Anti‐inflammatory and anti‐insulin resistance activities of aqueous extract from Anoectochilus burmannicus

This study investigated biological activities including antioxidative stress, anti‐inflammation, and anti‐insulin resistance of Anoectochilus burmannicus aqueous extract (ABE). The results showed abilities of ABE to scavenging DPPH and ABTS free radicals in a dose‐dependent manner. Besides, ABE significantly reduced nitric oxide (NO) production in the lipopolysaccharide (LPS)‐treated RAW 264.7 via inhibition of mRNA and protein expressions of nitric oxide synthase (iNOS). The LPS‐induced mRNA expressions of cyclooxygenase‐2 (COX‐2) and interleukin 1β (IL‐1β) were suppressed by ABE. Moreover, ABE exerted anti‐insulin resistance activity as it significantly improved the glucose uptake in tumor necrosis factor (TNF)‐α treated 3T3‐L1 adipocytes. In addition, ABE at the concentration of up to 200 μg/mL was not toxic to human peripheral blood mononuclear cells (PBMCs) and did not induce mutations. Finally, the results of our study suggest the potential use of A. burmannicus as anti‐inflammatory, anti‐insulin resistance agents, or food supplement for prevention of chronic diseases

Anti-Inflammatory and Anti-Adipocyte Dysfunction Effects of <i>Ficus lindsayana</i> Latex and Root Extracts

Low-grade chronic inflammation and adipocyte dysfunction are prominent risk factors of insulin resistance and type 2 diabetes mellitus (T2DM) in obesity. Thus, prevention of inflammation and adipocyte dysfunction could be one possible approach to mitigate T2DM development. Several Ficus species have been used in traditional medicine for ameliorating inflammation and T2DM. Our previous studies reported biological effects of Ficus lindsayana including antioxidant, anti-cancer, and anti-α-glucosidase activities. Further, this study therefore investigated whether F. lindsayana latex (FLLE) and root (FLRE) extracts inhibit inflammation-stimulated insulin resistance in adipocytes and inflammation in macrophages. FLLE and FLRE (200 µg/mL) had no significant cytotoxicity for macrophages, adipocytes, and blood cells (PBMCs and RBCs). FLRE had a total flavonoid content about three times higher than FLLE, while both had similar levels of total phenolic content. FLRE showed higher abilities than FLLE in suppressing inflammation in both macrophages and adipocytes and reversing the inflammation-induced insulin resistance in adipocytes. In TNF-α-induced adipocytes, FLRE significantly improved insulin-induced glucose uptake and insulin-suppressed lipolysis, while FLLE only significantly improved glucose uptake. Moreover, FLRE and FLLE remarkably reduced chemoattractant (MCP-1) but improved adipogenic (PPARγ and CEBPα) gene expression, leading to the promotion of adipogenesis and the suppression of insulin resistance. In LPS-induced macrophages, FLRE, but not FLLE, significantly inhibited LPS-induced NO production. Moreover, FLRE significantly reduced LPS-stimulated iNOS, COX-2, IL-1β, IL-6, and TNF-α gene expression. These results may provide the potential data for the development of this plant, especially the root part, as an alternative medicine, functional ingredient, or food supplement for the prevention of inflammation and obesity-associated insulin resistance, as well as T2DM

Insulin-like growth factor-I receptor blockade reduces the invasiveness of gastrointestinal cancers via blocking production of matrilysin

