-related beneficial properties. However, few works have studied its effect mechanism on immunity. The present study was conducted to investigate the effects of resveratrol on splenic immunity in restraint stressed mice and the mechanism was further studied as autophagy induction. METHODS AND RESULTS: Mice were administered with resveratrol for 7 days consecutively, fixed in restraint cages for 18 h, and recovered for 12 h after the last administration. Data showed that restraint led to spleen damages, including declined spleen index, decreased CD4(+) T-cell number, increased mitochondrial oxidative damage, and apoptosis of splenocytes. Resveratrol, vitamin C (antioxidant), and rapamycin (autophagy agonist) protected spleen functions. Meanwhile, rapamycin augmented the effects of resveratrol that were abolished by chloroquine (autophagy antagonists). Further studies showed that expressions of Beclin 1 and LC3ß required in autophagy development were significantly upregulated by resveratrol but not by vitamin C. CONCLUSION: This study demonstrated that resveratrol preserved splenic immunity of restraint stressed mice. It is meaningful to find that autophagy, apart from reactive oxygen species clearance, is included as a potential mechanism via which resveratrol ameliorated the state of oxidative stress and thus protected splenocytes in mice.


Subject(s)
Apoptosis/drug effects , Autophagy/drug effects , Oxidative Stress/drug effects , Spleen/drug effects , Stilbenes/pharmacology , Animals , Antioxidants/pharmacology , Apoptosis Regulatory Proteins/metabolism , Ascorbic Acid/pharmacology , Beclin-1 , In Situ Nick-End Labeling , Male , Membrane Potential, Mitochondrial , Mice , Microtubule-Associated Proteins/metabolism , Reactive Oxygen Species/metabolism , Resveratrol , Sirolimus/pharmacology , Spleen/cytology , Spleen/immunology , T-Lymphocyte Subsets/cytology , Up-Regulation
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