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  • American Association for Cancer Research (AACR)  (4)
  • 1
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 70, No. 8_Supplement ( 2010-04-15), p. 458-458
    Abstract: Hypoxia-inducible factor-1α (HIF-1α), a transcription factor, over- expressed in many human tumors and their metastases, and is closely associated with more aggressive tumor phenotype. An important objective of anti-cancer therapy is the development of new drugs that suppress hypoxic responses in solid tumors. In many studies, resveratrol has been shown to chemopreventive effect in various cancer cells. However, resveratrol's biological activity is limited by its photosensitivity and metabolic instability. This study was investigated the effects of a novel analogue of resveratrol, HS-1793, on the expression levels of HIF-1α and vascular endothelial growth factor (VEGF) in PC-3 human prostate cancer cells. Hypoxic condition induced a time-dependent increase in the level of HIF-1α protein in PC-3 cells, and treatment with HS-1793 markedly decreased HIF-1α expression level. HS-1793 also inhibited VEGF expression level. Mechanistically, HS-1793 inhibited HIF-1α and VEGF expression through multiple mechanisms. Firstly, HS-1793 inhibited both PI3K and Erk phosphorylations in PC-3 cells. Secondly, HS-1793 substantially induced HIF-1α protein degradation through the proteasome pathway. Finally, HS-1793 inhibited hypoxia-induced cell migration. These data suggested that HS-1793 may inhibit human prostate cancer progression and angiogenesis by inhibiting HIF-1α and VEGF expression. Moreover, HS-1793 showed more potent effect than resveratrol on the cytotoxic effects on PC-3 cells. Taken together, these results implied that HS-1793, a novel analogue of resveratrol, might be a new potent chemopreventive agent against human prostate cancer cells. [This work was supported by the Korea Science and Engineering Foundation (KOSEF) grant funded by the Korea government (MOST) (R01-2006-000-11117-0)]. 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 458.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
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    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2010
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    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
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  • 2
    In: Molecular Cancer Therapeutics, American Association for Cancer Research (AACR), Vol. 14, No. 11 ( 2015-11-01), p. 2613-2622
    Abstract: The MET receptor tyrosine kinase, the receptor for hepatocyte growth factor (HGF), has been implicated in cancer growth, invasion, migration, angiogenesis, and metastasis in a broad variety of human cancers, including human hepatocellular carcinoma (HCC). Recently, MET was suggested to be a potential target for the personalized treatment of HCC with an active HGF–MET signaling pathway. However, the mechanisms of resistance to MET inhibitors need to be elucidated to provide effective treatment. Here, we show that HCC cells exhibit different sensitivities to the MET inhibitor PHA665752, depending on the phosphorylation status of FGFR. Treatment of cells expressing both phospho-FGFR and phospho-MET with the inhibitor PHA665752 did not cause growth inhibition and cell death, whereas treatment with AZD4547, a pan-FGFR inhibitor, resulted in decreased colony formation and cleavage of caspase-3. Moreover, silencing of endogenous FGFR1 and FGFR2 by RNAi of HCC cells expressing phospho-FGFR, phospho-FGFR2, and phospho-MET overcame the resistance to PHA665752 treatment. Treatment of primary cancer cells from patients with HCC expressing both phospho-FGFR and phospho-MET with PHA665752 did not induce cell death, whereas AZD4547 treatment induced cell death through the cleavage of caspase-3. In addition, treatment of cells resistant to PHA665752 with AZD4547 abrogated the activation of downstream effectors of cell growth, proliferation, and survival. On the basis of these results, we conclude that the FGFR pathway is critical for HCC survival, and that targeting this pathway with AZD4547 may be beneficial for the treatment of patients with HCC-expressing phospho-FGFR and phospho-MET. Mol Cancer Ther; 14(11); 2613–22. ©2015 AACR.
