Meng RD, Shelton CC, Li Y-M, Qin L-X, Notterman D, Paty PB, Schwartz GKγ-Secretase inhibitors abrogate oxaliplatin-induced activation of the Notch-1 signaling pathway in colon cancer cells resulting in enhanced chemosensitivity. Cancer Res 69(2): 573-582

Department of Medicine, Division of Solid Tumor Oncology, Laboratory of New Drug Development, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA.
Cancer Research (Impact Factor: 9.33). 02/2009; 69(2):573-82. DOI: 10.1158/0008-5472.CAN-08-2088
Source: PubMed


Because Notch signaling is implicated in colon cancer tumorigenesis and protects cells from apoptosis by inducing prosurvival targets, it was hypothesized that inhibition of Notch signaling with gamma-secretase inhibitors (GSI) may enhance the chemosensitivity of colon cancer cells. We first show that the Notch-1 receptor, as well as its downstream target Hes-1, is up-regulated with colon cancer progression, similar to other genes involved in chemoresistance. We then report that chemotherapy induces Notch-1, as oxaliplatin, 5-fluorouracil (5-FU), or SN-38 (the active metabolite of irinotecan) induced Notch-1 intracellular domain (NICD) protein and activated Hes-1. Induction of NICD by oxaliplatin was caused by an increase in the activity and expression of gamma-secretase complex, as suppression of the protein subunit nicastrin with small interfering RNA (siRNA) prevented NICD induction after oxaliplatin. Subsequent inhibition of Notch-1 signaling with a sulfonamide GSI (GSI34) prevented the induction of NICD by chemotherapy and blunted Hes-1 activation. Blocking the activation of Notch signaling with GSI34 sensitized cells to chemotherapy and was synergistic with oxaliplatin, 5-FU, and SN-38. This chemosensitization was mediated by Notch-1, as inhibition of Notch-1 with siRNA enhanced chemosensitivity whereas overexpression of NICD increased chemoresistance. Down-regulation of Notch signaling also prevented the induction of prosurvival pathways, most notably phosphoinositide kinase-3/Akt, after oxaliplatin. In summary, colon cancer cells may up-regulate Notch-1 as a protective mechanism in response to chemotherapy. Therefore, combining GSIs with chemotherapy may represent a novel approach for treating metastatic colon cancers by mitigating the development of chemoresistance.

