PMCC PMCC

Search tips
Search criteria

Advanced
Results 1-8 (8)
 

Clipboard (0)
None

Select a Filter Below

Journals
Year of Publication
Document Types
1.  Direct targeting of MEK1/2 and RSK2 by silybin induces cell cycle arrest and inhibits melanoma cell growth 
Abnormal functioning of multiple gene products underlies the neoplastic transformation of cells. Thus, chemopreventive and/or chemotherapeutic agents with multigene targets hold promise in the development of effective anticancer drugs. Silybin, a component of milk thistle, is a natural anticancer agent. In the present study, we investigated the effect of silybin on melanoma cell growth and elucidated its molecular targets. Our study revealed that silybin attenuated the growth of melanoma xenograft tumors in nude mice. Silybin inhibited the kinase activity of mitogen-activated protein kinase kinase (MEK)-1/2 and ribosomal S6 kinase (RSK)-2 in melanoma cells. The direct binding of silybin with MEK1/2 and RSK2 was explored using a computational docking model. Treatment of melanoma cells with silybin attenuated the phosphorylation of extracellular signal-regulated kinase (ERK)-1/2 and RSK2, which are regulated by the upstream kinases MEK1/2. The blockade of MEK1/2-ERK1/2-RSK2 signaling by silybin resulted in a reduced activation of nuclear factor-kappaB, activator protein-1 and signal transducer and activator of transcription-3, which are transcriptional regulators of a variety of proliferative genes in melanomas. Silybin, by blocking the activation of these transcription factors, induced cell cycle arrest at the G1 phase and inhibited melanoma cell growth in vitro and in vivo. Taken together, silybin suppresses melanoma growth by directly targeting MEK- and RSK-mediated signaling pathways.
doi:10.1158/1940-6207.CAPR-12-0425
PMCID: PMC3644346  PMID: 23447564
Silybin; BRAF/MEK/ERK/RSK signaling pathway; melanoma
2.  Ceftriaxone, an FDA-approved cephalosporin antibiotic, suppresses lung cancer growth by targeting Aurora B 
Carcinogenesis  2012;33(12):2548-2557.
Ceftriaxone, an FDA-approved third-generation cephalosporin antibiotic, has antimicrobial activity against both gram-positive and gram-negative organisms. Generally, ceftriaxone is used for a variety of infections such as community-acquired pneumonia, meningitis and gonorrhea. Its primary molecular targets are the penicillin-binding proteins. However, other activities of ceftriaxone remain unknown. Herein, we report for the first time that ceftriaxone has antitumor activity in vitro and in vivo. Kinase profiling results predicted that Aurora B might be a potential ‘off’ target of ceftriaxone. Pull-down assay data confirmed that ceftriaxone could bind with Aurora B in vitro and in A549 cells. Furthermore, ceftriaxone (500 µM) suppressed anchorage-independent cell growth by targeting Aurora B in A549, H520 and H1650 lung cancer cells. Importantly, in vivo xenograft animal model results showed that ceftriaxone effectively suppressed A549 and H520 lung tumor growth by inhibiting Aurora B. These data suggest the anticancer efficacy of ceftriaxone for the treatment of lung cancers through its inhibition of Aurora B.
doi:10.1093/carcin/bgs283
PMCID: PMC3510736  PMID: 22962305
3.  Taxifolin suppresses UV-induced skin carcinogenesis by targeting EGFR and PI3-K 
Skin cancer is one of the most commonly diagnosed cancers in United States. Taxifolin reportedly exerts multiple biological effects but the molecular mechanisms and direct target(s) of taxifolin in skin cancer chemoprevention are still unknown. In silico computer screening and kinase profiling results suggest that the epidermal growth factor receptor (EGFR), phosphatidyl inositol 3-kinase (PI3-K) and Src are potential targets for taxifolin. Pull-down assay results showed that EGFR, PI3-K and Src directly interacted with taxifolin in vitro, whereas taxifolin bound to EGFR and PI3-K but not to Src in cells. ATP-competition and in vitro kinase assay data revealed that taxifolin interacted with EGFR and PI3-K at the ATP binding pocket and inhibit their kinase activities. Western blot analysis showed that taxifolin suppressed UVB-induced phosphorylation of EGFR and Akt, and subsequently suppressed their signaling pathways in JB6 P+ mouse skin epidermal cells. Expression levels and promoter activity of COX-2 and prostaglandin E2 (PGE2) generation induced by UVB were also attenuated by taxifolin. The effect of taxifolin on UVB-induced signaling pathways and PGE2 generation was reduced in EGFR knockout murine embryonic fibroblasts (MEFs) compared with EGFR wildtype MEFs. Taxifolin also inhibited EGF-induced cell transformation. Importantly, topical treatment of taxifolin to the dorsal skin significantly suppressed tumor incidence, volume and multiplicity in a solar-UV (SUV)-induced skin carcinogenesis mouse model. Further analysis showed that the taxifolin-treated group had a substantial reduction in SUV-induced phosphorylation of EGFR and Akt in mouse skin. These results suggest that taxifolin exerts chemopreventive activity against UV-induced skin carcinogenesis by targeting EGFR and PI3-K.
