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.
Highlights
Cancer is a complex disease; it affects various tissues in multiple ways and has many subtypes [1]
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
We found these combinations of the two compounds significantly decreased cell viability in different cancer cell lines compared with the single agents alone, and their combination index (CI) in different cancer cells were all < 1 (Figure 1B)
Summary
Cancer is a complex disease; it affects various tissues in multiple ways and has many subtypes [1]. Drug developers have observed that combinations of some anticancer drugs exhibit synergistic effects, presumably via simultaneously targeting multiple pathways This multi-pronged effect could lead to maximal therapeutic efficacy with minimal adverse effects [3, 4]. ATS and HF are two active compounds coming from Artemisia carvifolia (Qinghao in Chinese) and Dichroa febrifuga Lour (Changshan in Chinese), respectively, which are two herbs commonly used together as a formula to treat a variety of diseases in Chinese folk medicine, including cancer. In recent years, both ATS and HF have been intensively studied because of their potential www.impactjournals.com/oncotarget therapeutic effects in cancer treatment. To the best of our knowledge, there is no published research on the synergistic effect of HF and ATS on inhibiting cancer cells growth
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