PMID- 28445830 OWN - NLM STAT- MEDLINE DCOM- 20180326 LR - 20180326 IS - 1950-6007 (Electronic) IS - 0753-3322 (Linking) VI - 91 DP - 2017 Jul TI - Overexpression of heme oxygenase-1 in bone marrow stromal cells promotes microenvironment-mediated imatinib resistance in chronic myeloid leukemia. PG - 21-30 LID - S0753-3322(17)31329-X [pii] LID - 10.1016/j.biopha.2017.04.076 [doi] AB - Neoplasm cells from patients with chronic myeloid leukemia (CML) interact with stromal cells of the surrounding microenvironment. Bone marrow stromal cells (BMSCs) represent the main population in CML marrow stroma, which may play a key role in disease support and progression. Heme oxygenase-1 (HO-1) is a key enzyme of antioxidative metabolism that is associated with cell proliferation and resistance to apoptosis. We herein up-regulated HO-1 expression of BMSCs and evaluated whether BMSCs influenced K562 cells survival. BMSCs were isolated from the bone marrow of normal people and CML patients. Following co-culture of BMSCs and K562 cells, up-regulating HO-1 expression in bone marrow stromal cells increased the imatinib (IM) resistance of K562 cells, whereas the apoptosis of K562 cells was effectively promoted without BMSCs co-culture. The protection may be mediated by CXCL12 (stromal derived factors 1, SDF-1)/CXCR4 signaling. The CXCL12/CXCR4 interaction significantly enhanced the phosphorylation of AKT. As far as drug resistance was concerned, BMSCs counteracted the cytotoxic effect of IM administration in vitro, and they protected K562 cells from the apoptosis induced by kinase inhibitor IM. The regulated HO-1 expression of BMSCs provides a new putative target for CML therapy. CI - Copyright (c) 2017 Elsevier Masson SAS. All rights reserved. FAU - Liu, Ping AU - Liu P AD - Department of Hematology, Affiliated Hospital of Guizhou Medical University, Hematological Institute of Guizhou Province, Guizhou Province Laboratory of Hematopoietic Stem Cell Transplantation Centre, Guiyang 550004, PR China. FAU - Ma, Dan AU - Ma D AD - Department of Hematology, Affiliated Hospital of Guizhou Medical University, Hematological Institute of Guizhou Province, Guizhou Province Laboratory of Hematopoietic Stem Cell Transplantation Centre, Guiyang 550004, PR China. FAU - Yu, Zhengyu AU - Yu Z AD - Department of Hematology, Affiliated Hospital of Guizhou Medical University, Hematological Institute of Guizhou Province, Guizhou Province Laboratory of Hematopoietic Stem Cell Transplantation Centre, Guiyang 550004, PR China. FAU - Zhe, Nana AU - Zhe N AD - Department of Hematology, Affiliated Hospital of Guizhou Medical University, Hematological Institute of Guizhou Province, Guizhou Province Laboratory of Hematopoietic Stem Cell Transplantation Centre, Guiyang 550004, PR China. FAU - Ren, Mei AU - Ren M AD - Department of Hematology, Affiliated Hospital of Guizhou Medical University, Hematological Institute of Guizhou Province, Guizhou Province Laboratory of Hematopoietic Stem Cell Transplantation Centre, Guiyang 550004, PR China. FAU - Wang, Ping AU - Wang P AD - Department of Hematology, Affiliated Hospital of Guizhou Medical University, Hematological Institute of Guizhou Province, Guizhou Province Laboratory of Hematopoietic Stem Cell Transplantation Centre, Guiyang 550004, PR China. FAU - Yu, Meisheng AU - Yu M AD - Department of Internal Medicine, Jiangxi Medical College, Shangrao 334000, PR China. FAU - Huang, Jun AU - Huang J AD - Department of Hematology, Affiliated Hospital of Guizhou Medical University, Hematological Institute of Guizhou Province, Guizhou Province Laboratory of Hematopoietic Stem Cell Transplantation Centre, Guiyang 550004, PR China. FAU - Fang, Qin AU - Fang Q AD - Department of Pharmacy, Affiliated Hospital of Guizhou Medical University, Guiyang 550004, PR China. Electronic address: fq_fangqin@sina.com. FAU - Wang, Jishi AU - Wang J AD - Department of Hematology, Affiliated Hospital of Guizhou Medical University, Hematological Institute of Guizhou Province, Guizhou Province Laboratory of Hematopoietic Stem Cell Transplantation Centre, Guiyang 550004, PR China. Electronic address: wangjishi9646@163.com. LA - eng PT - Journal Article DEP - 20170423 PL - France TA - Biomed Pharmacother JT - Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie JID - 8213295 RN - 0 (CXCL12 protein, human) RN - 0 (CXCR4 protein, human) RN - 0 (Chemokine CXCL12) RN - 0 (Chromones) RN - 0 (Morpholines) RN - 0 (Receptors, CXCR4) RN - 31M2U1DVID (2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one) RN - 8A1O1M485B (Imatinib Mesylate) RN - EC 1.14.14.18 (Heme Oxygenase-1) RN - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt) SB - IM MH - Adolescent MH - Adult MH - Aged MH - Apoptosis/drug effects MH - Bone Marrow Cells/drug effects/*metabolism MH - Cell Line, Tumor MH - *Cellular Microenvironment/drug effects MH - Chemokine CXCL12/metabolism MH - Chromones/pharmacology MH - Cytoprotection/drug effects MH - *Drug Resistance, Neoplasm/drug effects MH - Female MH - Heme Oxygenase-1/*metabolism MH - Humans MH - Imatinib Mesylate/pharmacology/*therapeutic use MH - Leukemia, Myelogenous, Chronic, BCR-ABL Positive/*drug therapy/*pathology MH - Male MH - Middle Aged MH - Morpholines/pharmacology MH - Phosphorylation/drug effects MH - Proto-Oncogene Proteins c-akt/metabolism MH - Receptors, CXCR4/metabolism MH - Recurrence MH - Signal Transduction/drug effects MH - Solubility MH - Stromal Cells/drug effects/metabolism MH - Survival Analysis MH - Up-Regulation/drug effects MH - Young Adult OTO - NOTNLM OT - Chronic myeloid leukemia OT - Heme oxygenase-1 OT - Imatinib OT - Microenvironment OT - Resistance EDAT- 2017/04/27 06:00 MHDA- 2018/03/27 06:00 CRDT- 2017/04/27 06:00 PHST- 2017/03/22 00:00 [received] PHST- 2017/04/17 00:00 [revised] PHST- 2017/04/17 00:00 [accepted] PHST- 2017/04/27 06:00 [pubmed] PHST- 2018/03/27 06:00 [medline] PHST- 2017/04/27 06:00 [entrez] AID - S0753-3322(17)31329-X [pii] AID - 10.1016/j.biopha.2017.04.076 [doi] PST - ppublish SO - Biomed Pharmacother. 2017 Jul;91:21-30. doi: 10.1016/j.biopha.2017.04.076. Epub 2017 Apr 23.