title: Halofuginone and artemisinin synergistically arrest cancer cells at the G1/G0 phase by upregulating p21Cip1 and p27Kip1.
abstract: Combinational drug therapy is one of the most promising strategies in modern anticancer research. Traditional Chinese medicine (TCM) formulas represent a wealth of complex combinations proven successful over centuries of clinical application. One such formula used to treat a variety of diseases, including cancer, contains two herbs, whose main active components are Halofuginone (HF) and Artemisinin (ATS). Here we studied the anticancer synergism of HF and ATS in various cancer cell lines and in a xenograft nude mice model. We found that the HF-ATS combination arrested more cells at the G1/G0 phase than either one alone, with the concomitant increased levels of CDK2 inhibitors, p21Cip1 and p27Kip1. By knocking down p21Cip1 and p27Kip1 separately or simultaneously in HCT116 cells and MCF-7 cells, we found that p21Cip1 was required for HF induced G1/G0 arrest, whereas p21Cip1 and p27Kip1 were both required for ATS or HF-ATS combination-mediated cell cycle arrest. Moreover, HF-ATS combination synergistically inhibited tumor growth in xenograft nude mice, and this was associated with the increased levels of p21Cip1 and p27Kip1. Collectively, these data indicate that the upregulation of p21Cip1 and p27Kip1 contributes to the synergistic anticancer effect of the HF-ATS combination.
authors.affiliation: School of Chinese Medicine, Hong Kong Baptist University, Hong Kong, China.|Chongqing Academy of Chinese Materia Medica, Chongqing, China.
authors.forename: Guoqing
authors.initials: G
authors.lastname: Chen
authors.affiliation: School of Chinese Medicine, Hong Kong Baptist University, Hong Kong, China.
authors.forename: Ruihong
authors.initials: R
authors.lastname: Gong
authors.affiliation: Department of Biomedical Sciences, City University of Hong Kong, Hong Kong, China.
authors.forename: Xianli
authors.initials: X
authors.lastname: Shi
authors.affiliation: Chongqing Academy of Chinese Materia Medica, Chongqing, China.
authors.forename: Dajian
authors.initials: D
authors.lastname: Yang
authors.affiliation: School of Chinese Medicine, Hong Kong Baptist University, Hong Kong, China.
authors.forename: Ge
authors.initials: G
authors.lastname: Zhang
authors.affiliation: School of Chinese Medicine, Hong Kong Baptist University, Hong Kong, China.
authors.forename: Aiping
authors.initials: A
authors.lastname: Lu
authors.affiliation: Department of Biomedical Sciences, City University of Hong Kong, Hong Kong, China.
authors.forename: Jianbo
authors.initials: J
authors.lastname: Yue
authors.affiliation: School of Chinese Medicine, Hong Kong Baptist University, Hong Kong, China.
authors.forename: Zhaoxiang
authors.initials: Z
authors.lastname: Bian
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage*; D037621:Artemisinins / Q000008:administration & dosage*; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism*; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000378:metabolism*; D004357:Drug Synergism; D005260:Female; D016193:G1 Phase; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D045325:HCT116 Cells; D006801:Humans; D061986:MCF-7 Cells; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D010880:Piperidines / Q000008:administration & dosage*; D052999:Quinazolinones / Q000008:administration & dosage*; D016192:Resting Phase, Cell Cycle; D015854:Up-Regulation
chemical_list: D037621:Artemisinins; C493956:CDKN1A protein, human; C436291:CDKN1B protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D010880:Piperidines; D052999:Quinazolinones; D050760:Cyclin-Dependent Kinase Inhibitor p27; C031327:artemisinin; C010176:halofuginone
keywords: artemisinin; cell cycle; cell proliferation; halofuginone; synergy