    Type of Medium: Online Resource
    ISSN: 1535-7163 , 1538-8514
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2015
    detail.hit.zdb_id: 2062135-8
    SSG: 12
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  • 3
    In: Clinical Cancer Research, American Association for Cancer Research (AACR), Vol. 19, No. 15 ( 2013-08-01), p. 4218-4227
    Abstract: Purpose: Insulin-like growth factor-I (IGF-I) reflects hepatic synthetic function and plays an important role in the development and progression of various cancers. In this study, we investigated whether pretreatment serum IGF-I levels predict time-to-recurrence (TTR) and overall survival (OS) in patients with early-stage hepatocellular carcinoma after curative treatment. Experimental Design: Consecutive patients with hepatocellular carcinoma who had undergone surgical resection, radiofrequency ablation, or percutaneous ethanol injection as curative treatments of early hepatocellular carcinoma were included from two prospective cohorts and the training set (n = 101) and the validation set (n = 91) were established. Serum samples were collected before treatment and the levels of IGF-I and IGF-binding protein-3 (IGFBP-3) were analyzed with regard to their associations with recurrence and survival. Results: In the training set, patients with low IGF-I levels showed significantly shorter TTR [median, 14.6 months; 95% confidence interval (CI), 1.8–27.5] than patients with high IGF-I levels (median, 50.8 months; 95% CI, 36.9–64.7; P & lt; 0.001) during a median follow-up period of 52.4 months. In the multivariate analysis, low levels of IGF-I were an independent predictor of recurrence (HR, 2.49; 95% CI, 1.52–4.08; P & lt; 0.001). Furthermore, together with high-serum α-fetoprotein and multiple tumors, low levels of IGF-I remained an independent predictor of poorer survival (HR, 8.00; 95% CI, 1.94–33.01; P = 0.004). Applied to the independent validation set, low-serum IGF-I levels maintained their prognostic value for shorter TTR and OS. Conclusions: Low-baseline IGF-I levels independently correlated with shorter TTR and poorer survival in patients with early-stage hepatocellular carcinoma after curative treatment. Clin Cancer Res; 19(15); 4218–27. ©2013 AACR.
    Type of Medium: Online Resource
    ISSN: 1078-0432 , 1557-3265
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    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2013
    detail.hit.zdb_id: 1225457-5
    detail.hit.zdb_id: 2036787-9
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  • 4
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 71, No. 8_Supplement ( 2011-04-15), p. 2238-2238
    Abstract: Introduction: The addition of the anti-CD20 monoclonal antibody rituximab to conventional chemotherapy has dramatically improved overall survival (OS) in patients with diffuse large B-cell lymphoma (DLBCL), with more than 50% of these patients achieving long-term disease-free survival. However, approximately one-third of patients eventually die due to disease progression, treatment-related toxicities, another cancer, or other causes, and some patients show progression during or immediately after treatment. We sought to determine the characteristics of patients with DLBCL who were refractory or resistant to R-CHOP (rituximab, cyclophosphamide, adriamycin, vincristine, prednisone) chemotherapy and the factors influencing patient outcomes. Patients and Methods: Of all patients newly diagnosed with DLBCL at nine institutions in Korea and treated with R-CHOP with curative intent, 94 failed to achieve complete (CR) or partial response (PR) during or after R-CHOP chemotherapy or showed disease progression within 12 months of diagnosis. Results: Median patient age was 53 years (range 18∼85 years), and median time to progression was 5.7 months (range 1.1∼11.2 months). According to the International Prognostic Index (IPI), 44 patients (46.8%) were of low risk (0 to 2) and 50 (53.2%) were of high risk (3 to 5). Of the 94 patients, 59 (62.8%) had progression of primary lesions, 19 (20.2%) had progression at other sites, and 16 (17%) had progression at both primary and other sites. Sixty-three patients (67%) had progression during R-CHOP treatment, including 22 (23.4%) with progression after no response and 41 (43.6%) with progression after CR or PR. The remaining 31 patients (33.0%) showed disease progression after 6∼8 cycles of R-CHOP chemotherapy. Of the 74 patients (78.7%) who received second-line chemotherapy, 8 (10.8%) achieved CR or unconfirmed CR (CRu), 14 (18.9%) achieved PR, 3 (4.1%) achieved stable disease and 36 (48.6%) showed progressive disease. The overall response rate was 29.7% and the median duration of response was 4.2 months. Median OS was 4.7 months and median progression-free survival (PFS) was 3.0 months. Median OS after diagnosis of lymphoma was 10.7 months. Multivariate analysis showed that normal (vs. elevated) LDH concentration and absence (vs. presence) of B symptoms were significant predictors of longer OS. However, other IPI variables, such as age, performance status, and extranodal disease, did not predict survival of R-CHOP resistant/refractory patients. Conclusion: The prognosis of patients with R-CHOP refractory/resistant DLBCL was dismal, with conventional salvage chemotherapy having little effect on survival. Novel biomarkers and new treatment strategies are needed to further improve survival in R-CHOP refractory/resistant DLBCL patients. 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 2238. doi:10.1158/1538-7445.AM2011-2238
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
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    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2011
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    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
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