title: The critical role of redox homeostasis in shikonin-induced HL-60 cell differentiation via unique modulation of the Nrf2/ARE pathway.
abstract: Among various cancer cell lines, the leukemia cell line HL-60 was most sensitive to Shikonin, with evidence showing both the prooxidative activities and proapoptotic effects of micromolar concentrations of Shikonin. However, the mechanism involved in the cytotoxicity of Shikonin in the submicromolar range has not been fully characterized. Using biochemical and free radical biological experiments in vitro, we identified the prodifferentiated profiles of Shikonin and evaluated the redox homeostasis during HL-60 differentiation. The data showed a strong dose-response relationship between Shikonin exposure and the characteristics of HL-60 differentiation in terms of morphology changes, nitroblue tetrazolium (NBT) reductive activity, and the expression level of surface antigens CD11b/CD14. During drug exposure, intercellular redox homeostasis changes towards oxidation are necessary to support Shikonin-induced differentiation, which was proven by additional enzymatic and non-enzymatic redox modulators. A statistically significant and dose-dependent increase (P < 0.05) was recorded with regard to the unique expression levels of the Nrf2/ARE downstream target genes in HL-60 cells undergoing late differentiation, which were restored with further antioxidants employed with the Shikonin treatment. Our research demonstrated that Shikonin is a differentiation-inducing agent, and its mechanisms involve the Nrf2/ARE pathway to modulate the intercellular redox homeostasis, thus facilitating differentiation.
authors.affiliation: Key Laboratory of Xinjiang Endemic Phytomedicine Resources of Ministry of Education, School of Pharmacy, Shihezi University, Shihezi 832002, China.
authors.forename: Bo
authors.initials: B
authors.lastname: Zhang
authors.forename: Na
authors.initials: N
authors.lastname: Chen
authors.forename: Hongmei
authors.initials: H
authors.lastname: Chen
authors.forename: Zhenhua
authors.initials: Z
authors.lastname: Wang
authors.forename: Qiusheng
authors.initials: Q
authors.lastname: Zheng
mesh_terms: D000975:Antioxidants / Q000378:metabolism*; D039481:CD11b Antigen / Q000235:genetics / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects; D048430:Cell Shape / Q000187:drug effects; D005110:Extracellular Space / Q000187:drug effects / Q000378:metabolism; D018922:HL-60 Cells; D006706:Homeostasis / Q000187:drug effects*; D006801:Humans; D018950:Lipopolysaccharide Receptors / Q000235:genetics / Q000378:metabolism; D008954:Models, Biological; D051267:NF-E2-Related Factor 2 / Q000378:metabolism*; D009285:Naphthoquinones / Q000494:pharmacology*; D009580:Nitroblue Tetrazolium / Q000378:metabolism; D010084:Oxidation-Reduction / Q000187:drug effects; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D020218:Response Elements / Q000235:genetics*; D015398:Signal Transduction / Q000187:drug effects*
chemical_list: D000975:Antioxidants; D039481:CD11b Antigen; D018950:Lipopolysaccharide Receptors; D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; D009285:Naphthoquinones; D012333:RNA, Messenger; D009580:Nitroblue Tetrazolium; C016101:shikonin