Article

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

ABSTRACT

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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    • "Furthermore, g-secretase inhibitor monotherapy is associated with gastrointestinal toxicities[12], particularly with continuous dosing schedules[27], which may limit the ability to achieve optimal exposure times. g-Secretase inhibitor therapy combined with chemotherapy[28]and glucocorticoids[29]may be more effective in preventing tumour growth and progression while limiting unwanted toxicity mon- otherapy[30,31]. For instance, glucocorticoid treatment protects against g-secretase inhibitor-induced intestinal toxicity in mice[32]. "
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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.
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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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