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ABSTRACT: Signal transducer and activator of transcription 3 (STAT3) constitutively expresses in human liver cancer cells and has been implicated in apoptosis resistance and tumorigenesis. Alantolactone, a sesquiterpene lactone, has been shown to possess anticancer activities in various cancer cell lines. In our previous report, we showed that alantolactone induced apoptosis in U87 glioblastoma cells via GSH depletion and ROS generation. However, the molecular mechanism of GSH depletion remained unexplored. The present study was conducted to envisage the molecular mechanism of alantolactone-induced apoptosis in HepG2 cells by focusing on the molecular mechanism of GSH depletion and its effect on STAT3 activation. We found that alantolactone induced apoptosis in HepG2 cells in a dose-dependent manner. This alantolactone-induced apoptosis was found to be associated with GSH depletion, inhibition of STAT3 activation, ROS generation, mitochondrial transmembrane potential dissipation, and increased Bax/Bcl-2 ratio and caspase-3 activation. This alantolactone-induced apoptosis and GSH depletion were effectively inhibited or abrogated by a thiol antioxidant, N-acetyl-L-cysteine (NAC). The data demonstrate clearly that intracellular GSH plays a central role in alantolactone-induced apoptosis in HepG2 cells. Thus, alantolactone may become a lead chemotherapeutic candidate for the treatment of liver cancer.
BioMed research international. 01/2013; 2013:719858.
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Journal of Biomedicine and Biotechnology 10/2012; · 2.44 Impact Factor
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ABSTRACT: Glioblastoma multiforme (GBM) is the most malignant and aggressive primary brain tumor in adults. Despite concerted efforts to improve current therapies, the prognosis of glioblastoma remains very poor. Alantolactone, a sesquiterpene lactone compound, has been reported to exhibit antifungal, antibacteria, antihelminthic, and anticancer properties. In this study, we found that alantolactone effectively inhibits growth and triggers apoptosis in glioblastoma cells in a time- and dose-dependent manner. The alantolactone-induced apoptosis was found to be associated with glutathione (GSH) depletion, reactive oxygen species (ROS) generation, mitochondrial transmembrane potential dissipation, cardiolipin oxidation, upregulation of p53 and Bax, downregulation of Bcl-2, cytochrome c release, activation of caspases (caspase 9 and 3), and cleavage of poly (ADP-ribose) polymerase. This alantolactone-induced apoptosis and GSH depletion were effectively inhibited or abrogated by a thiol antioxidant, N-acetyl-L-cysteine, whereas other antioxidant (polyethylene glycol (PEG)-catalase and PEG-superoxide-dismutase) did not prevent apoptosis and GSH depletion. Alantolactone treatment inhibited the translocation of NF-κB into nucleus; however, NF-κB inhibitor, SN50 failed to potentiate alantolactone-induced apoptosis indicating that alantolactone induces NF-κB-independent apoptosis in glioma cells. These findings suggest that the sensitivity of tumor cells to alantolactone appears to results from GSH depletion and ROS production. Furthermore, our in vivo toxicity study demonstrated that alantolactone did not induce significant hepatotoxicity and nephrotoxicity in mice. Therefore, alantolactone may become a potential lead compound for future development of antiglioma therapy.
International Union of Biochemistry and Molecular Biology Life 07/2012; 64(9):783-94. · 3.51 Impact Factor
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ABSTRACT: Dracorhodin perchlorate has been recently shown to induce apoptotic cell death in cancer cells. However, the molecular mechanisms underlying these effects are unknown in human gastric tumor cells. In this study, effects of Dracorhodin perchlorate on cell viability, cell cycle, and apoptosis were investigated in SGC-7901 cells. The results showed that Dracorhodin perchlorate induced cellular and DNA morphological changes and decreased the viability of SGC-7901 cells. Dracorhodin perchlorate-mediated cell cycle arrest was associated with a marked decrease in protein levels of phosphorylated retinoblastoma and E2F1. Dracorhodin perchlorate-induced apoptosis is mediated via upregulation of p53, inhibiting the activation of PI3K/Akt, and NF-κB, thereby decreasing the expression of the anti-apoptotic proteins, Bcl-2 and Bcl-XL. Interestingly, we also found that Dracorhodin perchlorate significantly suppressed the IGF-1-induced phosphorylation of Akt in the stably expressing EGFP-Akt recombinant CHO-hIR cells and inhibited TNF-induced NF-κB transcriptional activity in the NF-κBp65-EGFP recombinant U2OS cells, indicating that inhibition of PI3K/Akt and NF-κB may provide a molecular basis for the ability of Dracorhodin perchlorate to induce apoptosis. Dracorhodin perchlorate induced up-regulation of p53, thereby resulting in the activation of its downstream targets p21 and Bax following the dissipation of mitochondrial membrane potential and activation of caspase-3 and its substrate, PARP. Moreover, Dracorhodin perchlorate dramatically enhanced the wortmannin- and TNF-induced apoptosis in SGC-7901 cells. These results reveal functional interplay among the PI3K/Akt, p53 and NF-κB pathways that are frequently deregulated in cancer and suggest that their simultaneous targeting by Dracorhodin perchlorate could result in efficacious and selective killing of cancer cells.
