Soon-Do Cha

Keimyung University, Sŏul, Seoul, South Korea

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Publications (16)37.24 Total impact

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    ABSTRACT: Dysregulated cyclin-dependent kinases (CDKs) are considered a potential target for cancer therapy. Flavopiridol is a potent CDK inhibitor. In this study, the antiproliferative effect of the flavonoid compound flavopiridol and its mechanism in human uterine leiomyoma cells were investigated. The present study focused on the effect of flavopiridol in cell proliferation and cell cycle progression in primary cultured human uterine leiomyoma cells. Cell viability and cell proliferation assays were conducted. Flow cytometry was performed to determine the effect of flavopiridol on cell cycle. The expression of cell cycle regulatory-related proteins was evaluated by Western blotting. Cell viability and proliferation of uterine leiomyoma cells were significantly reduced by flavopiridol treatment in a dose-dependent manner. Flow cytometry results showed that flavopiridol induced G1 phase arrest. Flavopiridol-induced growth inhibition in uterine leiomyoma cells was associated with increased expression of p21(cip/wafl) and p27(kip1) in a dose-dependent manner. Downregulation of CDK2/4 and Cyclin A with a concomitant increase in dephosphorylation of retinoblastoma was observed. This study demonstrates that flavopiridol inhibits cell proliferation by initiating G1 cell cycle arrest in human uterine leiomyoma. We also found that flavopiridol is effective in inhibiting xenografted human uterine leiomyoma growth. These results indicate that flavopiridol could prove to be a promising chemopreventive and therapeutic agent for human uterine leiomyoma.
    Reproductive sciences (Thousand Oaks, Calif.) 02/2014; · 2.31 Impact Factor
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    ABSTRACT: BACKGROUND: Chemo-resistance to cisplatin-centered cancer therapy is a major obstacle to effective disease treatment. Recently, salinomycin was proven to be highly-effective for the elimination of cancer stem cells both in vitro and in vivo. The objective of the present study was to evaluate the anticancer properties of salinomycin in cisplatin-resistant ovarian cancer cells (A2780cis). MATERIALS AND METHODS: The tetrazolium dye (MTT) assay was used to determine cell viability. Flow cytometric analysis was performed to analyze the effect on cell cycle and apoptosis. The expression of apoptosis-related proteins was evaluated by western blot analysis. RESULTS: Cell viability was significantly reduced by salinomycin treatment in a dose-dependent manner. Flow cytometry showed an increase in sub-G1 phase cells. Salinomycin increased the expression of death receptor-5 (DR5), caspase-8 and Fas-associated protein with death domain (FADD). A decline in the expression of FLICE-like inhibitory protein (FLIP), activation of caspase-3 and increased poly ADP-ribose polymerase (PARP) cleavage, triggered apoptosis. Furthermore, annexin-V staining also revealed the apoptotic induction. CONCLUSION: These findings provide important insights regarding the activation of caspase-8 and DR5, to our knowledge, for the first time in salinomycin-treated cisplatin-resistant ovarian cancer and demonstrate that salinomycin could be a prominent anticancer agent.
    Anticancer research 04/2013; 33(4):1457-1462. · 1.71 Impact Factor
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    ABSTRACT: Induction of apoptosis in target cells is a key mechanism by which chemotherapy promotes cell killing. The purpose of this study was to determine whether Indole-3-Carbinol (I3C) and Genistein in combination with tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) induce apoptosis in endometrial cancer cell (Ishikawa) and to assess apoptotic mechanism. The MTT assay and flow cytometry were performed to determine cell viability and cell cycle. The induction of apoptosis was measured by caspase-3 activity test, DNA fragmentation assay, annexin V binding assay and western blot analysis. There was no effect in cell growth inhibition and cell cycle progression alone or in two-combination. However, the treatment of I3C and Genistein followed by TRAIL showed significant cell death and marked increase in sub-G1 arrest. Three-combination treatment revealed elevated expression of DR4, DR5 and cleaved forms of caspase-3, caspase-8, PARP. The Flip was found down regulated. Moreover, increase in caspase-3 activity and DNA fragmentation indicated the induction of apoptosis. The results indicate that I3C and Genistein with TRAIL synergistically induced apoptosis via death receptor dependent pathway. Our findings might provide a new insight into the development of novel combination therapies against endometrial cancer.
