title: Oroxylin A reverses the drug resistance of chronic myelogenous leukemia cells to imatinib through CXCL12/CXCR7 axis in bone marrow microenvironment.
abstract: Imatinib (IM), a tyrosine-kinase inhibitor, is used in treatment of multiple cancers, most notably Philadelphia chromosome-positive (Ph+) chronic myelogenous leukemia (CML). However, the majority of patients continue to present with minimal residual disease occurred in the bone marrow (BM) microenvironment. One of the key factors that contribute to leukemia cell drug resistance is chemokine CXCL12. In the current study, co-culturing CML cell K562 and KU812 with BM stromal cell M2-10B4 attenuated IM-induced apoptosis. CXCL12/CXCR7 pathway was activated in co-culture models, which was further proved to be related to drug resistance by silencing CXCR7. ERK phosphorylation and downstream apoptosis related proteins' activation were also observed in co-culture group after the activation of CXCR7. Moreover, oroxylin A, a bioactive flavonoid isolated from the root of Scutellaria baicalensis Georgi, was found to be effective in reversing BM stroma induced CML resistance to IM. After cells were treated with weakly toxic concentration of oroxylin A, cell apoptosis induced by IM in co-culture model was enhanced. And the activated CXCL12/CXCR7 pathway, the expression of p-ERK and downstream apoptosis related proteins were suppressed. The in vivo study also showed that oroxylin A increased apoptosis of CML cells with low systemic toxicity, and the mechanism was consistent with the in vitro study. In conclusion, oroxylin A improved sensitivity of CML cells to IM treatment in BM microenvironment through regulating CXCL12/CXCR7 pathway. © 2016 Wiley Periodicals, Inc.
authors.affiliation: State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Carcinogenesis and Intervention, China Pharmaceutical University, Nanjing, People's Republic of China.
authors.forename: Wenjun
authors.initials: W
authors.lastname: Li
authors.affiliation: Experimental and Teaching Center of Medical Basis for Pharmacy, China Pharmaceutical University, Nanjing, People's Republic of China.
authors.forename: Qilong
authors.initials: Q
authors.lastname: Ding
authors.affiliation: State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Carcinogenesis and Intervention, China Pharmaceutical University, Nanjing, People's Republic of China.
authors.forename: Youxiang
authors.initials: Y
authors.lastname: Ding
authors.affiliation: State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Carcinogenesis and Intervention, China Pharmaceutical University, Nanjing, People's Republic of China.
authors.forename: Lu
authors.initials: L
authors.lastname: Lu
authors.affiliation: State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Carcinogenesis and Intervention, China Pharmaceutical University, Nanjing, People's Republic of China.
authors.forename: Xiaoping
authors.initials: X
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Carcinogenesis and Intervention, China Pharmaceutical University, Nanjing, People's Republic of China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Carcinogenesis and Intervention, China Pharmaceutical University, Nanjing, People's Republic of China.
authors.forename: Xiaobo
authors.initials: X
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Carcinogenesis and Intervention, China Pharmaceutical University, Nanjing, People's Republic of China.
authors.forename: Qinglong
authors.initials: Q
authors.lastname: Guo
authors.affiliation: State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Carcinogenesis and Intervention, China Pharmaceutical University, Nanjing, People's Republic of China.
authors.forename: Li
authors.initials: L
authors.lastname: Zhao
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000494:pharmacology; D001853:Bone Marrow / Q000187:drug effects / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D054377:Chemokine CXCL12 / Q000378:metabolism*; D018920:Coculture Techniques; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D005419:Flavonoids / Q000008:administration & dosage* / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D000068877:Imatinib Mesylate; D020014:K562 Cells; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy* / Q000378:metabolism; D051379:Mice; D054387:Receptors, CXCR / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D059016:Tumor Microenvironment / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: C501896:ACKR3 protein, human; D000970:Antineoplastic Agents; C515255:CXCL12 protein, human; D054377:Chemokine CXCL12; D005419:Flavonoids; D054387:Receptors, CXCR; C080669:5,7-dihydroxy-6-methoxy-2-phenylchromen-4-one; D000068877:Imatinib Mesylate
keywords: CXCL12/CXCR7; Oroxylin A; bone marrow microenvironment; co-culture