Apoptosis 06/2012; 17(10):1104-19. · 4.07 Impact Factor
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International Union of Biochemistry and Molecular Biology Life 06/2012; · 3.51 Impact Factor
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ABSTRACT: Dracorhodin perchlorate has been recently shown to induce apoptotic cell death in cancer cells. However, the molecular mechanisms underlying these effects are unknown in human gastric tumor cells. In this study, effects of Dracorhodin perchlorate on cell viability, cell cycle, and apoptosis were investigated in SGC-7901 cells. The results showed that Dracorhodin perchlorate induced cellular and DNA morphological changes and decreased the viability of SGC-7901 cells. Dracorhodin perchlorate-mediated cell cycle arrest was associated with a marked decrease in protein levels of phosphorylated retinoblastoma and E2F1. Dracorhodin perchlorate-induced apoptosis is mediated via upregulation of p53, inhibiting the activation of PI3K-Akt, and NF-κB, thereby decreasing the expression of the anti-apoptotic proteins, Bcl-2 and Bcl-XL. Interestingly, we also found that Dracorhodin perchlorate significantly suppressed the IGF-1-induced phosphorylation of Akt in the stably expressing EGFP-Akt recombinant CHO-hIR cells and inhibited TNF-induced NF-κB transcriptional activity in the NF-κBp65-EGFP recombinant U2OS cells, indicating that inhibition of PI3K/Akt and NF-κB may provide a molecular basis for the ability of Dracorhodin perchlorate to induce apoptosis. Dracorhodin perchlorate induced up-regulation of p53, thereby resulting in the activation of its downstream targets p21 and Bax following the dissipation of mitochondrial membrane potential and activation of caspase-3 and its substrate, PARP. Moreover, Dracorhodin perchlorate dramatically enhanced the wortmannin- and TNF-induced apoptosis in SGC-7901 cells. These results reveal functional interplay among the PI3K/AKT, p53 and NF-κB pathways that are frequently deregulated in cancer and suggest that their simultaneous targeting by Dracorhodin perchlorate could result in efficacious and selective killing of cancer cells.
APOPTOSIS 05/2012; · 4.79 Impact Factor
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ABSTRACT: Evodiamine, an alkaloid isolated from Evodia rutaecarpa, possesses potent anticancer activity. Although many reports have elucidated the cytotoxic effects of evodiamine in a variety of cancer cells, little is known about the mechanism of evodiamine-induced cytotoxic activity in gastric cancer cells. To date, no report has addressed the synchronized role of autophagy and apoptosis in evodiamine-induced cytotoxic activity. This study was conducted to investigate the synchronized role of autophagy and apoptosis in evodiamine-induced cytotoxic activity on SGC-7901 human gastric adenocarcinoma cells and further to elucidate the underlying molecular mechanisms. The MTT assay was used to examine the cytotoxicity of evodiamine against SGC-7901 gastric adenocarcinoma cells. The effects of evodiamine on the cell cycle and apoptosis were measured by flow cyto-metry and cellular morphology was observed under a phase contrast microscope. Acridine orange (AO) staining was used to detect autophagy. The expression levels of Bcl-2 and Bax were detected by Western blotting. The expression level of Beclin‑1 in SGC-7901 cells was monitored by reverse transcription-polymerase chain reaction (RT-PCR). Here, we found that evodiamine significantly inhibited the proliferation of SGC-7901 cells and induced G2/M phase cell cycle arrest. Furthermore, both autophagy and apoptosis were activated during the evodiamine-induced death of SGC-7901 cells. Evodiamine-induced autophagy is partially involved in the death of SGC-7901 cells which was confirmed by using the autophagy inhibitor 3-methyladenine (3-MA). Additionally, Beclin-1 is involved in evodiamine-induced autophagy and the pro-apoptotic mechanisms of evodiamine may be associated with down-regulation of Bcl-2 and up-regulation of Bax expression. The inhibitory effects on SGC-7901 cells were associated with apoptosis, autophagy and cell cycle arrest at the G2/M phase in a dose-dependent manner. These results suggest that evodiamine is an effective natural compound for the treatment of gastric cancer and may represent a candidate for in vivo studies of monotherapies or combined antitumor therapies.
