title: CXCL12/CXCR4 axis confers adriamycin resistance to human chronic myelogenous leukemia and oroxylin A improves the sensitivity of K562/ADM cells.
abstract: This study was aimed at investigating the reversal effect of oroxylin A, a naturally bioactive monoflavonoid separated and purified from Scutellaria baicalensis Georgi, in human chronic myeloid leukemia (CML) and the underlying mechanisms. The results showed that CXCL12 could enhance the resistance of K562 cells to adriamycin (ADM) by increasing the expression of CXCR4, up-regulating the downstream PI3K/Akt pathway, and promoting translocation of NF-κB dimers into nucleus and subsequently decreasing the expression of apoptosis-related proteins in K562 cells. And we found that ADM resistance was partially reversed by CXCR4 siRNA transfection. Moreover, the sensitivity enhancement of oroxylin A was demonstrated by decreasing the expression of CXCR4 at both protein and mRNA levels, via PI3K/Akt/NF-κB pathway and triggering the apoptosis pathway in vitro. In addition, the in vivo study showed that oroxylin A increased apoptosis of leukemic cells with low systemic toxicity, and the mechanism was the same as in vitro study. In conclusion, all these results showed that oroxylin A improved the sensitivity of K562/ADM cells by increasing apoptosis in leukemic cells and decreasing the expression of CXCR4 and PI3K/Akt/NF-κB pathway, and probably served as a most promising agent for CML treatment.
authors.affiliation: State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Carcinogenesis and Intervention, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, People's Republic of China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Carcinogenesis and Intervention, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, People's Republic of China.
authors.forename: Hanchi
authors.initials: H
authors.lastname: Miao
authors.affiliation: State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Carcinogenesis and Intervention, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, People's Republic of China.
authors.forename: Wei
authors.initials: W
authors.lastname: Li
authors.affiliation: State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Carcinogenesis and Intervention, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, People's Republic of China.
authors.forename: Jing
authors.initials: J
authors.lastname: Yao
authors.affiliation: State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Carcinogenesis and Intervention, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, People's Republic of China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Sun
authors.affiliation: School of Pharmacy, China Pharmaceutical University, Nanjing 210009, People's Republic of China.
authors.forename: Zhiyu
authors.initials: Z
authors.lastname: Li
authors.affiliation: State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Carcinogenesis and Intervention, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, People's Republic of China. Electronic address: zhaolicpu@126.com.
authors.forename: Li
authors.initials: L
authors.lastname: Zhao
authors.affiliation: State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Carcinogenesis and Intervention, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, People's Republic of China. Electronic address: anticancer_drug@163.com.
authors.forename: Qinglong
authors.initials: Q
authors.lastname: Guo
mesh_terms: D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D054377:Chemokine CXCL12 / Q000378:metabolism*; D004317:Doxorubicin / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D005260:Female; D005419:Flavonoids / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D006801:Humans; D015466:Leukemia, Myeloid, Chronic-Phase / Q000188:drug therapy* / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D009363:Neoplasm Proteins / Q000819:agonists / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D058539:Phosphatidylinositol 3-Kinase / Q000737:chemistry / Q000378:metabolism; D034622:RNA Interference; D011897:Random Allocation; D019718:Receptors, CXCR4 / Q000819:agonists / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*; D023041:Xenograft Model Antitumor Assays
chemical_list: D000903:Antibiotics, Antineoplastic; D000972:Antineoplastic Agents, Phytogenic; C515255:CXCL12 protein, human; C527276:CXCR4 protein, human; D054377:Chemokine CXCL12; D005419:Flavonoids; D009363:Neoplasm Proteins; D019718:Receptors, CXCR4; C080669:5,7-dihydroxy-6-methoxy-2-phenylchromen-4-one; D004317:Doxorubicin; D058539:Phosphatidylinositol 3-Kinase
keywords: Adriamycin (PubChem CID: 31703); Agarose (PubChem CID: 11966311); CXCL12/CXCR4 axis; DAPI (PubChem CID: 2954); DMSO (PubChem CID: 679); K562/ADM; MTT formazan (PubChem CID: 16218671); Oroxylin A; Oroxylin A (PubChem CID: CID 5320315); PI3K/Akt/NF-κB pathway; Reversal effect