Halofuginone and artemisinin synergistically arrest cancer cells at the G1/G0 phase by upregulating p21Cip1 and p27Kip1
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Guoqing Chen1,2,*, Ruihong Gong1,*, Xianli Shi3, Dajian Yang2, Ge Zhang1, Aiping Lu1, Jianbo Yue3, Zhaoxiang Bian1
1School of Chinese Medicine, Hong Kong Baptist University, Hong Kong, China
2Chongqing Academy of Chinese Materia Medica, Chongqing, China
3Department of Biomedical Sciences, City University of Hong Kong, Hong Kong, China
*These authors have contributed equally to this work
Jianbo Yue, email: firstname.lastname@example.org
Zhaoxiang Bian, email: email@example.com
Keywords: halofuginone, artemisinin, synergy, cell proliferation, cell cycle
Received: February 24, 2016 Accepted: June 9, 2016 Published: July 1, 2016
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.
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