Oncology Reports 05/2012; 27(5):1481-7. · 1.84 Impact Factor
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Journal of medicinal plant research 04/2012; · 0.59 Impact Factor
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Journal of Chemotherapy. 04/2012;
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ABSTRACT: Mesenchymal stem cells (MSCs) are adult stem cells with a self-renewal and multipotent capability and express extensively in multitudinous tissues. We found that water channel aquaporin-5 (AQP5) is expressed in bone marrow-derived MSCs (BMMSCs) in the plasma membrane pattern. BMMSCs from AQP5(-/-) mice showed significantly lower plasma membrane water permeability than those from AQP5(+/+) mice. In characterizing the cultured BMMSCs from AQP5(-/-) and AQP5(+/+) mice, we found no obvious differences in morphology and proliferation between the 2 genotypes. However, the multiple differentiation capacity was significantly higher in AQP5(-/-) than AQP5(+/+) BMMSCs as revealed by representative staining by Oil Red O (adipogenesis); Alizarin Red S and alkaline phosphatase (ALP; osteogenesis); and type II collagen and Safranin O (chondrogenesis) after directional induction. Relative mRNA expression levels of 3 lineage differentiation markers, including PPARγ2, C/EBPα, adipsin, collagen 1a, osteopontin, ALP, collagen 11a, collagen 2a, and aggrecan, were significantly higher in AQP5(-/-) -differentiating BMMSCs, supporting an increased differentiation capacity of AQP5(-/-) BMMSCs. Furthermore, a bone-healing process was accelerated in AQP5(-/-) mice in a drill-hole injury model. Mechanistic studies indicated a significantly lower apoptosis rate in AQP5(-/-) than AQP5(+/+) BMMSCs. Apoptosis inhibitor Z-VAD-FMK increased the differentiation capacity to a greater extent in AQP5(+/+) than AQP5(-/-) BMMSCs. We conclude that AQP5-mediated high plasma membrane water permeability enhances the apoptosis rate of differentiating BMMSCs, thus decreasing their differentiation capacity. These data implicate AQP5 as a novel determinant of differentiation of BMMSCs and therefore a new molecular target for regulating differentiation of BMMSCs during tissue repair and regeneration.
Stem cells and development 03/2012; 21(13):2495-507. · 4.15 Impact Factor
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Evidence-based Complementary and Alternative Medicine 03/2012; · 4.77 Impact Factor
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Asian Pacific journal of cancer prevention: APJCP 03/2012; · 0.66 Impact Factor
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ABSTRACT: Tubeimoside-1 (TBMS1) is a triterpenoid saponin isolated from the tubers of Bolbostemma paniculatum (Maxim.) and possesses cytotoxic properties. In this study, for the first time, we examined the anti-proliferative effects of Tubeimoside-1 on human gastric adenocarcinoma SGC-7901 cells and its ability to induce apoptosis and cell cycle arrest. TBMS1 specifically induced morphological changes in SGC-7901 cells and its inhibitory effects were associated with the DNA damage, apoptosis, and cell cycle arrest at G2/M phase in a dose-dependent manner. To determine the mechanism of the apoptotic effect of TBMS1, the apoptosis-related proteins were analyzed in SGC-7901 cells. TBMS1-induced apoptosis was regulated by activation of caspase-3, down-regulation of Bcl-2, and up-regulation of Bax. Furthermore, TBMS1 induced a depolarization of mitochondrial membranes to facilitate cytochrome c release into cytosol. These results suggest that TBMS1 should be further examined for molecular mechanisms and in vivo activity in human gastric cancer.
