Cross-talk between G Protein–Coupled Receptor and Epidermal Growth Factor Receptor Signaling Pathways Contributes to Growth and Invasion of Head and Neck Squamous Cell Carcinoma

Q1 · MEDICINE

Article

Author: Thomas, Sufi Mary ; Gooding, William E. ; Siegfried, Jill M. ; Bhola, Neil E. ; Chan, Daniel C. ; Zhang, Qing ; Wentzel, Abbey L. ; Contrucci, Sarah C. ; Freilino, Maria L. ; Grandis, Jennifer Rubin

AbstractG protein–coupled receptors (GPCR) and the epidermal growth factor receptor (EGFR) are often both overexpressed and contribute to the growth of cancers by activating autocrine pathways. GPCR ligands have been reported to trigger EGFR signaling via receptor cross-talk in cancer cells. Here, we show that GPCR ligands prostaglandin E2 (PGE2) and bradykinin (BK) activate EGFR signaling. Inhibition of EGFR using several strategies, including small-molecule inhibitors and an EGFR-specific antibody, resulted in partial attenuation of signaling downstream of EGFR. PGE2 and BK triggered EGFR signaling by increasing selective autocrine release of transforming growth factor-α (TGF-α). Inhibition of tumor necrosis factor-α–converting enzyme abrogated BK- or PGE2-mediated activation of EGFR signaling. Both PGE2 and BK stimulated head and neck squamous cell carcinoma (HNSCC) invasion via EGFR. Treatment of HNSCC cells with the BK antagonist CU201 resulted in growth inhibition. The combination of CU201 with the EGFR small-molecule inhibitor erlotinib resulted in additive inhibitory effects on HNSCC cell growth in vitro. Inhibition of the PGE2 synthesis pathway with sulindac induced HNSCC cytotoxicity at high doses (EC50, 620 μmol/L). However, combined inhibition of both EGFR with the tyrosine kinase inhibitor erlotinib and GPCR with sulindac at low doses of 6 and 310 μmol/L, respectively, resulted in synergistic killing of HNSCC tumor cells. Combined blockade of both EGFR and GPCRs may be a rational strategy to treat cancers, including HNSCC that shows cross-talk between GPCR and EGFR signaling pathways. (Cancer Res 2006; 66(24): 11831-9)

01 Apr 2002·Canadian Journal of Physiology and PharmacologyQ4 · MEDICINE

Bradykinin-related compounds as new drugs for cancer and inflammation

Q4 · MEDICINE

Article

Author: Simkeviciene, Vitalija ; Bunn, Paul A. Jr. ; Helfrich, Barbara ; Chan, Daniel C. ; Stewart, John M. ; York, Eunice J. ; Gera, Lajos

Bradykinin (BK) (Arg-Pro-Pro-Gly-Phe-Ser-Pro-Phe-Arg) is an important growth factor for small-cell lung cancer (SCLC) and prostate cancer (PC). These cancers have cells of neuroendocrine origin and express receptors for a variety of neuropeptides. BK receptors are expressed on almost all lung cancer cell lines and on many PC cells. Our very potent BK antagonist B9430 (D-Arg-Arg-Pro-Hyp-Gly-Igl-Ser-D-Igl-Oic-Arg) (Hyp, trans-4-hydroxy-L-proline; Igl, α-2-indanylglycine; Oic, octahydroindole-2-carboxylic acid) is a candidate anti-inflammatory drug but does not inhibit growth of SCLC or PC. When B9430 is dimerized by N-terminal cross-linking with a suberimide linker, the product B9870 is a potent growth inhibitor for SCLC both in vitro and in vivo in athymic nude mice. Daily i.p. injection at 5 mg·kg1·day1 beginning on day 8 after SCLC SHP-77 cell implantation gave 65% inhibition of tumor growth. B9870 stimulates apoptosis in SCLC by a novel "biased agonist" action. We have also developed new small mimetic antagonists. BKM-570 (F5C-OC2Y-Atmp) (F5C, pentafluorocinnamic acid; OC2Y, O-2,6-dichlorobenzyl tyrosine; Atmp, 4-amino-2,2,6,6-tetramethylpiperidine) is very potent for inhibition of SHP-77 growth in nude mice. When injected daily i.p. at 5 mg·kg1, M-570 gave 90% suppression of tumor growth. M-570 is more potent than the well-known anticancer drug cisPlatin (60% inhibition) or the recently developed SU5416 (40% inhibition) in this model. M-570 also showed activity against various other cancer cell lines in vitro (SCLC, non-SCLC, lung, prostate, colon, cervix) and inhibited growth of prostate cell line PC3 in nude mice. M-570 and related compounds evidently act in vivo through pathways other than BK receptors. These compounds have clinical potential for treatment of human lung and prostate cancers.Key words: bradykinin antagonists, cancer, inflammation, prostate cancer, small cell lung cancer.

FoodsQ2 · AGRICULTURAL & FORESTRY SCIENCE

Effect of Structurally Different Pectin on Dough Rheology, Structure, Pasting and Water Distribution Properties of Partially Meat-Based Sugar Snap Cookies

Q2 · AGRICULTURAL & FORESTRY SCIENCE

ArticleOA

Author: Irshad, Sana ; Barakat, Hassan ; Liu, Jianhua ; Li, Enpeng ; Walayat, Noman ; Nilofar ; Pateiro, Mirian ; Khalifa, Ibrahim ; Inam-Ur-Raheem, Muhammad ; Lorenzo, José M. ; Siddiqui, Shahida Anusha ; Muhammad Ahsan, Hafiz ; Nawaz, Asad

Pectin has been widely used as a hydrocolloid in foods, but its effectiveness based on hydrodynamics radius (Rh), average side chain length (ACL) and degree of esterification (DE) has been less studied. This study investigated the effect of 4 types of pectin (with different molecular weight and structures) at a level of 1.5% w/w of wheat flour on functional, structural and water binding properties of sugar snap cookies partially substituted with fish meat. The results showed that pectin (CU-201 and CU-601) with higher ACL and Rh controlled excessive expansion, while the improved rheology of dough in terms of behavior as viscous matrix compared to control and other pectin. Texture was found to be highly dependent on Rh and ACL compared to DE of pectin. The pasting properties, especially peak viscosity and final viscosity, were significantly (p < 0.05) increased with increasing DE, as well as ACL, by entangling and increasing the interaction between starch and pectin. The scanning electron microscopy (SEM) analysis exhibited that control sample showed wide voids and more intercellular spaces, while samples prepared with CU-601, CU-201, and CUL displayed compact structure, which was also evidenced by controlled expansion and improved hardness of the cookies. Low field nuclear magnetic resonance (LF-NMR) analysis showed that T21 relaxation time and amplitude were found to be shorter for CU-601 and CU-201 treatments, signifying the high amount of tightly bound water compared to control. The findings endorse the feasibility of adding CU-601, and CU-201 as an efficient hydrocolloid for the improved structural and functional properties of cookies.

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