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      NC2213: a novel methionine aminopeptidase 2 inhibitor in human colon cancer HT29 cells

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          Abstract

          Methionine aminopeptidase 2 (MetAP2) is a bifunctional protein that plays a critical role in the regulation of post-translational processing and protein synthesis. MetAP2 is overexpressed in human colon cancer. In this report we screened various MetAP2 inhibitors and treated HT29 cells with various concentrations of compounds. We evaluated the expression of MetAP2 and pp60 c-src expressions in HT29 cells. In addition we also carried out the cell proliferation and cell cycle analysis in the MetAP2 inhibitor-treated HT29 cells. The cell cycle analysis of HT29 treated with 1.0 μM of NC2213 showed an arrest in the G2 phase followed by an induction in the percentage of cells undergoing apoptosis in the sub-G1 phase. Western blot analysis revealed that the MetAP2 expression was dose-dependently decreased when the HT29 cells were treated with the 3,5-bis(benzylidene)-4-piperidone derivative (NC2213). In addition, phosphorylation of Src, a myristoylated oncoprotein was significantly decreased by 1.0 μM of NC2213 as revealed by Western blot analysis. Furthermore, NC2213 also inhibits the expression of pp60 c-src in HT29 cells. Interestingly, this compound also inhibits the phosphorylation at Tyr416 of pp60 c-src while increasing the phosphorylation at Tyr527 of pp60 c-src. NC2213 inhibits the growth of HT29 cells by inducing apoptosis and might be useful for the treatment of human colon cancer.

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          Synthesis and biological evaluation of novel curcumin analogs as anti-cancer and anti-angiogenesis agents.

          Brian K. Adams, Eva M Ferstl, Matthew C. Davis … (2004)
          A series of novel curcumin analogs were synthesized and screened for anti-cancer and anti-angiogenesis activities at Emory University and at the National Cancer Institute (NCI). These compounds are symmetrical alpha,beta-unsaturated and saturated ketones. The majority of the analogs demonstrated a moderate degree of anti-cancer activity. Compounds 10, 11, and 14 exhibited a high degree of cytotoxicity in the NCI in vitro anti-cancer cell line screen. In addition, this screen revealed that these compounds inhibit tumor cell growth with a higher potency than the commonly used chemotherapeutic drug, cisplatin. In independent in vitro screens conducted at Emory, the same compounds plus 4, 5, 8, 9, and 13 exhibited a high degree of cytotoxicity to tumor cells. Analogs that were effective in the anti-cancer screens were also effective in in vitro anti-angiogenesis assays. Compounds 4, 9, 11, and 14 were most effective in the anti-angiogenesis assays run at Emory. In the assays conducted by the NCI, compound 14 was almost as potent as the anti-angiogenic drug TNP-470, which has undergone clinical trials. Based on the favorable in vitro anti-cancer and anti-angiogenesis results with 14, further in vivo tests were conducted. This compound effectively reduced the size of human breast tumors grown in female athymic nude mice and showed little toxicity. This data, coupled with the remarkable in vitro data, suggests that compound 14 may potentially be an effective chemotherapeutic agent. As a follow-up, a 3D quantitative structure relationship based on 14 has been developed. It shows a cross-validated r2(q2) and a predictive r2(p2) = 0.71. COMPARE analysis suggests the compound to be a possible RNA/DNA antimetabolite, but also implies that the compound's cytotoxicity may arise from a presently unknown mechanism.
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            Molecular recognition of angiogenesis inhibitors fumagillin and ovalicin by methionine aminopeptidase 2.