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    • "In human beings, Notch signaling was shown to be strongly activated in primary human colorectal cancers, and has an important role in cancer initiation and progression through the regulation of the main cellular functions associated with tumorigenesis, such as apoptosis, proliferation, angiogenesis, and cell migration. Microarray analysis discovered that the expression levels of Notch1, and its target Hes1, increased with increasing tumor grade (139). In situ hybridization on 130 colorectal cancer samples found that Notch signaling is constantly activated as measured by Hes1 expression (86). "
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    ABSTRACT: The Notch pathway is increasingly attracting attention as a source of therapeutic targets for cancer. Ligand-induced Notch signaling has been implicated in various aspects of cancer biology; as a consequence, pan-Notch inhibitors and therapeutic antibodies targeting one or more of the Notch receptors have been investigated for cancer therapy. Alternatively, Notch ligands provide attractive options for therapy in cancer treatment due to their more restricted expression and better-defined functions, as well as their low rate of mutations in cancer. One of the Notch ligands, Jagged1 (JAG1), is overexpressed in many cancer types, and plays an important role in several aspects of tumor biology. In fact, JAG1-stimulated Notch activation is directly implicated in tumor growth through maintaining cancer stem cell populations, promoting cell survival, inhibiting apoptosis, and driving cell proliferation and metastasis. In addition, JAG1 can indirectly affect cancer by influencing tumor microenvironment components such as tumor vasculature and immune cell infiltration. This article gives an overview of JAG1 and its role in tumor biology, and its potential as a therapeutic target.
    Frontiers in Oncology 09/2014; 4:254. DOI:10.3389/fonc.2014.00254
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    • "Recently, they were widely used as a tool in anti-cancer studies. An increasing number of reports are revealing that GSIs offer a potential clinical application in cancer therapeutics, including treatment of glioblastomas11,12,13,14,15,16. A phase I trial of the γ-secretase inhibitor MK-0752 has been performed, and the results show that it is well-tolerated in children with recurrent CNS malignancies. "
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    ABSTRACT: Aim: Trans-4-[4-(3-adamantan-1-yl-ureido)-cyclohexyloxy]-benzoic acid (t-AUCB) is a soluble epoxide hydrolase inhibitor that suppresses glioblastoma cell growth in vitro. The aim of this study was to examine whether the γ-secretase inhibitor N-[N-(3,5-difluorophenacetyl)-l-alanyl]-S-phenylglycine t-butyl ester (DAPT) could sensitize glioma cells to t-AUCB-induced apoptosis. Methods: Both U251 and U87 human glioblastoma cell lines were tested. Cell growth was assessed using the cell counting kit-8. Cell apoptosis was detected with caspase-3 activity assay kits and flow cytometry. The protein levels in the p38 MAPK/MAPKAPK2/Hsp27 pathway in the cells were analyzed using Western blots. Results: Pretreatment with DAPT (2 μmol/L) substantially potentiated the growth inhibition caused by t-AUCB (200 μmol/L) in U251 and U87 cells. Furthermore, pretreatment with DAPT markedly increased t-AUCB-induced apoptosis of U251 and U87 cells. T-AUCB alone did not significant affect caspase-3 activity in the cells, but t-AUCB plus DAPT pretreatment caused significant increase of caspase-3 activity. Furthermore, pretreatment with DAPT completely blocked t-AUCB-induced phosphorylation of p38 MAPK, MAPKAPK2 and Hsp27 in the cells. Conclusion: The γ-secretase inhibitor DAPT sensitizes t-AUCB-induced apoptosis of human glioblastoma cells in vitro via blocking the p38 MAPK/MAPKAPK2/Hsp27 pathway, suggesting that the combination of t-AUCB and DAPT may be a potentially effective strategy for the treatment of glioblastoma.
    Acta Pharmacologica Sinica 05/2014; 35(6). DOI:10.1038/aps.2013.195 · 2.91 Impact Factor
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    • "Downregulating Notch1 may be an effective approach to inactivating Snail/E-cadherin by regulating cyclooxygenase-2, which results in the inhibition of HCC cell invasion and migration [24]. The overexpression of the key transcription factor RBP-Jκ and its downstream target Hes1 has also been previously reported in HCC [15], [25]. Our results indicate that SIL treatment decreased NICD, RBP-Jκ, and Hes1 in HepG2 cells. "
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    ABSTRACT: Hepatocellular carcinoma (HCC) is a global health burden that is associated with limited treatment options and poor patient prognoses. Silybin (SIL), an antioxidant derived from the milk thistle plant (Silybum marianum), has been reported to exert hepatoprotective and antitumorigenic effects both in vitro and in vivo. While SIL has been shown to have potent antitumor activity against various types of cancer, including HCC, the molecular mechanisms underlying the effects of SIL remain largely unknown. The Notch signaling pathway plays crucial roles in tumorigenesis and immune development. In the present study, we assessed the antitumor activity of SIL in human HCC HepG2 cells in vitro and in vivo and explored the roles of the Notch pathway and of the apoptosis-related signaling pathway on the activity of SIL. SIL treatment resulted in a dose- and time-dependent inhibition of HCC cell viability. Additionally, SIL exhibited strong antitumor activity, as evidenced not only by reductions in tumor cell adhesion, migration, intracellular glutathione (GSH) levels and total antioxidant capability (T-AOC) but also by increases in the apoptotic index, caspase3 activity, and reactive oxygen species (ROS). Furthermore, SIL treatment decreased the expression of the Notch1 intracellular domain (NICD), RBP-Jκ, and Hes1 proteins, upregulated the apoptosis pathway-related protein Bax, and downregulated Bcl2, survivin, and cyclin D1. Notch1 siRNA (in vitro) or DAPT (a known Notch1 inhibitor, in vivo) further enhanced the antitumor activity of SIL, and recombinant Jagged1 protein (a known Notch ligand in vitro) attenuated the antitumor activity of SIL. Taken together, these data indicate that SIL is a potent inhibitor of HCC cell growth that targets the Notch signaling pathway and suggest that the inhibition of Notch signaling may be a novel therapeutic intervention for HCC.
    PLoS ONE 12/2013; 8(12):e83699. DOI:10.1371/journal.pone.0083699 · 3.23 Impact Factor
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