doi:10.1158/1940-6207.CAPR-11-0397
PMCID: PMC3435475  PMID: 22805054
taxifolin; EGFR; PI3-K; skin carcinogenesis
4.  Norathyriol suppresses solar UV-induced skin cancer by targeting ERKs 
Cancer Research  2011;72(1):260-270.
Ultraviolet (UV) irradiation is the most important factor contributing to the development of skin cancer. The use of chemopreventive agents, especially naturally occurring plant products, to prevent skin cancer caused by UV might an effective therapeutic or preventive intervention. Using in silico virtual screening of the Chinese Medicine Library, we identified norathyriol as a potential ERK2 inhibitor. Norathyriol is a metabolite of mangiferin, which is found in mango, Hypericum elegans, and Tripterospermum lanceolatum, and has potent anticancer-promoting activity. Here, we show that norathyriol inhibits ERK1/2 kinase activities and attenuates UVB-induced phosphorylation of the mitogen-activated protein kinase (MAPK) cascades. Direct binding of norathyriol with ERK2 was confirmed by a co-crystal structure. The norathyriol xanthone moiety acts as an adenine mimeric and anchors the compound by hydrogen bonds to the hinge region of the protein ATP-binding site. Norathyriol inhibited cell growth in mouse skin epidermal JB6 P+ cells by inducing G2-M phase arrest. Mouse skin tumorigenesis data clearly showed that treatment with norathyriol significantly suppressed solar UV-induced skin carcinogenesis in vivo. Results also indicated that norathyriol exhibits a potent chemopreventive activity through the inhibition of transcription factor AP-1 and NF-κB by targeting ERKs in UV-induced skin carcinogenesis.
doi:10.1158/0008-5472.CAN-11-2596
PMCID: PMC3251698  PMID: 22084399
cancer; skin cancer; solar UV; UVB; chemoprevention; norathyriol; MAPK; ERK; ERK2 crystal structure
5.  Tissue-Specific Expression of Human Calcineurin-Binding Protein 1 in Mouse Synovial Tissue Can Suppress Inflammatory Arthritis 
Calcineurin (CN) is a calcium- and calmodulin-dependent serine/threonine phosphatase. In immune cells, CN controls the activity of a wide range of transcription factors, including nuclear factor of activated T, nuclear factor-kappa B, c-fos, and Elk-1. CN plays an important role in synoviocyte activation and arthritis progression in vivo and this function is tightly linked to dysregulated intracellular Ca2+ store and Ca2+ response triggered by proinflammatory cytokines. In the present study, transgenic mice expressing human calcineurin-binding protein 1 (hCabin1) were generated, driven by type II collagen promoter, and the efficiency of these mice was investigated by experimental arthritis. These transgenic mice successfully expressed hCabin1 in joint tissue as well as other organs such as liver, heart, and brain. The overexpression of hCabin1 reduced the disease severity during collagen-induced arthritis. In fibroblast-like synoviocytes (FLSs) from hCabin1 transgenic mice, the productions of these cytokines, including interleukin (IL)-2, IL-4, and IFN-γ, were decreased and matrix metalloproteinases were also depressed in transgenic mice FLS. In addition, these effects were only found in the joint tissue, which is a major inflammation site. These findings will provide a better knowledge of the pathogenic mechanisms of rheumatoid arthritis and a potential animal model of the chronic inflammatory conditions, including atherosclerosis and transplantation.
doi:10.1089/jir.2010.0155
PMCID: PMC3255519  PMID: 22175542
6.  (3-Chloroacetyl)-indole, a novel allosteric AKT inhibitor suppresses colon cancer growth in vitro and in vivo 
