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ABSTRACT: This experimental study investigated the antitumor effect of Cordyceps militaris in NCI-H406 cell transplanted nude mice. After feeding an aqueous solution of C. militaris extracts in NCI-H460 cell xenografted nude mice for 4 weeks, we measured the size of a tumor mass and calculated the inhibition rate. We also estimated survival time and calculated mean survival time and percent increase in lifespan. Results showed that the inhibition rate of water extract of the 150 mg/kg/day C. militaris-administered group was 94.73-75.08% and that of the 300 mg/kg/day C. militaris-administered group was 85.81-73.81%. The tumor weights and volumes decreased in a dose-dependent manner. Mean survival time of the 150 mg/kg/day C. militaris-administered group was extended to 19.43 +/- 2.44 days and 5.42% increased in lifespan (ILS) and that of the 300 mg/kg/day C. militaris-administered group was 21.86 +/- 3.53 days and 18.61% ILS. The relative liver weight was significantly increased in 300 mg/kg/day C. militaris-administered group, but there was no histopathological difference. In conclusion, C. militaris, shrunk tumors and increased mouse lifespan, suggesting that C. militaris was effective in treating tumors in nude mice.
Journal of acupuncture and meridian studies. 12/2009; 2(4):294-300.
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ABSTRACT: Acetylcholinesterase (AChE) plays a key role in terminating neurotransmission at cholinergic synapses. This catalytic property
of acetylcholinesterase made it focus of intense research for much of the past century. However, the rapidly accumulating
evidence for involvement of this protein in novel functions, such as cell adhesion, differentiation and proliferation, deserves
to be summarized. In addition, several recent studies have indicated that acetylcholinesterase is potentially a marker and
a regulator of apoptosis. In addition, we elucidated that AChE plays a pivotal role in apoptosome formation during apoptosis.
In this chapter, we will first review briefly not only classical but also non-classical roles of acetylcholinesterase. We
will next discuss the involvement of acetylcholinesterase in apoptosis, focusing the role of AChE in apoptosome formation.
Finally, we will also discuss the therapeutic consideration of AChE for cancer therapy.
KeywordsAcetylcholinesrase-apoptosis-apoptosome-cancer-inhibitors
11/2009: pages 221-236;
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ABSTRACT: Cordyceps militaris is well known as a traditional medicinal mushroom and is a potentially interesting candidate for use in cancer treatment. In this study, the potential of the water extract of C. militaris (WECM) to induce apoptosis in human lung carcinoma A549 cells and its effects on telomerase activity were investigated. The growth inhibition and apoptosis induction by WECM treatment in A549 cells was associated with the induction of Fas, catalytic activation of caspase-8, and Bid cleavage. Activation of caspases, downregulation of anti-apoptotic Bcl-2 expression, and upregulation of pro-apoptotic Bax protein were also observed in WECM-treated cells. However, the cytotoxic effects and apoptotic characteristics induced by WECM were significantly inhibited by z-DEVD-fmk, a caspase-3 inhibitor, which demonstrates the important role that caspase-3 plays in the process. In addition, WECM exerted a dose-dependent inhibition of telomerase activity via downregulation of human telomerase reverse transcriptase (hTERT), c-myc and Sp1 expression. Taken together, the data from this study indicate that WECM induces the apoptosis of A549 cells through a signaling cascade of death receptor-mediated extrinsic and mitochondria-mediated intrinsic caspase pathways. It was also conclude that apoptotic events due to WECM were mediated with diminished telomerase activity through the inhibition of hTERT transcriptional activity.
Food and chemical toxicology: an international journal published for the British Industrial Biological Research Association 05/2009; 47(7):1667-75. · 2.99 Impact Factor
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ABSTRACT: Korean red ginseng (KRG, Panax ginseng C.A. Meyer Radix rubra) has been used to treat various diseases including cancer. However, the molecular mechanisms responsible for KRG extract induced apoptosis and telomerase inhibition remain unclear.
The hot water extract from KRG was used to evaluate the mechanism of induction of apoptosis in U937 human leukemia cells and its effects on cyclooxgenase-2 (COX-2) and telomerase activity.
