This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The cell-surface CXCR4 chemokine receptor is over-expressed in human malignant and metastatic breast cells but is not present in normal breast tissue. This receptor is involved in the metastasis of breast and other types of tumor cells. Hence, we hypothesize that blocking this receptor with synthetic peptide ligands offers the potential for a new class of chemotherapeutic agents targeted specifically to prevent cancer metastasis. In order to test this hypothesis our first step was to design, synthesize and evaluate synthetic peptide ligands as potential CXCR4 receptor antagonists. Using a radioligand binding assay, our results demonstrate that several of our analogues have high affinity for CXCR4. Further, these ligands are antagonists as they are able to successfully reverse agonist activity of the endogenous ligand at CXCR4 in a GTPase functional assay. However, our most exciting finding stems from the inability to correlate receptor affinity with antagonist potency for our series of analogues. The 150-fold increase in antagonist potency of our new lead compound could not have been predicted from receptor affinity that suggests the potential for a new paradigm for peptide ligand interaction with CXCR4. Our future work focuses on the central hypothesis that structural requirements for peptide-based antagonists are not identical to those of the endogenous protein for interaction at CXCR4. We will further investigate the interaction between peptides and CXCR4 using a two-tiered method. This will include chemical modification of the peptides in combination with molecular biology approaches to modify the receptor.

Agency
National Institute of Health (NIH)
Institute
National Center for Research Resources (NCRR)
Type
Exploratory Grants (P20)
Project #
5P20RR015563-07
Application #
7381085
Study Section
Special Emphasis Panel (ZRR1-RI-8 (01))
Project Start
2006-05-01
Project End
2007-04-30
Budget Start
2006-05-01
Budget End
2007-04-30
Support Year
7
Fiscal Year
2006
Total Cost
$68,327
Indirect Cost
Name
University of Kansas Lawrence
Department
Pharmacology
Type
Schools of Pharmacy
DUNS #
076248616
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
Kong, Bo; Huang, Jiansheng; Zhu, Yan et al. (2014) Fibroblast growth factor 15 deficiency impairs liver regeneration in mice. Am J Physiol Gastrointest Liver Physiol 306:G893-902
Hall, Sonia; Bone, Courtney; Oshima, Kenzi et al. (2014) Macroglobulin complement-related encodes a protein required for septate junction organization and paracellular barrier function in Drosophila. Development 141:889-98
Grogan, Patrick T; Sarkaria, Jann N; Timmermann, Barbara N et al. (2014) Oxidative cytotoxic agent withaferin A resensitizes temozolomide-resistant glioblastomas via MGMT depletion and induces apoptosis through Akt/mTOR pathway inhibitory modulation. Invest New Drugs 32:604-17

Showing the most recent 10 out of 240 publications