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  • 1
    Online Resource
    Online Resource
    American Association for Cancer Research (AACR) ; 2011
    In:  Cancer Research Vol. 71, No. 8_Supplement ( 2011-04-15), p. 4089-4089
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 71, No. 8_Supplement ( 2011-04-15), p. 4089-4089
    Abstract: Cholangiocarcinoma is a highly malignant tumor with limited therapeutic options. Gemcitabine (GMT) is currently used as a first line chemotherapeutical reagent for many cancers, including cholangiocarcinoma. However, it is often used in combination with other therapeutical strategies, due to high toxicity of GMT. We have previously reported that antagonists of calmodulin (CaM), including tamoxifen (TMX), trifluoperazine (TFP) and W7, induce apoptosis of cholangiocarcinoma cells and reduce cholangiocarcinoma tumorigenesis in mice. In the present studies, we determined the effect of combination therapy of TMX and GMT on cholangiocarcinoma tumorigenesis and investigated the mechanisms responsible for their efficacy. The effect of TMX and GMT on cholangiocarcinoma cell growth and apoptosis in vitro was determined by MTS and Annexin V staining analysis. The expression/activation of apoptotic signaling molecules were assessed by Western blot analysis. A nude mouse xenograft model was utilized for in vivo cholangiocarcinoma tumorigenesis as we previously reported. TMX (15mg/kg), GMT (15mg/kg) and combination of both were administrated by intraperitoneal injection. Tumor growth was measured every 3 days. Apoptosis in xenograft tumors was determined by TUNEL and cleaved caspase 3 staining. GMT inhibited cell growth and induced apoptosis of cholangiocarcinoma cells in a concentration-dependent manner. TMX enhanced GMT-induced apoptosis and GMT inhibition of cell growth in cholangiocarcinoma cells. GMT (15mg/kg, every third day) inhibited cholangiocarcinoma tumorigenesis in nude mice by 50%. TMX (15mg/kg, two out of three days) enhanced the inhibitory effect of GMX on tumorigenesis by 33%. The inhibition of tumor growth correlated with enhanced apoptosis in tumor tissues. To elucidate the mechanisms underlying the additive effects of TMX on GMT-induced apoptosis, we determined activation of caspases in cholangiocarcinoma cells exposed to GMT, TMX or both. Activation of caspase 9 and caspase 3, as well as cytochrome c release to the cytosol were demonstrated in cells exposed to either reagent alone. By contrast, TMX but not GMT activated caspase 2. Pharmacologic inhibition of caspase 2 activation decreased TMX-, but not GMT-, induced activation of caspase 3 and apoptosis of cholangiocarcinoma cells. Similarly, activation of caspase 2 was found in tumors from TMX-treated mice, but not GMT-treated mice. Therefore, the enhanced effect of TMX on GMT-induced cholangiocarcinoma cell death is partially mediated by activation of caspase 2. TMX and GMT both induce apoptosis and inhibit cholangiocarcinoma tumorigenesis, which may be attributed to the activation of distinct apoptosis signals by TMX and GMT. Our studies provide in vivo evidence and molecular insight to support the use of TMX and GMT in combination as an effective therapy for cholangiocarcinoma. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4089. doi:10.1158/1538-7445.AM2011-4089
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    RVK:
    RVK:
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2011
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  • 2
    Online Resource
    Online Resource
    American Association for Cancer Research (AACR) ; 2011
    In:  Cancer Research Vol. 71, No. 8_Supplement ( 2011-04-15), p. 4776-4776
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 71, No. 8_Supplement ( 2011-04-15), p. 4776-4776
    Abstract: Pancreatic cancer remains a devastating malignancy with poor prognosis, which is largely resistant to current therapies. Death receptor-initiated apoptotic pathways have been implicated both in pancreatic cancer pathogenesis and therapy. To understand the resistance of pancreatic tumor to Fas death receptor-induced apoptosis, we investigated the molecular mechanisms of Fas-activated survival signaling in pancreatic cancer cells. Using lentivirus-mediated RNA interfering strategy, we generated pancreatic cancer cell lines MiaPaCa-2 and BxPc-3 with stable knockdown of the Fas associated protein with death domain (FADD), the adaptor that mediates downstream signaling upon Fas activation. Knockdown of FADD rendered these Fas-sensitive pancreatic cells resistant to apoptosis induced by the Fas agonist antibody, CH-11. Consistently, CH-11 induced recruitment of caspase-8 into the Fas-activated death inducing signaling complex was blocked in FADD knockdown cells, which was associated with no activation of caspase-8 and caspase-3. By contrast, CH-11 promoted the survival of the FADD knockdown MiaPaCa2 and BxPc3 cells in a concentration-dependant manner, as measured by MTS assay. Increased phosphorylation of ERK was demonstrated in the FADD knockdown cells in response to CH-11 treatment. The pharmacological inhibitor of ERK, PD98059, abrogated CH-11-promoted cell survival in FADD knockdown MiaPaCa-2 and BxPC-3 cells. Furthermore, increased phosphorylation of Src was demonstrated in FADD knockdown cells in response to CH-11. The Fas-induced activation of Src was blocked by the specific Src inhibitor, PP2, which further inhibited the Fas-induced activation of ERK and cell survival of the FADD knockdown cells. To elucidate the mechanisms underlying Fas-induced Src activation, we analyzed Fas-associated proteins by immunoprecipitaion of Fas in the FADD knockdown cells. Increased Src and phosphorylated Src was indentified in the Fas-associated protein complex activation by CH-11. Concomitantly, increased recruitment of calmodulin (CaM) into the Fas-associated protein complex was demonstrated as well. Trifluoperazine, a CaM antagonist, inhibited the Fas-induced recruitment of CaM, Src and phosphorylated Src. Consistently, trifluoperazine inhibited Fas-induced activation of Src and blocked Fas-promoted cell survival in the FADD knockdown cells. These results demonstrate that Fas induces FADD-independent survival signaling in pancreatic cancer cells via CaM-mediated activation of Src-ERK signaling pathways. Understanding the molecular mechanisms responsible for the resistance of pancreatic cells to apoptosis induced by Fas-death receptor signaling may provide molecular insights into designing novel therapies to treat pancreatic tumors. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4776. doi:10.1158/1538-7445.AM2011-4776