Insulin-like growth factor-I receptor (IGF-IR) signaling is required for carcinogenicity and proliferation of gastrointestinal (GI) cancers. We have previously shown significant therapeutic activity for recombinant adenoviruses expressing dominant-negative insulin-like growth factor-I receptor (IGF-IR/dn), including suppression of tumor invasion. In this study, we sought to evaluate the mechanism of inhibition of invasion and the relationship between IGF-IR and matrix metalloproteinase (MMP) activity in GI carcinomas. We analyzed the role of IGF-IR on invasion in three GI cancer cell lines, colorectal adenocarcinoma, HT29; pancreatic adenocarcinoma, BxPC3 and gastric adenocarcinoma, MKN45, using a modified Boyden chamber method and subcutaneous xenografts in nude mice. The impact of IGF-IR signaling on the expression of MMPs and the effects of blockade of matrilysin or IGF-IR on invasiveness were assessed using recombinant adenoviruses, a tyrosine kinase inhibitor NVP-AEW541 and antisense matrilysin. Invasive subcutaneous tumors expressed several MMPs. IGF-IR/dn reduced the expression of these MMPs but especially matrilysin (MMP-7). Insulin-like growth factor (IGF) stimulated secretion of matrilysin and IGF-IR/dn blocked IGF-mediated matrilysin induction in three GI cancers. Both IGF-IR/dn and inhibition of matrilysin reduced in vitro invasion to the same degree. NVP-AEW541 also reduced cancer cell invasion both in vitro and in murine xenograft tumors via suppression of matrilysin. Thus, blockade of IGF-IR is involved in the suppression of cancer cell invasion through downregulation of matrilysin. Strategies of targeting IGF-IR may have significant therapeutic utility to prevent invasion and progression of human GI carcinomas.Piao WH, 2008, MOL CANCER THER, V7, P1483, DOI 10.1158/1535-7163.MCT-07-2395Miyamoto S, 2007, CANCER SCI, V98, P685Imsumran A, 2007, CARCINOGENESIS, V28, P947, DOI 10.1093/carcin/bgl247Mitsui Y, 2006, CANCER RES, V66, P9913, DOI 10.1158/0008-5472.CAN-06-0377Girnita A, 2006, CLIN CANCER RES, V12, P1383, DOI 10.1158/1078-0432.CCR-05-1106Harper J, 2006, CANCER RES, V66, P1940, DOI 10.1158/0008-5472.CAN-05-2036ADACHI Y, 2006, DIGEST ENDOSC, V18, P245Shimizu M, 2005, BIOCHEM BIOPH RES CO, V334, P947, DOI 10.1016/j.bbrc.2005.06.182Nakamura M, 2005, BIOCHEM BIOPH RES CO, V333, P1011, DOI 10.1016/j.bbrc.2005.06.010Min Y, 2005, GUT, V54, P591, DOI 10.1136/gut.2004.048926Nosho K, 2005, BRIT J CANCER, V92, P1193, DOI 10.1038/sj.bjc.6602442Foulstone E, 2005, J PATHOL, V205, P145, DOI 10.1002/path.1712Nosho K, 2004, CLIN CANCER RES, V10, P7950Garcia-Echeverria C, 2004, CANCER CELL, V5, P231Mochizuki S, 2004, BIOCHEM BIOPH RES CO, V315, P79, DOI 10.1016/j.bbrc.2004.01.022Miyamoto S, 2004, CANCER RES, V64, P665Burtrum D, 2003, CANCER RES, V63, P8912Pavelic K, 2003, J PATHOL, V201, P430, DOI 10.1002/path.1465Min YF, 2003, CANCER RES, V63, P6432Zhang DL, 2003, ONCOGENE, V22, P974, DOI 10.1038/sj.onc.1206197Adachi Y, 2002, GASTROENTEROLOGY, V123, P1191, DOI 10.1053/gast.2002.36023Adachi Y, 2001, TUMOR BIOL, V22, P247Dunn SE, 2001, CANCER RES, V61, P1367Yu H, 2000, J NATL CANCER I, V92, P1472Adachi Y, 1999, GUT, V45, P252Yamamoto H, 1999, CANCER RES, V59, P3313Freier S, 1999, GUT, V44, P704Ma J, 1999, J NATL CANCER I, V91, P620Simmons JG, 1999, AM J PHYSIOL-GASTR L, V276, pG817Mira E, 1999, ENDOCRINOLOGY, V140, P1657Yamamoto H, 1999, JPN J CLIN ONCOL, V29, P58Adachi Y, 1998, INT J ONCOL, V13, P1031Long L, 1998, CANCER RES, V58, P3243Yamamoto H, 1997, GASTROENTEROLOGY, V112, P1290Wilson CL, 1997, P NATL ACAD SCI USA, V94, P1402StetlerStevenson WG, 1996, SEMIN CANCER BIOL, V7, P147Crawford HC, 1996, ENZYME PROTEIN, V49, P20BERGMANN U, 1995, CANCER RES, V55, P2007YAMAMOTO H, 1995, INT J CANCER, V61, P218BASERGA R, 1995, CANCER RES, V55, P249BASERGA R, 1994, CELL, V79, P927SELL C, 1993, P NATL ACAD SCI USA, V90, P11217LIU JP, 1993, CELL, V75, P59YOSHIMOTO M, 1993, INT J CANCER, V54, P614REMACLEBONNET M, 1992, INT J CANCER, V52, P910MIYAZAKI K, 1990, CANCER RES, V50, P7758THOMPSON MA, 1990, ENDOCRINOLOGY, V126, P3033WOESSNER JF, 1988, J BIOL CHEM, V263, P16918ULLRICH A, 1986, EMBO J, V5, P2503LIOTTA LA, 1986, CANCER RES, V46, P1

