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  • American Association for Cancer Research (AACR)  (5)
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  • American Association for Cancer Research (AACR)  (5)
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  • 1
    Online Resource
    Online Resource
    Abstract 4780: A novel, potent and selective FGFR4 inhibitor, HM81422 in hepatocellular carcinoma with FGFR4-driven pathway activation
    American Association for Cancer Research (AACR) ; 2018
    In:  Cancer Research Vol. 78, No. 13_Supplement ( 2018-07-01), p. 4780-4780
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 78, No. 13_Supplement ( 2018-07-01), p. 4780-4780
    Abstract: Introduction: Hepatocellular carcinoma (HCC) is the sixth most prevalent cancer and the second most frequent cause of cancer-related death, however, treatment options are very limited. In recent studies, aberrant signaling through FGFR4 and its ligand, FGF19 have been identified as the oncogenic driver in a subset of HCCs and reported to be associated with poor prognosis. About 30% of HCC patients have altered FGF19/FGFR4 pathway signaling, therefore, the treatment with FGFR4 inhibitor may produce benefit. Materials and Method: Using the structure-based design, we have generated a novel, potent and selective FGFR4 inhibitor, HM81422 with irreversible-covalent binding mode, and evaluated its anti-tumor activity in a variety of HCC cell lines, HCC cell line xenografts and orthotopic grafts. Results: Biochemical selectivity assays demonstrated that HM81422 is highly selective towards FGFR4 compared to other FGFR isotypes as well as a panel of several kinases. The treatment of HM81422 to FGF19 amplified and overexpressed HCC cell lines led to suppression of FGF19/FGFR4 signaling pathway and concomitant reduction in cell viability in dose-dependent manner. Oral administration of HM81422 to mice bearing FGF19 altered HCC cells showed dose-dependent pharmacokinetics, pharmacodynamic modulation of FGFR4 signaling and antitumor efficacy in xenograft models. And HM81422 demonstrated inhibition of tumor growth in an orthotopic liver xenograft model of FGF19 altered HCC in nude mice. Conclusion: In conclusion, the treatment of HCC patients with a potent and selective FGFR4 inhibitor, HM81422, can be an attractive approach targeting approximately 30% of HCC patients by inhibiting altered FGF19-mediated signaling cascade. Further preclinical studies with HM81422 will be performed and reported soon. Citation Format: JaeHo Lee, Hyunjeong Kang, Kyounghwa Koo, Youngeun Ha, Sun Young Lim, Joo-Yun Byun, Hyunkyung Yu, Taehun Song, Moonsub Lee, Seung Hyun Jung, Taewoo Kim, Hyojeong Bang, Eunyoung Kim, Jahoon Kang, Ho Jeong Lee, YoungHoon Kim, YoungGil Ahn, KweeHyun Suh, Sun-Jin Kim. A novel, potent and selective FGFR4 inhibitor, HM81422 in hepatocellular carcinoma with FGFR4-driven pathway activation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4780.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2018-4780
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2018
    detail.hit.zdb_id: 2036785-5
    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
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  • 2
    Online Resource
    Online Resource
    Abstract 3791: Sulphoraphane inhibits STAT3 and its related genes in Du 145 cancer cells
    American Association for Cancer Research (AACR) ; 2010
    In:  Cancer Research Vol. 70, No. 8_Supplement ( 2010-04-15), p. 3791-3791
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 70, No. 8_Supplement ( 2010-04-15), p. 3791-3791
    Abstract: Sulforaphane is a naturally occurring isothiocyanate compound mainly found in cruciferous vegetables. Sulforaphane has demonstrated cancer chemopreventive activities in a number of organ sites, including prostate. Mechanistic investigations have shown that SFN induces caspase-mediated apoptosis that is mediated through a rapid intracellular ROS generation. Since STAT3 signaling is crucial for cancer cell survival and ROS has been linked to inactivation of this transcriptional factor, we hypothesized that STAT3 may be an important target for SFN. Here, we investigated the effect of sulforaphane on the regulation of STAT3 in association of ROS in Du145 prostate cancer cells. We first confirmed that sulforaphane induced apoptosis by activation of caspase 8, 9, and 3, PARP cleavage and increase of TUNEL positive cells in Du145 cells, which were preceded for many hours by the increase of intracellular ROS, peaking at 30 minutes of exposure. We demonstrate for the first time that sulforaphane suppressed constitutive STAT3 activation and DNA-binding of STAT3 in a time- and dose-dependent manner in Du145 cells. These actions were also found in U266 multiple myeloma cells and U937 lymphoma cells. In addition, sulforaphane down-regulated the expression of STAT3-related genes such as bcl-2, bcl-xL, survivin, cyclin D1, and VEGF in Du145 cells. Furthermore, sulforaphane cross-linked JAK2, the upstream kinase of STAT3, in a time- and dose-dependent manner. Thiol-reducing agent dithiothreitol (DTT) reversed the inactivation of STAT3 and JAK2 induced by sulforaphane. Interestingly, N-acetyl cysteine (NAC), which leads to increased intracellular GSH synthesis, reversed the molecular patterns of PARP cleavage and inactivation of JAK2 and STAT3 induced by sulphoraphane. Taken together, these findings suggest that sulforaphane exposure leads to a rapid generation of ROS in Du145 cells and inhibition of JAK2/STAT3 pathway, followed by caspase-mediated apoptosis. Our data suggest that the JAK2/STAT3 pathway may be a novel target of SFN contributing to apoptosis. 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 3791.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM10-3791
    RVK:
    XA 36000
    RVK:
    XA 10000
    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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  • 3
    Online Resource
    Online Resource
    Abstract 849: Reactive oxygen species mediated activation of AMP activated protein kinase and c-Jun N-terminal kinase plays a critical role in beta sitosterol induced apoptosis in multiple myeloma U266 cells.