Pakistan journal of pharmaceutical sciences 01/2012; 25:In press. · 1.10 Impact Factor
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ABSTRACT: Artemisia argyi is a widely used medicinal plant in China. The present study was designed to identify the bioactive constituents with antiglioma activity from leaves of Artemesia argyi. A bioactivity guided approach based on MTT assay for cells growth inhibition led to the isolation of a flavonoid, "jaceosidin" from ethanol extract of leaves of Artemesia argyi. The growth inhibitory effect of jaceosidin was explored using flow cytometry and Western blot studies. Our results showed that jaceosidin exerts growth inhibitory effect by arresting the cells at G2/M phase and induction of apoptosis. Furthermore, our study revealed that induction of apoptosis was associated with cell cycle arrest at G2/M phase, upregulation of p53 and Bax, decrease in mitochondrial membrane potential, release of cytochrome c, and activation of caspase 3. This mitochondrial-caspase-3-dependent apoptosis pathway was confirmed by pretreatment with caspase 3 inhibitor, Ac-DEVD-CHO. Our findings suggested that jaceosidin induces mitochondrial-caspase-3-dependent apoptosis in U87 cells by arresting the cell cycle at G2/M phase.
Evidence-based Complementary and Alternative Medicine 01/2012; 2012:703034. · 4.77 Impact Factor
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ABSTRACT: Pseudolaric acid B (PLAB) is one of the major bioactive components of Pseudolarix kaempferi. It has been reported to exhibit inhibitory effect on cell proliferation in several types of cancer cells. However, there is no report elucidating its effect on glioma cells and organ toxicity in vivo. In the present study, we found that PLAB inhibited growth of U87 glioblastoma cells in a dose-dependent manner with IC(50)~10 μM. Flow cytometry analysis showed that apoptotic cell death mediated by PLAB was accompanied with cell cycle arrest at G2/M phase. Using Western blot, we found that PLAB induced G2/M phase arrest by inhibiting tubulin polymerization in U87 cells. Apoptotic cell death was only partially inhibited by pancaspase inhibitor, z-VAD-fmk, which suggested that PLAB-induced apoptosis in U87 cells is partially caspase-independent. Further mechanistic study demonstrated that PLAB induced caspase-dependent apoptosis via upregulation of p53, increased level of proapoptotic protein Bax, decreased level of antiapoptotic protein Bcl-2, release of cytochrome c from mitochondria, activation of caspase-3 and proteolytic cleavage of poly (ADP-ribose) polymerase (PARP) and caspase-independent apoptosis through apoptosis inducing factor (AIF). Furthermore, in vivo toxicity study demonstrated that PLAB did not induce significant structural and biochemical changes in mouse liver and kidneys at a dose of 25 mg/kg. Therefore, PLAB may become a potential lead compound for future development of antiglioma therapy.
Evidence-based Complementary and Alternative Medicine 01/2012; 2012:957568. · 4.77 Impact Factor
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Muhammad Khan,
Chuan Ding,
Azhar Rasul,
Fei Yi,
Ting Li,
Hongwen Gao,
Rong Gao,
Lili Zhong,
Kun Zhang,
Xuedong Fang,
Tonghui Ma
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ABSTRACT: Isoalantolactone, a sesquiterpene lactone compound possesses antifungal, antibacteria, antihelminthic and antiproliferative activities. In the present study, we found that isoalantolactone inhibits growth and induces apoptosis in pancreatic cancer cells. Further mechanistic studies revealed that induction of apoptosis is associated with increased generation of reactive oxygen species, cardiolipin oxidation, reduced mitochondrial membrane potential, release of cytochrome c and cell cycle arrest at S phase. N-Acetyl Cysteine (NAC), a specific ROS inhibitor restored cell viability and completely blocked isoalantolactone-mediated apoptosis in PANC-1 cells indicating that ROS are involved in isoalantolactone-mediated apoptosis. Western blot study showed that isoalantolactone increased the expression of phosphorylated p38 MAPK, Bax, and cleaved caspase-3 and decreased the expression of Bcl-2 in a dose-dependent manner. No change in expression of phosphorylated p38 MAPK and Bax was found when cells were treated with isoalantolactone in the presence of NAC, indicating that activation of these proteins is directly dependent on ROS generation. The present study provides evidence for the first time that isoalantolactone induces ROS-dependent apoptosis through intrinsic pathway. Furthermore, our in vivo toxicity study demonstrated that isoalantolactone did not induce any acute or chronic toxicity in liver and kidneys of CD1 mice at dose of 100 mg/kg body weight. Therefore, isoalantolactone may be a safe chemotherapeutic candidate for the treatment of human pancreatic carcinoma.