Indole-3-carbinol (I3C) is produced in Brassica vegetables such as broccoli and cabbage and has been shown to inhibit proliferation and induce apoptosis in various cancer cells, including breast, prostate, colon, and leukemia. However, only high doses of I3C were shown to inhibit cell proliferation (IC50 = 200∼300 μM). Our goal here was to develop a more potent antitumor agent by modifying the structure of I3C. We created I3C derivatives and found that (3-chloroacetyl)-indole (3CAI) more strongly inhibited colon cancer cell growth compared to I3C. Additionally, by screening 85 kinases in a competitive kinase assay, we found that 3CAI was a specific AKT inhibitor. AKT is a serine/threonine kinase that plays a pivotal role in promoting transformation and chemoresistance by inducing proliferation and inhibiting apoptosis. Therefore, AKT is regarded as a critical target for cancer therapy. 3ICA, a derivative of I3C, is a potent and specific AKT inhibitor. This compound showed significant inhibition of AKT in an in vitro kinase assay and suppressed expression of AKT direct downstream targets such as mTOR and GSK3β as well as induced growth inhibition and apoptosis in colon cancer cells. Additionally, oral administration of this potent AKT inhibitor suppressed cancer cell growth in an in vivo xenograft mouse model.
doi:10.1158/1940-6207.CAPR-11-0158
PMCID: PMC3244047  PMID: 21885813
(3-Chloroacetyl)-indole; AKT1; AKT2; indole-3-carbinol; colon cancer
7.  Over-expression of extracellular superoxide dismutase in mouse synovial tissue attenuates the inflammatory arthritis 
Experimental & Molecular Medicine  2012;44(9):529-535.
Oxidative stress such as reactive oxygen species (ROS) within the inflamed joint have been indicated as being involved as inflammatory mediators in the induction of arthritis. Correlations between extracellular-superoxide dismutase (EC-SOD) and inflammatory arthritis have been shown in several animal models of RA. However, there is a question whether the over-expression of EC-SOD on arthritic joint also could suppress the progression of disease or not. In the present study, the effect on the synovial tissue of experimental arthritis was investigated using EC-SOD over-expressing transgenic mice. The over-expression of EC-SOD in joint tissue was confirmed by RT-PCR and immunohistochemistry. The degree of the inflammation in EC-SOD transgenic mice was suppressed in the collagen-induced arthritis model. In a cytokine assay, the production of pro-inflammatory cytokines such as, IL-1β, TNFα, and matrix metalloproteinases (MMPs) was decreased in fibroblast-like synoviocyte (FLS) but not in peripheral blood. Histological examination also showed repressed cartilage destruction and bone in EC-SOD transgenic mice. In conclusion, these data suggest that the over-expression of EC-SOD in FLS contributes to the activation of FLS and protection from joint destruction by depressing the production of the pro-inflammatory cytokines and MMPs. These results provide EC-SOD transgenic mice with a useful animal model for inflammatory arthritis research.
doi:10.3858/emm.2012.44.9.060
PMCID: PMC3465746  PMID: 22718219
arthritis, experimental; reactive oxygen species; rheumatoid arthritis; superoxide dismutase; synovial membrane
8.  TRPV1-antagonist AMG9810 promotes mouse skin tumorigenesis through EGFR/Akt signaling 
Carcinogenesis  2011;32(5):779-785.
In addition to capsaicin, a transient receptor potential channel vanilloid subfamily 1 (TRPV1) agonist, two kinds of antagonists against this receptor are used as therapeutic drugs for pain relief. Indeed, a number of small molecule TRPV1 antagonists are currently undergoing Phase I/II clinical trials to determine their effect on relieving chronic inflammatory pain and migraine headache pain. However, we previously reported that the absence of TRPV1 in mice results in a striking increase in skin carcinogenesis, suggesting that chronic blockade of TRPV1 might increase the risk of tumor development. In this study, we found that a typical TRPV1 antagonist, AMG9810, promotes mouse skin tumor development. The topical application of AMG9810 resulted in a significant increase in the expression level of the epidermal growth factor receptor (EGFR) and its downstream Akt/mammalian target of rapamycin (mTOR)-signaling pathway. This increase was not only observed in AMG9810-treated tumor tissue but was also found in skin tissue treated with AMG9810. In telomerase-immortalized primary human keratinocytes, AMG9810 promoted proliferation that was mediated through the EGFR/Akt/mTOR-signaling pathway. In summary, our data suggest that the TRPV1 antagonist, AMG9810, promotes mouse skin tumorigenesis mediated through EGFR/Akt/mTOR signaling. Thus, the application of this compound for pain relief might increase the risk of skin cancer.
doi:10.1093/carcin/bgr037
PMCID: PMC3086704  PMID: 21349818

Results 1-8 (8)