    American Association for Cancer Research (AACR) ; 2013
    In:  Cancer Research Vol. 73, No. 8_Supplement ( 2013-04-15), p. 849-849
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 73, No. 8_Supplement ( 2013-04-15), p. 849-849
    Abstract: Although beta sitosterol has been well known to have anti-tumor activity in liver, lung, colon, stomach, breast and prostate cancers via cell cycle arrest and apoptosis induction, the underlying mechanism of anti-cancer effect of beta sitosterol in multiple myeloma cells was never elucidated until now. Thus, in the present study, the role of reactive oxygen species (ROS) in association with AMP-activated protein kinase (AMPK) and c-Jun N-terminal kinase (JNK) pathways was demonstrated in beta sitosterol treated multiple myeloma U266 cells. Beta sitosterol exerted cytotoxicity, increased sub-G1 apoptotic population and activated caspase-9 and -3, cleaved poly (ADP-ribose) polymerase (PARP) followed by decrease in mitochondrial potential in U266 cells. Beta sitosterol promoted ROS production, activated AMPK, acetyl-CoA carboxylase (ACC) and JNK in U266 cells. Also, beta sitosterol attenuated the phosphorylation of AKT, mammalian target of rapamycin (mTOR) and S6K, and the expression of cyclooxygenase (COX)2 and VEGF in U266 cells. Conversely, AMPK inhibitor compound C and JNK nhibitor SP600125 suppressed apoptosis induced by beta sitosterol in U266 cells. Furthermore, ROS scavenger N-acetyl-L-cysteine (NAC) attenuated beta sitosterol mediated sub-G1 accumulation, PARP cleavage, JNK and AMPK activation in U266 cells. Overall, these findings for the first time suggest that ROS mediated activation of cancer metabolism related genes such as AMPK and JNK plays an important role in beta sitosterol induced apoptosis in U266 multiple myeloma cells. Citation Format: Sun-Mi Cho, Ji-Sung Kim, Hyosook song, Eun-Jung Sohn, Ji-Hyun Kim, Ji Hoon Jung, Jung-Hyo Kim, Soo-Jin Jeong, Eun-OK Lee, HyoJeong Lee, Sung Hoon Kim. Reactive oxygen species mediated activation of AMP activated protein kinase and c-Jun N-terminal kinase plays a critical role in beta sitosterol induced apoptosis in multiple myeloma U266 cells. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 849. doi:10.1158/1538-7445.AM2013-849
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2013-849
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2013
    detail.hit.zdb_id: 2036785-5
    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
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  • 4
    Online Resource
    Online Resource
    Abstract A83: Inhibition of hypoxia inducible factor alpha and astrocyte elevated gene-1 mediates cryptotanshionone induced anti-tumor activity in hypoxic PC-3 cells
    American Association for Cancer Research (AACR) ; 2012
    In:  Cancer Prevention Research Vol. 5, No. 11_Supplement ( 2012-11-01), p. A83-A83
    Details
    In: Cancer Prevention Research, American Association for Cancer Research (AACR), Vol. 5, No. 11_Supplement ( 2012-11-01), p. A83-A83
    Abstract: Although cryptotanshinone (CT) from Salvia miltiorrhiza Bunge was known to exert antitumor activity in liver, breast and prostate cancers, its molecular mechanism under hypoxia still remain unclear. Thus, in the present study, the roles of astrocyte elevated gene 1 (AEG-1) and HIF-1α in crytotanshinone induced antitumor activity were investigated in PC-3 prostate cancer cells under hypoxia. Cryptotanshinone exerted cytotoxicity against prostate cancer cells and suppressed HIF-1α accumulation and transcriptional activity and AEG-1 expression in hypoxic PC-3 cells. Also, AGE-1 was overexpressed in prostate cancer cells and also upregulated along with HIF-1α in hypoxic PC-3 cells. Interestingly, HIF-1α siRNA transfection blocked AEG-1 expression and activated caspase 9/3 and PARP cleavage, while AEG-1 siRNA transfection did not affect HIF-1α activity in hypoxic PC-3 cells. Of note, HIF prolyl hydroxylase inhibitor, dimethyloxalylglycine enhanced the stability of AEG-1 and HIF-1α during hypoxia. In addition, CT also significantly reduced cellular levels of VEGF, a downstream of