AMD3100 and G-CSF disrupt the cross-talk between leukemia cells and the endosteal niche and enhance their sensitivity to chemotherapeutic drugs in biomimetic polystyrene scaffolds.
The multidrug resistance of leukemia cells is closely related to the microenvironment. The present leukemia microenvironment models focus on two-dimensional co-culture system in vitro which does not mimic the in vivo cell growth, while the 3D polystyrene (PS) scaffolds have the advantage. Stromal cell derived factor-1 may be involved in the shielding of endosteal niche from leukemia cells by binding to its receptor CXCR4, but the relationship between SDF-1/CXCR4 axis and leukemia cells is unclear.



The experiments were built on the 3D PS scaffolds coated with osteoblasts. Stromal cells and MV4-11 cells were plated on the scaffolds. Then G-CSF, AMD3100 and cytarabine were added. Adhesive rate, SDF-1 level, migration state, apoptosis rate, and cell cycle of leukemia cells were observed after incubation at 24h and 48h.



G-CSF decreased the level of SDF-1 and inhibited the expression of CXCR4 and promoted stationary phase leukemia cells to enter the mitotic phase and enhanced the killing effect of chemotherapeutic drugs. AMD3100 disrupted the interaction between tumors and matrix, mobilized the leukemia cells to keep away from the protective microenvironment and strengthened the cytotoxic effect of Ara-C. The combination of G-CSF and AMD3100 had stronger effects on killing the leukemia cells induced by Ara-C.



It demonstrates that AMD3100 and G-CSF may inhibit adhesion and migration abilities of leukemia cells with the bone marrow niche. Both of them inhibit the role of SDF-1/CXCR4 directly or indirectly. Thus inhibiting SDF-1/CXCR4 axis may be helpful to the treatment of refractory AML.
Department of Hematology, Xinqiao Hospital, The Third Military Medical University, Chongqing 400037, People's Republic of China.
Zhao-Hua
ZH
Shen
Department of Hematology, Xinqiao Hospital, The Third Military Medical University, Chongqing 400037, People's Republic of China.
Dong-Feng
DF
Zeng
Department of Hematology, Xinqiao Hospital, The Third Military Medical University, Chongqing 400037, People's Republic of China. Electronic address: peiyankong@aliyun.com.
Pei-Yan
PY
Kong
Department of Hematology, Xinqiao Hospital, The Third Military Medical University, Chongqing 400037, People's Republic of China.
Ying-Ying
YY
Ma
Department of Hematology, Xinqiao Hospital, The Third Military Medical University, Chongqing 400037, People's Republic of China.
Xi
X
Zhang
D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D001596:Benzylamines; D040761:Biomimetic Materials; D002448:Cell Adhesion; D002465:Cell Movement; D002478:Cells, Cultured; D054377:Chemokine CXCL12 / Q000378:metabolism; D000080027:Cyclams; D003561:Cytarabine / Q000494:pharmacology; D016179:Granulocyte Colony-Stimulating Factor / Q000494:pharmacology*; D006571:Heterocyclic Compounds / Q000494:pharmacology*; D006801:Humans; D007938:Leukemia / Q000473:pathology*; D015470:Leukemia, Myeloid, Acute / Q000473:pathology; D011137:Polystyrenes; D020239:Receptor Cross-Talk / Q000187:drug effects*; D019718:Receptors, CXCR4 / Q000378:metabolism; D017154:Stromal Cells / Q000166:cytology
D000970:Antineoplastic Agents; D001596:Benzylamines; C527276:CXCR4 protein, human; D054377:Chemokine CXCL12; D000080027:Cyclams; D006571:Heterocyclic Compounds; D011137:Polystyrenes; D019718:Receptors, CXCR4; D003561:Cytarabine; D016179:Granulocyte Colony-Stimulating Factor; C088327:plerixafor
AMD3100; Endosteal niche; Granulocyte colony-stimulating factor (G-CSF); SDF-1/CXCR4; Three-dimensional culture system