Cdc42 inhibitor ML141 enhances G-CSF-induced hematopoietic stem and progenitor cell mobilization

• Published in: International journal of hematology Vol. 101; no. 1; pp. 5 - 12
• Main Authors: Chen, Chong, Song, Xuguang, Ma, Sha, Wang, Xue, Xu, Jie, Zhang, Huanxin, Wu, Qingyun, Zhao, Kai, Cao, Jiang, Qiao, Jianlin, Sun, Xiaoshen, Li, Depeng, Zeng, Lingyu, Li, Zhengyu, Xu, Kailin
• Format: Journal Article
• Language: English
• Published: Tokyo Springer Japan 01.01.2015; Springer Nature B.V
• Subjects: Animals; Bone Marrow Cells - drug effects; Bone Marrow Cells - metabolism; cdc42 GTP-Binding Protein - antagonists & inhibitors; Chemokine CXCL12 - genetics; Chemokine CXCL12 - metabolism; Granulocyte Colony-Stimulating Factor - pharmacology; Hematology; Hematopoietic Stem Cell Mobilization - methods; Hematopoietic Stem Cells - drug effects; Hematopoietic Stem Cells - metabolism; Matrix Metalloproteinase 9 - genetics; Matrix Metalloproteinase 9 - metabolism; Medicine; Medicine & Public Health; Mice; Oncology; Original Article; Pyrazoles - pharmacology; Sulfonamides - pharmacology; Granulocyte colony–stimulating factor; Mobilization; Mouse; Cell division control protein 42 homolog; Hematopoietic stem and progenitor cell
• ISSN: 0925-5710; 1865-3774
• DOI: 10.1007/s12185-014-1690-z

G-CSF is the most often used agent in clinical hematopoietic stem and progenitor cell (HSPC) mobilization. However, in about 10 % of patients, G-CSF does not efficiently mobilize HSPC in clinically sufficient amounts. Cdc42 activity is involved in HSPC mobilization. In the present study, we explore the impact of Cdc42 inhibitor ML141 on G-CSF-mediated HSPC mobilization in mice. We found that the use of ML141 alone only triggered modest HSPC mobilization effect in mice. However, combination of G-CSF and ML141 significantly promoted HPSC counts and colony forming units in peripheral blood, as compared to mice treated with G-CSF alone. ML141 did not significantly alter the levels of SDF-1 and MMP-9 in the bone marrow, when used alone or in combination with G-CSF. We also found that G-CSF administration significantly increases the level of GTP-bound Cdc42, but does not alter the expression of Cdc42 in the bone marrow. Our data indicate that the Cdc42 signal is a negative regulator in G-CSF-mediated HSPC mobilization, and that inhibition of the Cdc42 signal efficiently improves mobilization efficiency. These findings may provide a new strategy for efficient HSPC mobilization, especially in patients with poor G-CSF response.