    Journal of Korean medical science 04/2013; 28(4):527-33. · 0.84 Impact Factor
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    ABSTRACT: BACKGROUND: Despite advances in treatment, ovarian cancer is the most lethal gynecologic malignancy. Therefore significant efforts are being made to develop novel strategies for the treatment of ovarian cancer. Salinomycin has been shown to be highly effective in the elimination of cancer stem cells both in vitro and in vivo. The present study focused on investigating important cell signaling molecules such as Akt and NF-κB during salinomycin-induced apoptosis in cisplatin resistant ovarian cancer cells (A2780cis). METHODS: MTT assay was performed to determine cell viability. Flow cytometry and DNA fragmentation assay were performed to analyze the effect on cell cycle and apoptosis. The expression of apoptosis related proteins was evaluated by Western blot analysis. RESULTS: The cell viability was significantly reduced by salinomycin treatment in a dose dependent manner. The flow cytometry result showed an increase in sub-G1 phase. Salinomycin inhibited the nuclear transportation of NF-κB, and downregulated Akt expression. Declined Bcl-2, activation of caspase-3 and increased PARP cleavage triggered apoptosis. Moreover, DNA fragmentation assay also revealed apoptotic induction. CONCLUSION: The result suggested that salinomycin-induced apoptosis in A2780cis was associated with inhibition of Akt/NF-κB. It may become a potential chemotherapeutic agent for the cisplatin resistant ovarian cancer therapy.
    Cancer epidemiology. 03/2013;
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    ABSTRACT: Osteopontin (OPN) involves in the tumor-promoting or metastasis in human endometrial cancer. Depletion of OPN gene expression in endometrial cancer cells was significantly decreased in cell viability and the cells undergo apoptotic cell death. The status of OPN in THESC, RL95, Hec1A and Ishikawa cell lines were analyzed by RT-PCR and western blot. After OPN-siRNA transfection, mRNA and protein expression levels of OPN were determined in Hec1A and Ishikawa cells. Cell proliferation and cell cycle distribution were observed by MTT and flow cytometry analysis. DNA fragmentation assay was used to measure cell apoptosis. Cell migration was assessed by wound healing assay. Depletion of OPN gene expression in endometrial cancer cell lines (Hec1A and Ishikawa cells) reproducibly changed their ability of proliferation. Concomitant changes were seen in the expression of OPN binding cell surface receptors, cell cycle-regulatory genes, cell invasion and colony formation nature of the tumor cells. Decreased colonizing potential in the absence of OPN was reversed in the presence of recombinant OPN. Inhibition of anchorage-independent growth was observed in the presence of metabolic inhibitors of the PI3K, Src and integrin signaling cascades, which was ameliorated in the presence of exogenously added OPN. Our result showed the role of OPN in endometrial cancer, in particular on the malignancy-promoting aspects of OPN that may pave way for new approaches to the clinical management of endometrial cancer.
    Molecular Biology Reports 12/2012; · 2.51 Impact Factor
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    ABSTRACT: Objective: To determine the anti-tumor effect of isoliquiritigenin (ISL) on endometrial cancer cell and to evaluate its effect on apoptosis in Hec1A endometrial cancer cell lines. Methods: Human endometrial cancer cell lines (Hec1A) and Ishikawa, and normal endometrial cell line (T-HESCS) were cultured in vitro. The viabilities of three cell lines on ISL were measured. Cell cycle distribution and induction of apoptosis were measured in Hec1A cells after ISL treatment. Results: ISL significantly reduced cell viabilities of endometrial cancer cell lines but not normal cell line in a dose-dependent manner. Cell cycle analysis indicated that ISL treatment increased the proportion of cells in the sub-G0/G1 phase. DNA frag-mentation and fluorometric TUNEL assays also revealed apoptotic cell death after ISL incubation. ISL treatment markedly up-regulated the expression of cyclin-dependent kinase inhibitor, p21 Cip1/Waf1 in a p53 independent manner and down regulated the expressions of cyclins and CDKs, with concomitant increase in FAS and cleavage of caspase 7, caspase 8, and caspase 9. In addition, elevation of caspase 3 activity also observed in a dose and time dependent manner. Conclusion: ISL inhibited cell proliferation and triggered apoptosis in human endometrial cancer cell line Hec1A. Hence, ISL can be used as a potentially potent clinical chemotherapeutic agent for treating endometrial cancer.