International journal of biological sciences 01/2012; 8(4):533-47. · 2.70 Impact Factor
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ABSTRACT: Gastric cancer is the fourth most commonly diagnosed cancer with the second highest mortality rate worldwide. Surgery, chemotherapy and radiation therapy are generally used for the treatment of stomach cancer but only limited clinical response is shown by these therapies and still no effectual therapy for advanced gastric adenocarcinoma patients is available. Therefore, there is a need to identify other therapeutic agents against this life-threatening disease. Plants are considered as one of the most important sources for the development of anticancer drugs. Magnolol, a natural compound possesses anticancer properties. However, effects of Magnolol on human gastric cancer remain unexplored. The effects of Magnolol on the viability of SGC-7901 cells were determined by the MTT assay. Apoptosis, mitochondrial membrane potential and cell cycle were evaluated by flow cytometry. Protein expression of Bcl-2, Bax, caspase-3 and PI3K/Akt was analysed by Western blotting. Magnolol induced morphological changes in SGC-7901 cells and its cytotoxic effects were linked with DNA damage, apoptosis and S-phase arrest in a dose-dependent manner. Magnolol triggered the mitochondrial-mediated apoptosis pathway as shown by an increased ratio of Bax/Bcl-2, dissipation of mitochondrial membrane potential (ΔΨm), and sequential activation of caspase-3 and inhibition of PI3K/Akt. Additionally, Magnolol induced autophagy in SGC-7901 cells at high concentration but was not involved in cell death. Magnolol-induced apoptosis of SGC-7901 cells involves mitochondria and PI3K/Akt-dependent pathways. These findings provide evidence that Magnolol is a promising natural compound for the treatment of gastric cancer and may represent a candidate for in vivo studies of monotherapies or combination antitumor therapies.
International Journal of Oncology 11/2011; 40(4):1153-61. · 2.40 Impact Factor
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ABSTRACT: Artemisia argyi is a widely used medicinal plant in China. The present study was designed to identify the bioactive constituents with anti-glioma activity from leaves of Artemesia argyi. A bioactivity guided approach based on MTT assay for cells growth inhibition, led to the isolation of a flavonoid, “jaceosidin” from ethanol extract of leaves of Artemesia argyi. The growth inhibitory effect of jaceosidin was explored using flow cytometry and Western blot studies. Our results showed that jaceosidin exerts growth inhibitory effect by arresting the cells at G2/M phase and induction of apoptosis. Furthermore, our study revealed that induction of apoptosis was associated with cell cycle arrest at G2/M phase, up regulation of p53 and Bax, decrease in mitochondrial membrane potential, release of cytochrome c and activation of caspase-3. This mitochondrial caspase-3 dependent apoptosis pathway was confirmed by pretreatment with caspase-3 inhibitor, Ac-DEVD-CHO. Our findings suggested that jaceosidin induces mitochondrial caspase-3 dependent apoptosis in U87 cells by arresting the cell cycle at G2/M phase.
Evidence-based Complementary and Alternative Medicine 01/2011; · 4.77 Impact Factor
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4th International Cancer Control Congress, Seoul, South Korea; 01/2011
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ABSTRACT: Jaceosidin, emodin and magnolol are natural compounds isolated from Chinese herbs and are reported
to have anticancer properties; although a combination of natural anticancer drugs could increase the
efficacy of anticancer activity. However, the combination of these compounds was examined by using
MTT assay, cell cycle arrest, flow cytometry and western blot on melanoma A375. The results showed
that the new combinations induced cell cycle arrest in G2 phase and apoptosis through Bcl-2
expression. Emodin enhanced the anticancer activity of jaceosidin and magnolol; as such, a
combination of emodin with magnolol was more effective. These observations indicated that a
combination of emodin with magnolol and jaceosidin enhanced anticancer activity through induced
apoptosis by Bcl-2 expression, while a combination of emodin with magnolol was more effective than
other combinations and could be considered further in future researches of melanoma.
Journal of Medicinal Plants Research. 01/2011;