KRG extract treatment to U937 cells resulted in growth inhibition and induction of apoptosis in a concentration-dependent manner as measured by hemacytometer counts, MTT assay, fluorescence microscopy, agarose gel electrophoresis and flow cytometry analysis. The increase in apoptosis was associated with the down-regulation of antiapoptotic Bcl-2, Bcl-X(L), and IAPs family members, and the activation of caspase-3. KRG extract treatment also decreased the expression levels of COX-2 and inducible nitric oxide synthase. Furthermore, KRG extract treatment progressively down-regulated the expression of human telomerase reverse transcriptase, a main determinant of the telomerase enzymatic activity, with inhibiting the expression of c-Myc in a concentration-dependent manner.
These results provide important new insights into the possible molecular mechanisms of the anticancer activity of KRG extract.
Journal of Ethnopharmacology 12/2008; 121(2):304-12. · 3.01 Impact Factor
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Sang Eun Park,
Sun Wha Lee,
Mohammad Akbar Hossain,
Min Young Kim,
Mi-Na Kim,
Eun Young Ahn,
Young Chul Park,
Hongsuk Suh,
Gi-Young Kim,
Yung Hyun Choi,
Nam Deuk Kim
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ABSTRACT: We previously reported that HS-1200, a synthetic chenodeoxycholic acid derivative, has apoptosis-inducing activity in various human cancer cells. The present study was undertaken to examine whether HS-1200 had an anticancer effect on HepG2 (wild-type p53) and Hep3B (p53 deleted) human hepatoma cells. Treatment of both cells with HS-1200 resulted in growth inhibition and induction of apoptosis as measured by MTT assay, nuclear staining, DNA fragmentation and flow cytometry analysis. The increase in apoptosis was associated with the alteration in the ratio of Bcl-2/Bax protein expression. In addition, flow cytometry analysis indicated that HS-1200 induced G1 phase arrest in both cells. When analyzing the expression of cell cycle-related proteins, we found that HS-1200 reduced the expression levels of cyclin D1, cyclin A, and Cdk2. HS-1200 treatment also caused an increase in the expression levels of p21 WAF1/CIP1 in HepG2 cells in a p53-dependent manner and in Hep3B cells in a p53-independent manner. Moreover, the expression level of p27 KIP1 was increased in both cell lines. We also observed that HS-1200 decreased the levels of cyclooxygenase (COX)-2 mRNA and protein expression. Furthermore, HS-1200 treatment markedly induced the Egr-1 expression at an early time point, and the increased expression levels of p53, p21 WAF1/CIP1, p27 KIP1, and COX-2 after treatment with HS-1200 were completely inhibited in HepG2 cells and partially inhibited in Hep3B cells by silencing of Egr-1, respectively. Taken together, these findings provide important new insights into the possible molecular mechanisms of the anticancer activity of the synthetic bile acid derivative, HS-1200, through Egr-1 regulation.
Cancer letters 07/2008; 270(1):77-86. · 4.86 Impact Factor
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Sang Eun Park,
Seung Hun Jeong,
Soo-Bog Yee,
Tae Hyun Kim,
Young Hwa Soung,
Nam Chul Ha,
Nam Deuk Kim,
Jae-Yong Park,
Hae Rahn Bae,
Bong Soo Park,
Hye Jeong Lee,
Young Hyun Yoo
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ABSTRACT: Acetylcholinesterase (AChE) is emerging as an important component in leading to apoptosis. Our previous study demonstrated that silencing of the AChE gene blocked the interaction between cytochrome c and apoptotic protease-activating factor-1 (Apaf-1) in etoposide-induced apoptosis of HT-29 cells. We undertook this study to further dissect the molecular role of AChE in apoptosome formation. The present study elicited that small interfering RNA (siRNA) to cytochrome c gene blocked the interaction of AChE with Apaf-1, whereas siRNA to Apaf-1 gene did not block the interaction of AChE with cytochrome c, indicating that the interaction of AChE with cytochrome c is required for the interaction between cytochrome c and protease-activating factor-1. We further observed that AChE is localized to caveolae via interacting with caveolin-1 during apoptosis and that the disruption of caveolae prevented apoptosome formation. These data indicate that the interactions of AChE with caveolin-1 and subsequently with cytochrome c appear to be indispensable for apoptosome formation.