    Journal of Women's Medicine. 01/2010; 3(3).
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    ABSTRACT: The molecular mechanism of the cell-cycle machinery in uterine leiomyoma has not yet been fully elucidated. Among the various types of cell-cycle regulators, p27(Kip1) (p27) is considered to be a potent tumor suppressor. To provide further molecular basis for understanding the progression of uterine leiomyoma, our objective was to evaluate the expression level of p27 in normal myometrium and uterine leiomyoma tissue and its effect on cytogenic growth. Western blot analysis, real-time polymerase chain reaction (PCR) and immunohistochemical staining revealed that p27 protein and messenger RNA were down-regulated in uterine leiomyoma tissue and cultured cells compared to normal myometrium. Full-length human p27 cDNA was transferred using a replication-deficient recombinant adenoviral vector (Ad.p27) into uterine leiomyoma cells and evaluated the effect on cell proliferation. Transfection of Ad.p27 into uterine leiomyoma cells resulted in the induction of apoptosis, reduction in viability and proliferation of uterine leiomyoma cells. Our results suggest a new paradigm that down-regulated p27 protein expression is the possible underlying mechanism for the growth of uterine leiomyoma and over-expression of p27 induces cell death. This study provides better understanding of the control exerted by p27 in regulating growth and disease progression of uterine leiomyoma.
    Journal of Korean Medical Science 09/2008; 23(4):667-73. · 1.25 Impact Factor
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    ABSTRACT: Isoliquiritigenin(ISL), a calchone flavonoid, has cancer-preventing properties and is often used in Chinese medicine. In the present study, the authors use ISL to determine its effect on cell proliferation and cell cycle progression in primary cultured human uterine leiomyoma cells. Cell viability and cell proliferation assays were conducted. Flow cytometry, annexin V apoptosis assay, and DNA fragmentation assay were performed to determine the effect of ISL on cell cycle and apoptosis. The expression of cell cycle regulatory-related proteins was evaluated by Western blot. The cell viability and proliferation of uterine leiomyoma cells were significantly reduced by ISL treatment in a dose-dependent manner. Flow cytometry results showed that ISL induced subG1 and G2/M arrest. DNA fragmentation assay and annexin V apoptosis assays revealed apoptosis induction. ISL-induced growth inhibition in uterine leiomyoma cells was associated with increased p21(Cip1/) Waf1 expression in a p53-dependent manner. Activation of caspase-3 and downregulation of Bcl-2, cdk 2/4, and E2F, with a concomitant increase in dephosphorylation of Rb and poly-ADP-ribose polymerase cleavage, were observed. This study demonstrates that ISL inhibits cell proliferation by initiating apoptosis in human uterine leiomyoma cells coupled with increased cell cycle arrest. These results indicate that ISL could prove to be a promising chemopreventive and therapeutic agent against human uterine leiomyoma.
    Reproductive sciences (Thousand Oaks, Calif.) 08/2008; 15(6):552-8. · 2.31 Impact Factor
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    ABSTRACT: The objectives of the present study were to evaluate the expression level of ATP-sensitive potassium (K(ATP)) channels in smooth muscle cells in human uterine leiomyoma and the involvement of the channel in potentiating effect of estrogen on leiomyoma growth. Reverse transcription-polymerase chain reaction (RT-PCR), real-time PCR and Western blot were used for the identification and quantification of K(ATP)-channel subunits in the control myometrial and leiomyoma cells. Furthermore, we measured the K(ATP)-channel activity in enzymatically isolated single uterine smooth muscle cells by whole-cell patch-clamp recordings. The estrogen-induced cell proliferation in leiomyoma was measured by the MTT assay. The subunits of K(ATP) channels (Kir6.1, Kir6.2, SUR2B) were more highly expressed in leiomyoma cells than in control cells. The whole-cell currents mainly through K(ATP) channels were also greater in the leiomyoma cells. Estrogen applied in the bath solution could acutely enhance the channel activity. Estrogen-induced proliferation of the leiomyoma cells was inhibited by pretreatment with glibenclamide, a K(ATP)-channel inhibitor. Estrogen may induce the proliferation of leiomyoma cells, at least in part, by activating the K(ATP) channel. Increased expression of the K(ATP) channel may be a causal factor for the high growth rate of uterine leiomyoma.
