title: Targeting of the leukemia microenvironment by c(RGDfV) overcomes the resistance to chemotherapy in acute myeloid leukemia in biomimetic polystyrene scaffolds.
abstract: The bone marrow microenvironment provides a relative sanctuary from cytotoxic drugs for leukemia cells. The present niche models concentrate on a two-dimensional (2D) co-culture systemin vitro, which does not imitate thein vivoenvironment, while the 3D scaffolds are more reflective of this. Osteopontin (Opn) secreted by bone marrow osteoblasts, may participate in protecting leukemia cells from apoptosis by binding to its receptor αvβ3, which can be expressed on the surface of the leukemia MV4-11 cell line. However, the association between the Opn/αvβ3 axis and leukemia cells is unknown. In the present study, experiments were conducted on 3D polystyrene scaffolds coated with osteoblasts and leukemia cells. The cells were exposed to cyclo(Arg-Gly-Asp-d-Phe-Val) [c(RGDfV)] (35 nmol/ml), which blocks αvβ3, for a period of 24 h. Cytarabine was applied 24 h later. The adhesion, migration and apoptosis rates, and the cell cycle of the leukemia cells were analyzed after incubation for 24 and 48 h. In contrast to the 2D culture system, the stromal cells in the scaffolds secreted significantly more alkaline phosphatase and Opn (P<0.05). c(RGDfV) disrupted the adhesion and migration between the tumor cells and the matrix, induced the leukemia cells to leave the protective microenvironment and increased their sensitivity to cell cycle-dependent agents (P<0.05). In summary, the data certified that the 3D scaffolds are suitable for the growth of cells, and that c(RGDfV) inhibits the adhesion and migration abilities of leukemia cells in the endosteal niche. Therefore, blocking the function of Opn may be beneficial in the treatment of acute myeloid leukemia.
authors.affiliation: Department of Hematology, Xinqiao Hospital, The Third Military Medical University, Chongqing 400037, P.R. China; Department of Gastroenterology, Third Xiangya Hospital, Central South University, Changsha, Hunan 410013, P.R. China.
authors.forename: Zhao-Hua
authors.initials: ZH
authors.lastname: Shen
authors.affiliation: Department of Hematology, Xinqiao Hospital, The Third Military Medical University, Chongqing 400037, P.R. China.
authors.forename: Dong-Feng
authors.initials: DF
authors.lastname: Zeng
authors.affiliation: Department of Gastroenterology, Third Xiangya Hospital, Central South University, Changsha, Hunan 410013, P.R. China.
authors.forename: Xiao-Yan
authors.initials: XY
authors.lastname: Wang
authors.affiliation: Department of Hematology, Xinqiao Hospital, The Third Military Medical University, Chongqing 400037, P.R. China.
authors.forename: Ying-Ying
authors.initials: YY
authors.lastname: Ma
authors.affiliation: Department of Hematology, Xinqiao Hospital, The Third Military Medical University, Chongqing 400037, P.R. China.
authors.forename: Xi
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Department of Hematology, Xinqiao Hospital, The Third Military Medical University, Chongqing 400037, P.R. China.
authors.forename: Pei-Yan
authors.initials: PY
authors.lastname: Kong
keywords: Opn; c(RGDfV); endosteal niche; three-dimensional culture system