Carcinogenesis 05/2008; 29(4):729-37. · 5.70 Impact Factor
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ABSTRACT: In this study, we investigated the effects of 2,3,6-tribromo-4,5-dihydroxybenzyl methyl ether (TDB), isolated from Symphyocladia latiuscula (marine red algae), on the proliferation of MCF-7 human breast cancer cells. TDB treatment for 48 h inhibited cancer cell growth and induced DNA fragmentation. Furthermore, morphological characterizations such as apoptotic bodies and membrane blebs were shown by electronic microscopy. TDB-induced apoptosis in the MCF-7 cells was closely linked with the down-regulation of Bcl-2 protein expression and the cleavage of caspase-3 substrates, with poly(ADP-ribose) polymerase cleavage occurring by TDB treatment. TDB treatment also caused a marked increase in the level of p21WAF1/CIP1 protein in a p53-dependent manner. In addition, the upregulation of p21WAF1/CIP1 in the MCF-7 cells was related to a decrease in c-Myc protein in a dose-dependent manner. Based on our data, TDB is a good candidate for further evaluation as an effective chemotherapeutic agent, acting through the induction of apoptosis.
Archives of Pharmacal Research 10/2007; 30(9):1132-7. · 1.59 Impact Factor
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ABSTRACT: In this study, we investigated the effects of 2,3,6-tribromo-4,5-dihydroxybenzyl methyl ether (TDB), isolated fromSymphyocladia latiuscula (marine red algae), on the proliferation of MCF-7 human breast cancer cells. TDB treatment for 48 h inhibited cancer cell
growth and induced DNA fragmentation. Furthermore, morphological characterizations such as apoptotic bodies and membrane blebs
were shown by electronic microscopy. TDB-induced apoptosis in the MCF-7 cells was closely linked with the down-regulation
of Bcl-2 protein expression and the cle⇑age of caspase-3 substrates, with poly(ADP-ribose) polymerase cleavage occurring by
TDB treatment. TDB treatment also caused a marked increase in the level ofp21
WAF1/CIP1 protein in a p53-dependent manner. In addition, the upregulation ofp21
WAF1/CIP1 in the MCF-7 cells was related to a decrease in c-Myc protein in a dose-dependent manner. Based on our data, TDB is a good
candidate for further evaluation as an effective chemotherapeutic agent, acting through the induction of apoptosis.
Archives of Pharmacal Research 08/2007; 30(9):1132-1137. · 1.59 Impact Factor
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ABSTRACT: The diphenyleneiodonium (DPI) is widely used as an inhibitor of flavoenzymes, particularly NADPH oxidase. In this study, we investigated the effect of DPI on the apoptosis of human RPE cells. DPI treatment in ARPE-19 cells evoked a dose- and time-dependent growth inhibition, and also induced DNA fragmentation and protein content of the proapoptotic factor Bax. In addition, DPI significantly induced the expression and phosphorylation of p53, which induces proapoptotic genes in response to DNA damage or irreparable cell cycle arrest. ROS have been implicated as a key factor in the activation of p53 by many chemotherapeutic drugs. Recent data on the regulation of intracellular ROS by DPI are controversial. Therefore, we analyzed whether DPI could contribute to the generation of intracellular ROS. Although there was increase in ROS level from cells treated for 24h with DPI, it was not detectable at early time points, required to induce p53 expression. And DPI-induced p53 expression was not affected by the ROS scavenger NAC. We conclude that DPI induces the expression of p53 by ROS-independent mechanism in ARPE-19 cells, and renders cells sensitive to drug-induced apoptosis by induction of p53 expression.
