Recent advances in our understanding of cancer cell biology provide new opportunities to identify drugs which target the molecular mechanisms involved in neoplastic transformation, cancer growth and metastasis. The proposed research analyzes two novel targets for anti-cancer therapeutics, the histamine H2-receptor (H2R) and the tetraspanins. The H2R mediates myeloid cell differentiation. Therefore, H2R agonists may be useful in treatment of acute myelogenous leukemia (AML). The feasibility of H2R agonists as differentiation therapy for AML will be addressed by 1) characterizing the differentiation of HL-60 pro-myelocytes and AML cells with histamine, all-trans retinoic acid (RA) and with histamine + RA, 2) analysis of the molecular basis for the signaling pathway- dependent pharmacological properties of the H2R. The H2R is a G- protein coupled preceptor that mediates activation of adenylyl cyclase via the G-protein Gs and activation of phospholipase C via G1/G16. This proposal will address the hypotheses that 1) pro-myelocytes express two H2R subtypes and that 2) specific G-proteins determine the pharmacological proteins of the H2R. The tetraspanins are a recently discovered, large, and broadly expressed family of integral membrane proteins. Tetraspanins are a recently discovered, large, and broadly expressed family of integral membrane proteins. Tetraspanins interact with, and regulate the activity of, specific integrins and regulate cell adhesion and migration. Tetraspanins suppress metastasis in several animal tumor models, and reduced tetraspanins expression correlates with increased metastatic potential and poor prognosis in six different cancers. We will 1) define the structural requirements for tetraspanin association with integrins and 2) define the mechanism of tetraspanin function in cell migration, activation and differentiation. Our hypothesis is that tetraspanins associate with integrins via the hypervariable loop in the second extracellular domain and that this association allows tetraspanins to modulate integrin avidity. The development of compounds that target the H2R or tetraspanins will involve 1) the optimized design of H2R agonists by evaluation alternative scaffolds, 2) the characterization of H2R agonists in biologic systems, 3) the development and screening of imadazole-based libraries for substituents possessing tetraspanin affinity and 4) the evaluation and refinement of H2R agonists tetraspanin ligands identified in high-throughput screening for combinatorial libraries. The proposed work will provide important information on the feasibility of cancer therapy strategies that are distinct from traditional cytostatic approaches.

Agency
National Institute of Health (NIH)
Institute
National Center for Research Resources (NCRR)
Type
Exploratory Grants (P20)
Project #
5P20RR015563-02
Application #
6499685
Study Section
Special Emphasis Panel (ZRR1)
Project Start
2001-09-01
Project End
2002-08-31
Budget Start
Budget End
Support Year
2
Fiscal Year
2001
Total Cost
Indirect Cost
Name
University of Kansas Lawrence
Department
Type
DUNS #
072933393
City
Lawrence
State
KS
Country
United States
Zip Code
66045
Subramanian, Chitra; Grogan, Patrick T; Opipari, Valerie P et al. (2018) Novel natural withanolides induce apoptosis and inhibit migration of neuroblastoma cells through down regulation of N-myc and suppression of Akt/mTOR/NF-?B activation. Oncotarget 9:14509-14523
Ishiguro, Susumu; Kawabata, Atsushi; Zulbaran-Rojas, Alejandro et al. (2018) Co-treatment with a C1B5 peptide of protein kinase C? and a low dose of gemcitabine strongly attenuated pancreatic cancer growth in mice through T cell activation. Biochem Biophys Res Commun 495:962-968
He, Chenchen; Duan, Shaofeng; Dong, Liang et al. (2017) Characterization of a novel p110?-specific inhibitor BL140 that overcomes MDV3100-resistance in castration-resistant prostate cancer cells. Prostate 77:1187-1198
White, Peter T; Subramanian, Chitra; Zhu, Qing et al. (2016) Novel HSP90 inhibitors effectively target functions of thyroid cancer stem cell preventing migration and invasion. Surgery 159:142-51
Ohta, Naomi; Ishiguro, Susumu; Kawabata, Atsushi et al. (2015) Human umbilical cord matrix mesenchymal stem cells suppress the growth of breast cancer by expression of tumor suppressor genes. PLoS One 10:e0123756
Li, Benyi; Thrasher, James Brantley; Terranova, Paul (2015) Glycogen synthase kinase-3: a potential preventive target for prostate cancer management. Urol Oncol 33:456-63
Ishiguro, Susumu; Yoshimura, Kiyoshi; Tsunedomi, Ryouichi et al. (2015) Involvement of angiotensin II type 2 receptor (AT2R) signaling in human pancreatic ductal adenocarcinoma (PDAC): a novel AT2R agonist effectively attenuates growth of PDAC grafts in mice. Cancer Biol Ther 16:307-16
Li, Benyi; Sun, Aijing; Jiang, Wencong et al. (2014) PI-3 kinase p110?: a therapeutic target in advanced prostate cancers. Am J Clin Exp Urol 2:188-98
Bibis, Stergios S; Dahlstrom, Kelly; Zhu, Tongtong et al. (2014) Characterization of Leishmania major phosphatidylethanolamine methyltransferases LmjPEM1 and LmjPEM2 and their inhibition by choline analogs. Mol Biochem Parasitol 196:90-9
Subramanian, Chitra; Zhang, Huaping; Gallagher, Robert et al. (2014) Withanolides are potent novel targeted therapeutic agents against adrenocortical carcinomas. World J Surg 38:1343-52

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