title: Targeting peroxiredoxin I potentiates 1,25-dihydroxyvitamin D3-induced cell differentiation in leukemia cells.
abstract: Although 1,25‑dihydroxyvitamin D3 (VD3) is regarded as a promising inducing agent for leukemia cell differentiation, it is not as effective an agent as all‑trans‑retinoic acid, and its usefulness is also limited by the adverse effects of hypercalcemia. The aim of the present study was to determine whether combining VD3 with adenanthin, a peroxiresoxin I (Prx I)‑targeting natural compound, improves the efficacy of VD3. Cell viability was assessed using a trypan blue exclusion assay and flow cytometry was used to evaluate the expression of cell surface markers, CD11b/CD14, and the level of reactive oxygen species (ROS). Wright's staining was used to examine morphological changes and RNA‑interference was used to knockdown Prx I and p65 gene expression. Protein expression was determined by western blot analysis. The results demonstrated that adenanthin markedly enhanced VD3‑induced cell differentiation of leukemia NB4 cells, as evidenced by the increased percentage of CD11b‑ and CD14‑positive cells, the mature morphology of the monocytes and the increased phagocytic ability. Consistent with these results, knockdown of Prx I, but not nuclear factor‑κB (p65), enhanced VD3‑induced cell differentiation. The combinatorial effects of adenanthin and VD3 were shown to be associated with the ROS‑CCAAT‑enhancer‑binding protein (C/EBP)β axis, since N‑acetylcysteine, a ROS scavenger, was able to abrogate the differentiation‑enhancing effects of adenanthin, and the knockdown of C/EBPβ also inhibited the combinatorial effects of adenanthin and VD3. In addition, co‑treatment with adenanthin and VD3 was able to induce differentiation in other non‑acute promyelocytic leukemia cells and primary leukemia cells. In conclusion, the results of the present study revealed a novel role for Prx I in VD3‑induced cell differentiation, and suggested that targeting Prx I may represent a novel strategy to enhance VD3‑induced leukemia cell differentiation.
authors.affiliation: Department of Hematology, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200092, P.R. China.
authors.forename: Wei
authors.initials: W
authors.lastname: Wei
authors.affiliation: Department of Hematology, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200092, P.R. China.
authors.forename: Chuanxu
authors.initials: C
authors.lastname: Liu
authors.affiliation: Department of Pathophysiology, Chemical Biology Division of Shanghai Universities E‑Institutes, Key Laboratory of Cell Differentiation and Apoptosis of the Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, P.R. China.
authors.forename: Dongjun
authors.initials: D
authors.lastname: Qin
authors.affiliation: Department of Pathophysiology, Chemical Biology Division of Shanghai Universities E‑Institutes, Key Laboratory of Cell Differentiation and Apoptosis of the Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, P.R. China.
authors.forename: Lili
authors.initials: L
authors.lastname: Song
authors.affiliation: Department of Pathophysiology, Chemical Biology Division of Shanghai Universities E‑Institutes, Key Laboratory of Cell Differentiation and Apoptosis of the Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, P.R. China.
authors.forename: Li
authors.initials: L
authors.lastname: Xia
authors.affiliation: Department of Pathophysiology, Chemical Biology Division of Shanghai Universities E‑Institutes, Key Laboratory of Cell Differentiation and Apoptosis of the Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, P.R. China.
authors.forename: Hu
authors.initials: H
authors.lastname: Lei
authors.affiliation: Department of Pathophysiology, Chemical Biology Division of Shanghai Universities E‑Institutes, Key Laboratory of Cell Differentiation and Apoptosis of the Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, P.R. China.
authors.forename: Yun
authors.initials: Y
authors.lastname: Yu
authors.affiliation: Department of Pathophysiology, Chemical Biology Division of Shanghai Universities E‑Institutes, Key Laboratory of Cell Differentiation and Apoptosis of the Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, P.R. China.
authors.forename: Weiwei
authors.initials: W
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming, Yunnan 650201, P.R. China.
authors.forename: Jianxin
authors.initials: J
authors.lastname: Pu
authors.affiliation: State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming, Yunnan 650201, P.R. China.
authors.forename: Handong
authors.initials: H
authors.lastname: Sun
authors.affiliation: Department of Pathophysiology, Chemical Biology Division of Shanghai Universities E‑Institutes, Key Laboratory of Cell Differentiation and Apoptosis of the Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, P.R. China.
authors.forename: Yingli
authors.initials: Y
authors.lastname: Wu
authors.affiliation: Department of Pathophysiology, Chemical Biology Division of Shanghai Universities E‑Institutes, Key Laboratory of Cell Differentiation and Apoptosis of the Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, P.R. China.
authors.forename: Hanzhang
authors.initials: H
authors.lastname: Xu
authors.affiliation: Department of Hematology, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200092, P.R. China.
authors.forename: Siguo
authors.initials: S
authors.lastname: Hao
mesh_terms: D000328:Adult; D022782:CCAAT-Enhancer-Binding Protein-beta / Q000378:metabolism; D002117:Calcitriol / Q000494:pharmacology*; D002454:Cell Differentiation / Q000187:drug effects*; D045744:Cell Line, Tumor; D045786:Diterpenes, Kaurane / Q000494:pharmacology; D005260:Female; D055785:Gene Knockdown Techniques; D006801:Humans; D015473:Leukemia, Promyelocytic, Acute / Q000378:metabolism / Q000473:pathology*; D009000:Monocytes / Q000187:drug effects / Q000473:pathology; D054464:Peroxiredoxins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D022782:CCAAT-Enhancer-Binding Protein-beta; D045786:Diterpenes, Kaurane; D017382:Reactive Oxygen Species; C000600164:adenanthin; D054464:Peroxiredoxins; D002117:Calcitriol