Abstract
Emerging evidence demonstrates that stromal cell-derived factor 1 (SDF-1) and CXCR4, a chemokine and chemokine receptor pair, play important roles in tumorigenesis. In this report, we describe a small cyclic peptide, LY2510924, which is a potent and selective CXCR4 antagonist currently in phase II clinical studies for cancer. LY2510924 specifically blocked SDF-1 binding to CXCR4 with IC50 value of 0.079 nmol/L, and inhibited SDF-1-induced GTP binding with Kb value of 0.38 nmol/L. In human lymphoma U937 cells expressing endogenous CXCR4, LY2510924 inhibited SDF-1-induced cell migration with IC50 value of 0.26 nmol/L and inhibited SDF-1/CXCR4-mediated intracellular signaling. LY2510924 exhibited a concentration-dependent inhibition of SDF-1-stimulated phospho-ERK and phospho-Akt in tumor cells. Biochemical and cellular analyses revealed that LY2510924 had no apparent agonist activity. Pharmacokinetic analyses suggested that LY2510924 had acceptable in vivo stability and a pharmacokinetic profile similar to a typical small-molecular inhibitor in preclinical species. LY2510924 showed dose-dependent inhibition of tumor growth in human xenograft models developed with non-Hodgkin lymphoma, renal cell carcinoma, lung, and colon cancer cells that express functional CXCR4. In MDA-MB-231, a breast cancer metastatic model, LY2510924 inhibited tumor metastasis by blocking migration/homing process of tumor cells to the lung and by inhibiting cell proliferation after tumor cell homing. Collectively, the preclinical data support further investigation of LY2510924 in clinical studies for cancer.
Highlights
Stromal cell–derived factor 1 (SDF-1, called CXCL12) and CXCR4, a chemokine and chemokine receptor pair play important roles in many stages of tumorigenesis [1,2,3]
The paracrine and endocrine effects mediated through stromal cell-derived factor 1 (SDF-1)/CXCR4 are critical for tumor growth, invasion, angiogenesis, and metastasis [2, 3]
In Namalwa cells, which express high level of CXCR4, treatment of SDF-1 enhanced the phosphorylation of ERK and Akt, and LY2510924 again inhibited SDF-1–stimulated ERK and Akt phosphorylation with IC50 values of 1.4 and 1.2 nmol/L, respectively (Fig. 2C and D). These results suggest that LY2510924 blocks CXCR4/SDF-1–regulated cell signaling in tumor cells
Summary
Stromal cell–derived factor 1 (SDF-1, called CXCL12) and CXCR4, a chemokine and chemokine receptor pair play important roles in many stages of tumorigenesis [1,2,3]. CXCR4 is overexpressed in a variety of human cancers, and this overexpression is correlated with increased risk for recurrence and poor overall survival in multiple cancer patients including breast, lung, kidney, colon, ovarian, and brain cancers, as well as lymphoma and leukemia [1,2,3,4,5]. SDF-1/CXCR4 interaction activates multiple signal transduction pathways including PI3K/Akt, Ras/Raf/MAPK cascades [6, 7]. The paracrine and endocrine effects mediated through SDF-1/CXCR4 are critical for tumor growth, invasion, angiogenesis, and metastasis [2, 3]. Within hypoxic areas of tumors, both SDF-1 secretion by fibroblasts and CXCR4 expres-. Note: Supplementary data for this article are available at Molecular Cancer Therapeutics Online (http://mct.aacrjournals.org/)
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