    Gynecological Endocrinology 06/2008; 24(5):250-6. · 1.30 Impact Factor
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    ABSTRACT: Observations from the authors' laboratory suggest a physiological role for increased cyclin G1 protein levels in human uterine leiomyoma. The hypothesis of the present study is that the strategic modulation of cyclin G1 by antisense technology will inhibit the survival of in vitro-grown uterine leiomyoma cells. Cultured uterine leiomyoma cells were transfected with cyclin G1 ribbon-type antisense oligonucleotide (cyclin G1 RiAS) to effectively reduce cyclin G1 expression. Cell viability, in situ terminal deoxyuridine nick end-labeling (TUNEL) assay, flow cytometry, DNA fragmentation, and expression of cell cycle regulatory-related proteins were evaluated by Western blot. Antisense oligonucleotides compromised uterine leiomyoma cell viability and inducted apoptosis in a caspase-independent mechanism. In situ TUNEL and DNA fragmentation revealed apoptosis induction, and fluorescent-activated cell sorting analysis showed increased sub-G1-phase cells. Furthermore, abrogation of cyclin G1 enhanced p53 accumulation, phosphorylation of p53 at Ser-15 residue, and increased expression of cyclin-dependent kinase inhibitors p21 and p27. These data imply that cyclin G1 expression is associated with growth promotion and the potential utility and novelty of using ribbon-type antisense oligonucleotides as a gene therapy strategy to treat human uterine leiomyoma.
    Reproductive sciences (Thousand Oaks, Calif.) 05/2008; 15(4):400-10. · 2.31 Impact Factor
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    ABSTRACT: The nuclear receptors PPARs (peroxisome proliferator-activated receptors) are transcription factors that play important roles in multiple disease conditions. The activation of PPARs by specific ligands is associated with growth suppression of several different types of human cancer, but the molecular mechanism responsible for this growth suppressive effect remains elusive. The aim of this study was to determine the distribution of PPARgamma protein/mRNA expression in uterine leiomyomas and to identify the PPARgamma induced signaling pathways responsible for the growth inhibition induced by treatment with ciglitizone, a synthetic ligand of PPARgamma, in view of identifying targets that could possibly affect the viability and proliferation of uterine leiomyoma cells. Dose-response studies on proliferation found that uterine leiomyoma was more sensitive to inhibition by ciglitizone treatments than normal myometrium. We also found that ciglitizone significantly stimulated gene expression driven by a PPAR-responsive element in cultured leiomyoma cells and reduced the survival of leiomyoma cells relative to the control cells. The reduced survival of ciglitizone treated leiomyoma cells resulted from a mechanism that involved the Fas receptor-mediated apoptosis signaling cascade. These results suggest that uterine leiomyomas growth and differentiation might be modulated through PPARgamma receptors and that PPARgamma ligands may be of potential use for uterine leiomyoma treatment.