HIF-1α, and disturbed tube formation in human umbilical vein endothelial cells maintained in conditioned medium of hypoxic PC-3 cells. Consistently, ChIP assay revealed that CT inhibited the binding of HIF-1α to VEGF promoter. Furthermore, CT at 10 mg/kg suppressed the growth of PC-3 cells in BALB/c athymic nude mice by 46.4% compared to untreated control. Consistently, immunohistochemistry revealed decreased expression of Ki-67(proliferation), CD34 (blood vessel), VEGF (angiogenesis), carbonic anhydrase(CA)IX (hypoxic marker) and AEG-1 indices in CT-treated group compared to untreated control. Overall, our findings suggest that CT exerts antitumor activity via inhibition of HIF-1α, AEG1 and VEGF as a potent chemotherapeutic agent. Citation Format: Sung Hoon Kim, Hyojeong Lee, Hanna Hyun Kim, Deok Beom Jung, Eunjung Sohn. Inhibition of hypoxia inducible factor alpha and astrocyte elevated gene-1 mediates cryptotanshionone induced antitumor activity in hypoxic PC-3 cells. [abstract]. In: Proceedings of the Eleventh Annual AAC R International Conference on Frontiers in Cancer Prevention Research; 2012 Oct 16-19; Anaheim, CA. Philadelphia (PA): AACR; Cancer Prev Res 2012;5(11 Suppl):Abstract nr A83.
    Type of Medium: Online Resource
    ISSN: 1940-6207 , 1940-6215
    URL: Article
    DOI: 10.1158/1940-6207.PREV-12-A83
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2012
    detail.hit.zdb_id: 2422346-3
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  • 5
    Online Resource
    Online Resource
    Abstract A58: Galbanic acid isolated from Ferula assafoetida exerts in vivo antitumor activity in association with antiangiogenesis and antiproliferation
    American Association for Cancer Research (AACR) ; 2012
    In:  Cancer Research Vol. 72, No. 4_Supplement ( 2012-02-06), p. A58-A58
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 72, No. 4_Supplement ( 2012-02-06), p. A58-A58
    Abstract: To investigate whether galbanic acid (GBA) exerts antiangiogenic and anticancer activities. Using human umbilical vein endothelial cell (HUVEC) model, we analyzed effects of GBA on cellular and molecular events related to angiogenesis. We tested its direct antiproliferative action on mouse Lewis lung cancer (LLC) cells and established its in vivo antiangiogenic and antitumor efficacy using LLC model. GBA significantly decreased vascular endothelial growth factor (VEGF)-induced proliferation and inhibited VEGF-induced migration and tube formation of HUVECs. These effects were accompanied by decreased phosphorylation of p38-mitogen-activated protein kinase (MAPK), c-jun N-terminal kinase (JNK), and AKT, and decreased expression of VEGFR targets endothelial nitric oxide synthase (eNOS) and cyclin D1 in VEGF-treated HUVECs. GBA also decreased LLC proliferation with an apparent G2/M arrest, but did not induce apoptosis. In vivo, inclusion of GBA in Matrigel plugs reduced VEGF-induced angiogenesis in mice. Galbanic acid given by daily i.p. injection (1 mg/kg) inhibited LLC-induced angiogenesis in an intradermal inoculation model and inhibited the growth of s.c. inoculated LLC allograft in syngenic mice. Immunohistochemistry revealed decreased CD34 microvessel density index and Ki-67 proliferative index in GBA-treated tumors. Overall, our findings suggest that GBA exerts anticancer activity in association with antiangiogenic and antiproliferative actions. Citation Format: Sunghoon Kim, Kwanhyun Kim, Soojin Jeong, Hyojeong Lee, Junxuan Lu. Galbanic acid isolated from Ferula assafoetida exerts in vivo antitumor activity in association with antiangiogenesis and antiproliferation [abstract]. In: Proceedings of the AACR Special Conference on Advances in Prostate Cancer Research; 2012 Feb 6-9; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2012;72(4 Suppl):Abstract nr A58.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.PRCA2012-A58
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2012
    detail.hit.zdb_id: 2036785-5
    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
    Location Call Number Limitation Availability
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