A Novel Designed Small Peptide Enhances Chemotherapy Sensitivity Of Leukemia Cells In Stromal Microenvironment

Proceedings: AACR Annual Meeting 2014; April 5-9, 2014; San Diego, CA Many types of leukemia cells highly express chemokine receptor (CXCR4) that actively responses to CXCL12, a chemokine constitutively secreted by stromal cells in bone marrow. Activation of CXCR4 induces leukemia cells trafficking and homing to the marrow microenvironment, where CXCL12 retains these cells in close contact with marrow stromal cells that provide growth, self-renewal, and drug resistance signals, which lead to poor prognosis and relapse. We report here a novel designed peptide targeting to CXCR4, named as XW1108-3. The patented sequence is GGQGCRFRNTVDD WISITRAL. We use flow cytometry, cell migration and adhesion assay to study the affinity of XW1108-3 to leukemia cells and the inhibitory effect on CXCL12-induced cell behaviors. The XW1108-3 shows high affinity to different types of leukemia cell highly expressing CXCR4 including HL-60, NB4, THP-1 and U937, the binding was maintained for up to 4 hours. The XW1108-3 treatment significantly inhibited CXCL12- or murine stromal cell MS-5-induced migration of leukemia cells in a concentration dependent manner in the transwell assay and significantly reduced the leukemia cells adhesion to MS-5 cell layer. Mechanistic study with western blot and confocal microscopy assay demonstrates that XW1108-3 treatment down regulates CXCL12-induced phosphorylation of Erk, Akt and p38 and affects F-actin organization, resulting in the suppression of the cell response to CXCL12 activation. It is notable that XW1108-3 treatment did not induce apoptosis of leukemia cells or human fibroblasts and endothelial cells even at 10 µM, instead enhanced the level of 10-hydroxy camptothecin-induced apoptosis of different leukemia cells co-incubated with the stromal cell MS-5 layer, thereby exhibiting great clinical implications in leukemia chemotherapies and immune therapies. Citation Format: Xiaojin Li, Hua Guo, Yanlian Yang, Jie Meng, Jian Liu, Chen Wang, Haiyan Xu. A novel designed small peptide enhances chemotherapy sensitivity of leukemia cells in stromal microenvironment. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1813. doi:10.1158/1538-7445.AM2014-1813