    Molecular Human Reproduction 12/2007; 13(11):829-36. · 4.54 Impact Factor
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    ABSTRACT: Peroxisome proliferator-activated receptor gamma (PPARgamma) is a member of the nuclear hormone receptor superfamily. Treatment of PPARgamma ligands has been shown to inhibit the growth of various human cancer cells. However, it has not been reported whether human cervical carcinoma cells express PPARgamma. In this study, we investigated the expression of PPARgamma in human normal cervix and cervical carcinoma tissues, and as well as the effect of PPARgamma ligands on cervical cancer cells survival. Fresh cervical tissues from a study group of 10 study patients diagnosed with cervical carcinoma were analyzed for the expression of PPARgamma using real-time RT-PCR and Western blot analysis. Immunohistochemical staining for PPARgamma was also performed on the serial sections of 40 cervical carcinomas. In addition, we evaluated the feasibility of PPARgamma ligands, as a potential therapeutic drug against cervical cancer cells using MTT assay and FACS analysis. We found that there were lower expression levels of PPARgamma mRNA and protein in cervical carcinoma tissues than in normal cervical tissues. The extent and intensity of immunoreactive PPARgamma in normal cervix tissues were statistically much greater than those of carcinoma tissues. In order to study effects of PPAR ligand on cell proliferation, we chose ciglitizone that showed very potent growth inhibitory effects on the proliferation of two human cervical cancer cell lines (C-33-A and C-4II). C-4II cells express high expression of PPARgamma, while C-33A cells express low level of PPARgamma. Treatment with ciglitizone inhibited the growth of C-4II cells in a dose-dependent manner, while the growth inhibitory effect of ciglitizone was much less in C-33A cells. In order to test whether ciglitizone-induced growth suppressive effects on cervical cancer cell lines is PPAR-dependent, we treated cervical cancer cells with ciglitizone and/or GW9662 (a PPARgamma antagonist). No significant difference in cell survival was found in cells treated with ciglitizone alone vs. co-treated with ciglitizone and GW9662. GW9662 alone did not induce any cell growth arrest in the cells that we used (data not shown). Thus, we concluded that growth suppressive effects by ciglitizone may not be dependent upon status of PPAR expression. To clarify the mechanism by which ciglitizone inhibits the growth of cervical carcinoma cells, flow cytometry and Western blotting assay were performed. As results, we demonstrated that a large portion of C-4II cells (but not in C-33A) after ciglitizone treatment were arrest at G1 phase with the induction of p21(Cip1/Waf1) and p27(kip1) protein. These results suggest that PPARgamma is down-regulated in multiple human cervical cancer tissues and cell lines. Ciglitizone may suppress human cervical cancer cells in PPAR-independent manner.
    Gynecologic Oncology 06/2005; 97(2):365-73. · 3.93 Impact Factor
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    ABSTRACT: This study investigated the acute effects of a peroxisome proliferator-activated receptor (PPAR)-gamma ligand, ciglitizone, on cell proliferation and intracellular Ca2+ signaling in human normal myometrium and uterine leiomyoma. Changes in intracellular Ca2+ concentration ([Ca2+]i) were measured with fura-2 AM, and cellular viabilities were determined by viable cell count and 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide reduction assay. Ciglitizone (100 microM) induced greater inhibition of cell proliferation in uterine leiomyoma than in myometrium. Ciglitizone also dose-dependently increased [Ca2+]i in both myometrium and uterine leiomyoma; these [Ca2+]i increases were inhibited by PPAR-gamma antagonists and raloxifene. Ciglitizone-induced [Ca2+]i increase showed only an initial peak in normal myometrial cells, whereas in uterine leiomyoma there was a second sustained [Ca2+]i increase as well. The initial [Ca2+]i increase in both myometrium and uterine leiomyoma resulted from the release of Ca2+ by the sarcoplasmic reticulum via activation of ryanodine receptors. The second [Ca2+]i increase was observed only in uterine leiomyoma because of a Ca2+ influx via an activation of store-operated Ca2+ channels (SOCCs). Cell proliferation was inhibited and secondary [Ca2+]i increase in uterine leiomyoma was attenuated by cotreatment of ciglitizone with a SOCC blocker, lanthanum. The results suggest that ciglitizone inhibits cell proliferation and increases [Ca2+]i through the activation of SOCCs, especially in human uterine leiomyoma.