            Alan Ramsay, Peter Chang, S Niwayama … (1998)
            Angiogenesis inhibitors are a novel class of promising therapeutic agents for treating cancer and other human diseases. Fumagillin and ovalicin compose a class of structurally related natural products that potently inhibit angiogenesis by blocking endothelial cell proliferation. A synthetic analog of fumagillin, TNP-470, is currently undergoing clinical trials for treatment of a variety of cancers. A common target for fumagillin and ovalicin recently was identified as the type 2 methionine aminopeptidase (MetAP2). These natural products bind MetAP2 covalently, inhibiting its enzymatic activity. The specificity of this binding is underscored by the lack of inhibition of the closely related type 1 enzyme, MetAP1. The molecular basis of the high affinity and specificity of these inhibitors for MetAP2 has remained undiscovered. To determine the structural elements of these inhibitors and MetAP2 that are involved in this interaction, we synthesized fumagillin analogs in which each of the potentially reactive epoxide groups was removed either individually or in combination. We found that the ring epoxide in fumagillin is involved in the covalent modification of MetAP2, whereas the side chain epoxide group is dispensable. By using a fumagillin analog tagged with fluorescein, His-231 in MetAP2 was identified as the residue that is covalently modified by fumagillin. Site-directed mutagenesis of His-231 demonstrated its importance for the catalytic activity of MetAP2 and confirmed that the same residue is covalently modified by fumagillin. These results, in agreement with a recent structural study, suggest that fumagillin and ovalicin inhibit MetAP2 by irreversible blockage of the active site.
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              Potential role of N-myristoyltransferase in cancer.

              Jonathan R Dimmock, Anuraag Shrivastav, Narendra Sharma … (2006)
              Colorectal cancer is the second leading cause of malignant death, and better preventive strategies are needed. The treatment of colonic cancer remains difficult because of the lack of effective chemotherapeutic agents; therefore it is important to continue to search for cellular functions that can be disrupted by chemotherapeutic drugs resulting in the inhibition of the development and progression of cancer. The current knowledge of the modification of proteins by myristoylation involving myristoyl-CoA: protein N-myristoyltransferase (NMT) is in its infancy. This process is involved in the pathogenesis of cancer. We have reported for the first time that NMT activity and protein expression were higher in human colorectal cancer, gallbladder carcinoma and brain tumors. In addition, an increase in NMT activity appeared at an early stage in colonic carcinogenesis. It is conceivable therefore that NMT can be used as a potential marker for the early detection of cancer. These observations lead to the possibility of developing NMT specific inhibitors, which may be therapeutically useful. We proposed that HSC70 and/or enolase could be used as an anticancer therapeutic target. This review summarized the status of NMT in cancer which has been carried in our laboratory.
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                Author and article information

                Journal
                Journal ID (nlm-ta): Mol Cancer
                Title: Molecular Cancer
                Publisher: BioMed Central
                ISSN (Electronic): 1476-4598
                Publication date Collection: 2009
                Publication date (Electronic): 24 August 2009
                Volume: 8
                Page: 65
                Affiliations
                [1 ]Department of Pathology and Laboratory Medicine, College of Medicine, University of Saskatchewan, Saskatoon, Saskatchewan, S7N 4H4, Canada
                [2 ]Cancer Research Unit, Health Research Division, Saskatchewan Cancer Agency, Saskatoon, Saskatchewan, S7N 4H4, Canada
                [3 ]Department of Biochemistry, College of Medicine, University of Saskatchewan, Saskatoon, Saskatchewan, S7N 4H4, Canada
                [4 ]College of Pharmacy and Nutrition, University of Saskatchewan, Saskatoon, Saskatchewan, S7N 5C9, Canada
                Article
                Publisher ID: 1476-4598-8-65
                DOI: 10.1186/1476-4598-8-65
                PMC ID: 2740849
                PubMed ID: 19703310
                SO-VID: fad77ca3-8ac2-4f79-b391-69df02c32f6f
                Copyright © Copyright © 2009 Selvakumar et al; licensee BioMed Central Ltd.
                License:

                This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                Date received : 19 June 2009
                Date accepted : 24 August 2009
                Categories
                Subject: Short Communication

                ScienceOpen disciplines: Oncology & Radiotherapy
                Data availability:
                ScienceOpen disciplines: Oncology & Radiotherapy

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