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    RVK:
    RVK:
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2011
    detail.hit.zdb_id: 2036785-5
    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
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  • 3
    In: Laboratory Investigation, Elsevier BV, Vol. 92, No. 1 ( 2012-01), p. 82-90
    Type of Medium: Online Resource
    ISSN: 0023-6837
    RVK:
    Language: English
    Publisher: Elsevier BV
    Publication Date: 2012
    detail.hit.zdb_id: 2041329-4
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  • 4
    In: Journal of Biological Chemistry, Elsevier BV, Vol. 286, No. 28 ( 2011-07), p. 24776-24784
    Type of Medium: Online Resource
    ISSN: 0021-9258
    Language: English
    Publisher: Elsevier BV
    Publication Date: 2011
    detail.hit.zdb_id: 2141744-1
    detail.hit.zdb_id: 1474604-9
    SSG: 12
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  • 5
    Online Resource
    Online Resource
    Elsevier BV ; 2011
    In:  Laboratory Investigation Vol. 91, No. 6 ( 2011-06), p. 896-904
    In: Laboratory Investigation, Elsevier BV, Vol. 91, No. 6 ( 2011-06), p. 896-904
    Type of Medium: Online Resource
    ISSN: 0023-6837
    RVK:
    Language: English
    Publisher: Elsevier BV
    Publication Date: 2011
    detail.hit.zdb_id: 2041329-4
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  • 6
    Online Resource
    Online Resource
    American Association for Cancer Research (AACR) ; 2010
    In:  Cancer Research Vol. 70, No. 8_Supplement ( 2010-04-15), p. 126-126
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 70, No. 8_Supplement ( 2010-04-15), p. 126-126
    Abstract: Gemcitabine enhances therapeutic effect of tamoxifen on cholangiocarcinoma Gu Jing, Amy N Turk, Yong Sun, Pritish Pawar, Yabing Chen, Jay M McDonald Cholangiocarcinoma is a highly malignant tumor with limited therapeutic options. We and others have reported that regulation of apoptosis of cancer cells is a promising avenue for cholangiocarcinoma therapy. Previous reports from our group have demonstrated that tamoxifen (TMX), as a calmodulin antagonist, induces apoptosis of cholangiocarcinoma cells via a mechanism related to Fas-death receptor mediated extrinsic apoptotic pathway (Clin Cancer Res, 2009: 15, 1288-96). The present studies determined whether gemcitabine (GMT), an inducer of intrinsic apoptotic signals, might enhancethe efficacy of tamoxifen therapy on cholangiocarcinoma. Nude mice xenograft model was utilized for in vivo cholangiocarcinoma tumorigenesis, as we previously reported. Tamoxifen (15mg/kg) and gemcitabine (120mg/kg) were administrated by intraperitoneal injection. The effect of tamoxifen and gemcitabine on cholangiocarcinoma cell apoptosis in vitro was determined by annexin V staining and flow cytometry analysis and downstream signaling events assessed by Western blotting.. Consistent with our previous reports, we observed that tumorigenesis of cholangiocarcinoma in nude mice was inhibited by tamoxifen by 59%, compared with control group (tumor size, control=1014±295 mm3, and TMX=416±63mm3, n=6, p=0.01). Importantly, gemcitabine was found to further enhance the inhibitory effect of tamoxifen on cholangiocarcinoma tumorigenesis by 54% (tumor size, GMT+TMX=228±38 mm3, n=6, p & lt;0.0001). Mechanistic analyses demonstrated that gemcitabine enhanced the apoptotic effect of tamoxifen on cholangiocarcinoma cells (% apoptotic cells: Control=10.5±2.8, TMX=24.1±1.6 and TMX+GMT=44.7±1.8, n=3, p & lt;0.05), which was found to be dependent on the concentration of gemcitabine. Activation of caspase-3 was induced by both tamoxifen and gemcitabine. However, gemcitabine did not affect the phosphorylation of AKT, which was inhibited by tamoxifen. Furthermore, activation of caspase-9 was induced by gemcitabine, whereas tamoxifen-induced apoptosis was associated with activation of caspase 8 and 10. Therefore, gemcitabine and tamoxifen appeared to induce apoptosis of cholangiocarcinoma cells via activation of distinct signals of the apoptotic machinery. In aggregation, we have demonstrated that gemcitabine enhanced the inhibitory effect of tamoxifen on cholangiocarcinoma tumorigenesis in nude mice. Gemcitabine and tamoxifen synergistically induce apoptosis of cholangiocarcinoma cells, which may be attributed to activation of distinct apoptosis signals by tamoxifen and gemcitabine. Our studies provide in vivo evidence and molecular insight to support the use of tamoxifen and gemcitabine in combination as an effective therapy for cholangiocarcinoma. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 126.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    RVK:
    RVK:
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2010
    detail.hit.zdb_id: 2036785-5
    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
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