Insulin-like growth factor-I receptor blockade by a specific tyrosine kinase inhibitor for human gastrointestinal carcinomas.

Insulin-like growth factor-I receptor (IGF-IR) signaling is required for carcinogenicity and proliferation of gastrointestinal (GI) cancers. In this study, we sought to evaluate the effect of a new tyrosine kinase inhibitor of IGF-IR, NVP-AEW541, on the signal transduction and the progression of GI carcinomas. We assessed the effect of NVP-AEW541 on signal transduction, proliferation, survival, and migration in four GI cancer cells: colorectal adenocarcinoma HT29, pancreatic adenocarcinoma BxPC3, esophageal squamous cell carcinoma TE1, and hepatoma PLC/PRF/5. The effects of NVP-AEW541 alone and with chemotherapy were studied in vitro and in nude mouse xenografts. We also analyzed the effects of NVP-AEW541 on insulin signals and hybrid receptor formation between IGF-IR and insulin receptor. NVP-AEW541 blocked autophosphorylation of IGF-IR and both Akt and extracellular signal-regulated kinase activation by IGF but not by insulin. NVP-AEW541 suppressed proliferation and tumorigenicity in vitro in a dose-dependent manner in all cell lines. The drug inhibited tumor as a single agent and, when combined with stressors, up-regulated apoptosis in a dose-dependent fashion and inhibited mobility. NVP-AEW541 augmented the effects of chemotherapy on in vitro growth and induction of apoptosis. Moreover, the combination of NVP-AEW541 and chemotherapy was highly effective against tumors in mice. This compound did not influence hybrid receptor formation. Thus, NVP-AEW541 may have significant therapeutic utility in human GI carcinomas both alone and in combination with chemotherapy

Targeting for insulin-like growth factor-I receptor with short hairpin RNA for human digestive/gastrointestinal cancers

