title: PHII-7 inhibits cell growth and induces apoptosis in leukemia cell line K562 as well as its MDR- counterpart K562/A02 through producing reactive oxygen species.
abstract: Multidrug resistance (MDR) is a major obstacle that hinders the efficacy of chemotherapy in many human malignancies. PHII-7 is a derivative of indirubin, which was designed and synthesized by our laboratory. Our preliminary work indicated its potent antitumor activities in vitro and in vivo. Furthermore, based on the model of MDR cell line, we found its powerful effects in inhibiting the expression of P-glycoprotein (P-gp) and killing multidrug-resistant (MDR) cells with the detailed mechanism remained to be explored. Reactive oxygen species are known for high reactive activity as they possess unmatched electrons. In this study, we showed that PHII-7 generated equal reactive oxygen species in parental K562 and its counterpart MDR K562/A02 cells. Pre-incubation with thiol antioxidants glutathione or N-acetyl-cysteine(NAC) almost abolished the cytotoxicity of PHII-7. Moreover, NAC abrogated DNA damage, cell cycle arrests and apoptosis induced by PHII-7. Our results collectively indicated that reactive oxygen species production induced by PHII-7 contributed to both apoptosis and cell cycle arrets in MDR K562/A02 cells, thus extending our prior related findings. Notably, JNK phosphorylation was also induced by PHII-7 and pre-incubated of K562/A02 cells with NAC or inhibitor of JNK(SP006125) eliminated P-gp downregulation. Taken together, our results may provide a detailed biochemical basis for further clinical application of PHII-7.
authors.affiliation: State Key Laboratory of Experimental Hematology, Institute of Hematology & Hospital of Blood Diseases, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, PR China; Department of Pharmacy, First affiliated Hospital of Nanchang University, Nanchang, Jiangxi, PR China.
authors.forename: Hongwei
authors.initials: H
authors.lastname: Peng
authors.forename: Xiangfei
authors.initials: X
authors.lastname: Yuan
authors.forename: Ruizan
authors.initials: R
authors.lastname: Shi
authors.forename: Xiaohua
authors.initials: X
authors.lastname: Wei
authors.forename: Simei
authors.initials: S
authors.lastname: Ren
authors.forename: Cihui
authors.initials: C
authors.lastname: Yan
authors.forename: Yahui
authors.initials: Y
authors.lastname: Ding
authors.forename: Yang
authors.initials: Y
authors.lastname: Lin
authors.forename: Dongmei
authors.initials: D
authors.lastname: Fan
authors.forename: Ming
authors.initials: M
authors.lastname: Yang
authors.forename: Yanjun
authors.initials: Y
authors.lastname: Zhang
authors.forename: Dongsheng
authors.initials: D
authors.lastname: Xiong
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004249:DNA Damage; D015536:Down-Regulation / Q000187:drug effects; D018432:Drug Resistance, Multiple / Q000187:drug effects*; D006801:Humans; D007211:Indoles / Q000494:pharmacology*; D020014:K562 Cells; D007938:Leukemia / Q000473:pathology*; D017382:Reactive Oxygen Species / Q000378:metabolism*
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000970:Antineoplastic Agents; D007211:Indoles; C569642:PHII-7 compound; D017382:Reactive Oxygen Species
keywords: Apoptosis; Cell cycle arrest; DNA damage; P-glycoprotein (P-gp); PHII-7; Reactive oxygen species