FEBS Letters 02/2007; 581(2):180-6. · 3.54 Impact Factor
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ABSTRACT: Evodiamine is one of the major bioactive compounds that have been isolated and purified from the fruit of Evodiae fructus. Evodiamine exhibits antitumor activities against the human tumor cells, including multidrug-resistant tumor cells. However, the molecular mechanism involved in cell death induced by evodiamine treatment remains poorly understood. In the present study, we showed that evodiamine activated the caspase-dependent apoptotic pathway. This apoptosis was only partially inhibited by a pancaspase inhibitor benzyloxycarbonyl-Val-Ala-Asp-fluoromethyl ketone, which suggested that evodiamine-induced apoptosis in leukemic U937 cells is partially caspase independent. We observed the nuclear translocation of apoptosis-inducing factor in evodiamine-induced apoptosis of U937 cells, which may be responsible for the caspase-independent apoptotic execution. We next showed that evodiamine induced the substantial amount of apoptosis both in Bcl-2- and Akt-overexpressing U937 cells but not in human peripheral blood mononuclear cells. Although benzyloxycarbonyl-Val-Ala-Asp-fluoromethyl ketone inhibited caspase activity in Bcl-2-overexpressing U937 cells, it completely prevented neither the induction of apoptosis or the nuclear translocation of apoptosis-inducing factor, which suggests that evodiamine is, at least in part, able to bypass the resistance of leukemia cells via caspase-independent apoptotic pathways. Thus, therapeutic strategy using evodiamine may warrant further evaluation.
Molecular Cancer Therapeutics 10/2006; 5(9):2398-407. · 5.23 Impact Factor
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ABSTRACT: To clarify the direct effects of aberrant overexpression of stromal cell-derived factor-1 (SDF-1) by the human endothelium on circulating progenitor cells, we overexpressed the SDF-1 gene in human umbilical vein endothelial cells using an adenoviral vector (HUVEC/AdeSDF-1) and examined the endothelium-supported trafficking and growth of hematopoietic progenitor cells (HPCs) in mobilized peripheral blood (mPB). In culture, the HUVEC/AdeSDF-1 monolayers induced the migration of mPB CD34(+) cells underneath the endothelium within a few hours, whereas HUVEC monolayers that expressed the LacZ gene (HUVEC/AdeLacZ) did not have this effect. In the Transwell system, the HUVEC/AdeSDF-1 cells supported a higher level of spontaneous transmigration of mPB CD34(+) cells than did the HUVEC/AdeLacZ cells. The co-culturing of mPB CD34(+) cells with HUVEC/ AdeSDF-1 cells led to a greater expansion of CD45(+) cells and colony-forming cells and reduced cellular apoptosis. Furthermore, the co-culturing of mPB CD34(+) cells with HUVEC/AdeSDF-1 cells led to the formation of numerous cobblestone-like areas, whereas co-cultures of mPB CD34(+) cells and HUVEC/AdeLacZ supported only a few cobblestone-like areas. These results indicate that SDF- 1 produced by endothelial cells plays an important role not only in the transmigration but also in the growth of HPCs that are in contact with endothelial cells. Our findings suggest that the enhanced expression and production of SDF-1 in the endothelium are essential steps for stem cell or progenitor cell recruitment to specific tissues and for the maintenance of these cells in situ.
Stem Cells and Development 05/2006; 15(2):260-8. · 4.46 Impact Factor
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Sang Eun Park,
Nam Sook Park,
Jae Min Chun,
Nam Whan Park,
Young Joon Yang,
Gak Won Yun,
Hyo Jin Lee,
Hwan Jung Yun,
Deog Yeon Jo,
Kyu Sang Song,
Samyong Kim
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ABSTRACT: Solid pseudopapillary tumor of the pancreas (SPTP) is a rare primary pancreatic tumor of an unknown etiology that is usually diagnosed in adolescent girls and young women. Most SPTPs are considered to be benign and only rarely metastasize. We report here on a 27-year old woman with recurrent SPTP with involvement of both the spleen and left kidney at the time of the initial diagnosis, and with aggressive behavior. In July 1995, she was admitted with abdominal discomfort and mass. She underwent exploratory laparotomy with distal pancreatectomy, left nephrectomy and splenectomy, and was diagnosed with SPTP with invasion to both the spleen and left kidney. In June 2001, she again presented with abdominal pain and was diagnosed as having recurrence of the tumor. She underwent mass excision and omentectomy. Then she was lost to follow-up. In November 2005, she presented once again with an abdominal mass and was diagnosed with recurred SPTP, which formed a huge intraperitoneal mass with peritoneal seeding and the tumor showed multiple metastases in the liver. She is currently being treated conservatively.