    AJP Cell Physiology 03/2005; 288(2):C389-95. · 3.71 Impact Factor
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    ABSTRACT: To evaluate and describe our experience in the management of recurrent second-trimester miscarriage and preterm delivery by laparoscopic transabdominal cervicoisthmic cerclage (LTCC), after failure of transvaginal cervical cerclage. Retrospective review (Canadian Task Force classification III). Tertiary care teaching hospital. Twenty women in whom it was not technically possible to perform transvaginal cerclage. LTCC. Mean operating time was 55 minutes (range 40-75 min). There were no operative or immediate postoperative complications. Mean gestational age at the time of cerclage placement was 12.1 weeks (range 11-14 wks). Nineteen women successfully delivered 21 live babies (2 sets of twins; live birth rate 95%). One loss occurred after rupture of membrane at 19 weeks' after cerclage. LTCC during pregnancy can be safe and effective treatment for well-selected patients with cervical incompetence, and eliminates the need for open laparotomy.
    The Journal of the American Association of Gynecologic Laparoscopists 08/2003; 10(3):363-6. · 1.61 Impact Factor
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    ABSTRACT: The purpose of this study was to detect the expression of cyclin G1 in leiomyoma and to investigate the alteration of its expression compared with normal myometrial tissue that was obtained from the same patient. With the use of Northern blot analysis, Western blot analysis, and immunohistochemistry, we analyzed the expression of cyclin G1 in 24 patients who underwent hysterectomies. We found that messenger RNA levels of cyclin G1 were elevated in human leiomyomas compared with their adjacent normal myometrial tissues. Consistent with elevated messenger RNA levels, high levels of cyclin G1 protein expression were detected by immunoblot analysis in all leiomyoma samples. Immunohistochemistry revealed that cyclin G1 is located mainly in the nucleus in both normal myometrium and leiomyoma. However, higher levels of cyclin G1 were apparent in tumor regions compared with adjacent normal myometrial regions. In addition, we found the expression levels of other cyclins (A and E) and CDK2 were elevated in leiomyomas compared with normal myometrium. Because cyclin G1 is a transcriptional target of the p53 tumor suppressor, we examined the p53 status of all eight leiomyoma samples and found no p53 mutations. These results suggest that cyclin G1 is frequently overexpressed in uterine leiomyoma in a p53-independent manner and that this abnormality could be attributed to the severe proliferation of human uterine leiomyomas.
    American Journal of Obstetrics and Gynecology 04/2003; 188(3):634-639. · 3.88 Impact Factor
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    ABSTRACT: Se-methylselenocysteine (Se-MSC) is a potent chemopreventive agent in many test systems and has been shown to inhibit tumor promotion and induce apoptosis, but its mechanism of action is still not well understood. The present study was designed to assess the mechanism of Se-MSC on the induction of apoptosis in SKOV-3 ovarian cancer cells. Se-MSC displayed strong inhibitory effects on cell proliferation and viability of SKOV-3 cells in dose and time dependent manners and induced apoptosis. Investigation of the mechanism of Se-MSC-induced apoptosis revealed that treatment with Se-MSC produced morphological features of apoptosis and DNA fragmentation. This was associated with caspase-3 activation and cleavage of poly(ADP-ribose) polymerase and phospholipase C-gamma1 proteins. However, SKOV-3 cells treated with Se-MSC did not demonstrate cytochrome c accumulation in the cytosol during apoptosis induction. Pretreatment of cells with the caspase inhibitors (z-VAD-fmk and DEVD-CHO) prevented Se-MSC-induced apoptosis. These results suggested that Se-MSC induces apoptosis through cytochrome c-independent caspase-3 activation in SKOV-3 cells. In late stage of apoptosis, p18kDa fragment of Bax was generated with the down-regulation of the expressions of survivin, X-linked inhibitor of apoptosis protein, and human inhibitor of apoptosis protein 1 following Se-MSC treatment, suggesting that the modulation of Bax and IAP (inhibitors of apoptosis) family proteins play some role in Se-MSC-mediated apoptosis. Pre-treatments of z-VAD-fmk and the calpain inhibitor, calpeptin inhibited Bax cleavage. These results suggested that Bax cleavage is mediated by calpain, and calpain activation may be a caspase-dependent one. Taken together, the chemopreventive effects of Se-MSC may be related in part to the caspase-3 activation, the down-regulation of IAP family proteins, and Bax cleavage mediated by caspase-dependent calpain activation.
    Cancer Letters 09/2002; 182(1):83-92. · 5.02 Impact Factor