Insulin-like growth factor (IGF)-I receptor (IGF-IR) signaling plays important parts in both the tumorigenicity and progression of digestive/gastrointestinal malignancies. In this study, we sought to test the effectiveness of a practical approach to blocking IGF-IR signaling using RNA interference delivered by recombinant adenoviruses. We constructed a recombinant adenovirus expressing short hairpin RNA targeting IGF-IR (shIGF-IR) and assessed its effect on signal transduction, proliferation, and survival in digestive/gastrointestinal cancer cell lines representing colorectal, gastric, and pancreatic adenocarcinoma, esophageal squamous cell carcinoma, and hepatoma. We analyzed the effects of shIGF-IR alone and with chemotherapy in vitro and in nude mouse xenografts, as well as on insulin signaling and hybrid receptor formation between IGF-IR and insulin receptor. shIGF-IR blocked expression and autophosphorylation of IGF-IR and downstream signaling by the IGFs, but not by insulin. shIGF-IR suppressed proliferation and carcinogenicity in vitro and up-regulated apoptosis in a dose-dependent fashion. shIGF-IR augmented the effects of chemotherapy on in vitro growth and apoptosis induction. Moreover, the combination of shIGF-IR and chemotherapy was highly effective against tumors in mice. shIGF-IR reduced hybrid receptor formation without effect on expression of insulin receptor. shIGF-IR may have therapeutic utility in human digestive/gastrointestinal cancers, both alone and in combination with chemotherapy.Kwon J, 2009, CANCER RES, V69, P1350, DOI 10.1158/0008-5472.CAN-08-1328Huang F, 2009, CANCER RES, V69, P161, DOI 10.1158/0008-5472.CAN-08-0835Law JH, 2008, CANCER RES, V68, P10238, DOI 10.1158/0008-5472.CAN-08-2755Piao WH, 2008, MOL CANCER THER, V7, P1483, DOI 10.1158/1535-7163.MCT-07-2395Dong AQ, 2008, ACTA BIOCH BIOPH SIN, V40, P497, DOI 10.1111/j.1745-7270.2008.00429.xImsumran A, 2007, CARCINOGENESIS, V28, P947, DOI 10.1093/carcin/bgl247Lee YJ, 2007, LUNG CANCER, V55, P279, DOI 10.1016/j.lungcan.2006.10.020Zhang H, 2007, CANCER RES, V67, P391, DOI 10.1158/0008-5472.CAN-06-1712Harper J, 2006, CANCER RES, V66, P1940, DOI 10.1158/0008-5472.CAN-05-2036ADACHI Y, 2006, DIGEST ENDOSC, V18, P245Nahta R, 2005, CANCER RES, V65, P11118, DOI 10.1158/0008-5472.CAN-04-3841Miller BS, 2005, CANCER RES, V65, P10123, DOI 10.1158/0008-5472.CAN-05-2752Schoen RE, 2005, GASTROENTEROLOGY, V129, P464, DOI 10.1053/j.gastro.2005.05.051Wang Y, 2005, MOL CANCER THER, V4, P1214, DOI 10.1158/1535-7163.MCT-05-0048Min Y, 2005, GUT, V54, P591, DOI 10.1136/gut.2004.048926Cohen BD, 2005, CLIN CANCER RES, V11, P2063Rochester MA, 2005, CANCER GENE THER, V12, P90, DOI 10.1038/sj.cgtFoulstone E, 2005, J PATHOL, V205, P145, DOI 10.1002/path.1712Burtrum D, 2003, CANCER RES, V63, P8912Min YF, 2003, CANCER RES, V63, P6432Bohula EA, 2003, J BIOL CHEM, V278, P15991, DOI 10.1074/jbc.M300714200Tuschl T, 2003, NATURE, V421, P220, DOI 10.1038/421220aLevitt RJ, 2002, CANCER RES, V62, P7372Pandini G, 2002, J BIOL CHEM, V277, P39684, DOI 10.1074/jbc.M202766200Adachi Y, 2002, GASTROENTEROLOGY, V123, P1191, DOI 10.1053/gast.2002.36023Hannon GJ, 2002, NATURE, V418, P244, DOI 10.1038/418244aLu YH, 2001, J NATL CANCER I, V93, P1852Ajisaka H, 2001, HEPATO-GASTROENTEROL, V48, P1788Yu H, 2000, J NATL CANCER I, V92, P1472Adams TE, 2000, CELL MOL LIFE SCI, V57, P1050Freier S, 1999, GUT, V44, P704Ma J, 1999, J NATL CANCER I, V91, P620Simmons JG, 1999, AM J PHYSIOL-GASTR L, V276, pG817Baselga J, 1998, CANCER RES, V58, P2825Fire A, 1998, NATURE, V391, P806, DOI 10.1038/35888Kim SO, 1996, CANCER RES, V56, P3831Lee CT, 1996, CANCER RES, V56, P3038BERGMANN U, 1995, CANCER RES, V55, P2007BASERGA R, 1995, CANCER RES, V55, P249BASERGA R, 1994, CELL, V79, P927LAHM H, 1994, INT J CANCER, V58, P452SELL C, 1993, P NATL ACAD SCI USA, V90, P11217LIU JP, 1993, CELL, V75, P59REMACLEBONNET M, 1992, INT J CANCER, V52, P910LAHM H, 1992, BRIT J CANCER, V65, P341CHEN SC, 1991, CANCER RES, V51, P1898SARA VR, 1990, PHYSIOL REV, V70, P591THOMPSON MA, 1990, ENDOCRINOLOGY, V126, P3033CARO JF, 1988, J CLIN INVEST, V81, P976ULLRICH A, 1986, EMBO J, V5, P2503