Cancer Research and Treatment 04/2006; 38(2):118-20.
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ABSTRACT: We investigated the possible mechanisms by which petrotetrayndiol A, a polyacetylene from the sponge Petrosia sp., exerts its anti-proliferative activity in cultured SK-MEL-2 human melanoma cells. Petrotetrayndiol A-treated SK-MEL-2 cells showed growth inhibition and induction of apoptosis in a dose-dependent manner as measured by MTT assay, fluorescent microscopy and flow cytometric analysis. Flow cytometric analysis revealed that petrotetrayndiol A resulted in G2/M arrest in the cell cycle progression which was associated with a marked decrease in the protein expression of cyclin B1 and its activating partner Cdc2 with concomitant inductions of p21WAF1/CIP1. The increase in apoptosis was associated with a dose-dependent up-regulation of cytosolic factor, such as Bax and release of cytochrome c, and down-regulation of Bcl-2. We also observed activation of caspase-9 and caspase-3, DNA ladder formation, proteolytic degradation of poly(ADP-ribose)-polymerase (PARP), and selective down-regulation of cIAP-1. The apoptotic manifestations, such as PARP cleavage and DNA fragmentation, were abolished in the presence of the tripeptide caspase inhibitor z-VAD-fmk and a caspase-3-specific inhibitor Ac-DEVD-cho. Our data thus demonstrate that petrotetrayndiol A-induced apoptosis and growth inhibition of SK-MEL-2 cells is dependent on caspase activation.
Cancer Letters 03/2006; 232(2):214-25. · 4.24 Impact Factor
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ABSTRACT: Androgens remain a common treatment for certain type of anemia, based upon its myelostimulating effects; however, it has not been established whether androgens affect apoptosis of hematopoietic progenitor cells (HPCs). We investigated the effects of the androgens, such as testosterone, 5beta-dihydrotestosterone (5-DHT), and oxymetholone, on apoptosis of normal hematopoietic progenitor cells in vitro. Androgens did not rescue normal bone marrow (BM) CD34+ cells and colony-forming cells (CFCs), other than mature erythroid CFCs, from apoptosis induced by serum- and growth factor deprivation. Oxymetholone did not affect growth factor-mediated survival of normal CD34+ cells or its inhibition by interferon-gamma (IFN-gamma). In a standard methylcellulose clonogenic assay, low concentrations of oxymetholone and 5-DHT stimulated the clonal growth of colony-forming unit (CFU)-erythroid, but did not affect growth of CFU-granulocyte/macrophage or burst-forming unit-erythroid. Oxymetholone and 5-DHT stimulated the production of stem cell factor in normal bone marrow stromal cells (BMSCs) via transcriptional regulation. In agreement with this, oxymetholone-treated BMSCs better supported the survival of HPCs. These data indicate that survival-enhancing or growth-stimulatory effects of androgens on hematopoietic progenitor cells are minimal and mostly restricted to mature erythroid progenitors, and its myelostimulating effects could be attributed, at least in part, to the stimulation of production of hematopoietic growth factors in BMSCs.
Journal of Korean Medical Science 07/2005; 20(3):409-16. · 0.99 Impact Factor
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ABSTRACT: As previously demonstrated, the synthetic bile acid derivatives mediate anti-proliferative properties in a variety of human cancer cells. In the present study, the effects of the synthetic derivatives of ursodeoxycholic acid (UDCA), HS-1030 and HS-1183, and chenodeoxycholic acid (CDCA), HS-1199 and HS-1200, on the proliferation of HT-29 human colon cancer cells were investigated. Whereas UDCA and CDCA had no effect on the growth of cells in the concentration ranges we have tested, HS-1199 and HS-1200 completely inhibited cell proliferation, while HS-1030 and HS-1183 showed weak inhibitory activities. Simultaneous estimation of cell cycle parameters and apoptosis by flow cytometry showed that the synthetic bile acid derivatives produced the arrest of cell cycle progression at the G1 phase and ensuing increase of sub-G1 fraction, which resulted in the induction of apoptosis. The induction of apoptosis was confirmed by observation of cleavages of poly(ADP-ribose) polymerase and DNA fragmentation. Furthermore, Western blot analysis showed decreased expression levels of cyclin D1, cyclin E, cyclin A, Cdk2, Cdk4, and Cdk6 proteins. In addition, the synthetic bile acid derivatives markedly induced the level of Cdk inhibitor, p21WAF1/CIP1, in a p53-independent manner. Furthermore, the exposure of cells to the synthetic bile acid derivatives resulted in a decrease in the level of pRb and enhanced binding between pRb and E2F-1. Based on these data, these synthetic bile acid derivatives may serve as potential lead compounds in the treatment of colon cancer.
International Journal of Oncology 08/2004; 25(1):231-6. · 2.40 Impact Factor
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ABSTRACT: Although a recent study (Zhang et al. Cell Death Differ 2002; 9; 790-800) presented that acetylcholinesterase (AChE) might be an important common component in leading to various types of apoptosis, the molecular mechanism, by which AChE functions, had remained elusive before that study. We explored the role of AChE in apoptosis by silencing the AChE gene. Silencing of the AChE gene abolished the expression of AChE and prevented caspase-9 activation, decrease of cell viability, nuclear condensation and poly(adenosine diphosphate-ribose) polymerase cleavage but not mitochondrial events. Importantly, silencing of the AChE gene blocked the interaction between apoptotic protease-activating factor-1 and cytochrome c. Here we propose that AChE plays a pivotal role in the formation of apoptosome.
Cancer Research 05/2004; 64(8):2652-5. · 7.86 Impact Factor
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ABSTRACT: Redox factor-1 (Ref-1) is a ubiquitously expressed protein with proven roles as a modulator of redox-sensitive transcription, and as an endonuclease in the base excision repair pathway of oxidatively damaged DNA. Although Ref-1 is induced by a variety of oxidative stress and protects cells against oxidative stress, the function of Ref-1 in regulating nitric oxide (NO) synthesis has not been elucidated to date. We investigated the role of Ref-1 in regulating NO synthesis and NO-mediated apoptosis employing adenoviral-mediated overexpression of Ref-1 in lipopolysaccharide (LPS)-stimulated macrophage RAW 264.7 cells. LPS treatment produced NO synthesis and NO-mediated apoptosis. Forced overexpression of Ref-1 suppressed LPS-stimulated NO synthesis. In parallel with this, Ref-1 also mitigated alteration of inducible NO synthase expression and NO-mediated apoptosis. Our findings suggest that Ref-1 is implicated in protection against cell death resulting from oxidative stimuli containing NO.
FEBS Letters 02/2004; 556(1-3):39-42. · 3.54 Impact Factor
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ABSTRACT: In the present study, we investigated the effects of the water extract of Euphorbiae humifusae (WEEH), an oriental medicinal herb, on the growth of Hep3B human hepatocarcinoma cells. We found that WEEH treatment resulted in a significant decrease in the cell viability of Hep3B cells depending on dosage. This decrease was revealed to be apoptosis, evidenced by chromatin condensation, DNA fragmentation and an accumulation of apoptotic fraction. WEEH induced the expression of death receptor-related proteins such as Fas, tumor necrosis factor-related apoptosis-inducing ligand, death receptor (DR) 4 and DR5, which further triggered caspase-8 activation and truncated Bid cleavage. Mitochondrial dysfunction, the catalytic activation of caspase-9, down-regulation of anti-apoptotic Bcl-2 and Bcl-xL expression, and up-regulation of the pro-apoptotic Bax protein were also observed in WEEH-treated cells. In addition, the increase in apoptosis induced by WEEH was correlated with caspase-3 activation and the concomitant degradation of poly (ADP-ribose) polymerase. However, the cytotoxic effects and apoptotic characteristics induced by WEEH were significantly inhibited by z-DEVD-fmk, a caspase-3 inhibitor. This demonstrates the important role played by caspase-3 in the process. Collectively, our data indicate that WEEH induces Hep3B cell apoptosis through a signaling cascade of death receptor-mediated extrinsic and mitochondria-mediated intrinsic caspase pathways.
Molecular Medicine Reports 2(2):221-7. · 0.42 Impact Factor
