Table 8.

The cell process and signal pathway regulated by artemisinins

Signal pathway	Related protein (expression or activity)
Proliferation pathway	Suppressed the transcription and protein expressions of the CDK2 and CDK4 cyclin-dependent kinases, cyclin E, cyclin D1, and the E2F1 transcription factor, up-regulated miR-34a expression correlating with down-regulation of the miR-34a target gene (CDK4), decreased Wnt5-α/β expression, increased the expressions of NKD2 and Axin2, down-regulated β-catenin, suppressed the phosphorylation of ERK1/2, inhibited the mRNA and protein expression of ERK1/2, suppressed the transcription and expression of ERK1/2 downstream effectors c-Fos and c-Myc, up-regulated expression of p53, inhibited calmodulin (CaM) and phosphodiesterase (PDE1), accumulated Camp, activated cAMP-dependent protein kinase A (PKA)
Apoptotic pathway	Decreased p53 expression [50]; up-regulated Bax expression, down-regulated Bcl-2, Bcl-xL and Procaspase-3, increased caspase-9 activation [55]; induced the translocation of apoptotic inducing factor (AIF) and the release of cytochrome c from the mitochondria, decreased the mitochondrial membrane potential, activated the caspase-3, caspase-8, and caspase-9 [106]; and increased the ratio of Bax/Bcl-2; increased ROS level, triggered the intrinsic pathway of apoptosis [114], activated p38 MAPK [115]; increased miR-16 expression and decreased COX-2 expression [38] and PGE2 production [19]; decreased Mcl-1 expression, increased Bak and Noxa expression [62]; inhibited ERK phosphorylation [95]; induced necroptosis [57]; decreased HSP70 expression [116]
Cell cycle	Reduced the transcription activity of CDK2, CDK4, cyclin E [55]; increased the expression of CD71 [117]; up-regulated the expression of p21Cip1 and p27Kip1 [118]; decreased G2/M-associated proteins cyclin B1, CDC2 and MDM2 expressions, suppressed the expression of Forkhead box protein M1 (FOXM1) [51]; increased miR-34a expression, down-regulated miR-34a target gene [83]
Invasion and metastasis	Down-regulated MMP-9 and MMP-2 [110]; suppressed Rac1 siRNA deactivates NF-κB activity [107]; down-regulated the expression of ADAM17, p-EGFR and p-AKT [103]; inhibited the transcription of u-PA, MMP-2 and MMP-7, suppressed AP-1 and NF-κB-transactivation [87]; activated Wnt/β-catenin signaling pathway [91]; reduced vWF expression and macrophage infiltration, decreased expression of pFAK [21]
Angiogenesis	Reduced expression of the vascularization-related proteins HIF-1α and VEGF [119]; reduced the level of KDR, decline the transcriptional activity of ανβ3, reduced the levels of MMP2, MMP9 and BMP1
Oxidative damage reaction	Reduced the level of CD71 [120]; increased intracellular levels of reactive oxygen species (ROS) [64, 115]
Chemosensitivity and radiosensitivity	Down-regulated RAD51 and impair DNA DSBs repair, induced DSBs and inhibited the clongenic formation of tumor cells [121]; activated the MAPK pathway by TGF β often in a DPC-4independent manner, down-regulated P15/CDKN1B, up-regulated CDCA4 and CDC2L6 with DPC4 activation [122]; increased Cyclin B1 expression, affected multiple pathways including RNA transport, the spliceosome, RNA degradation, p53 signaling and MAPK [123]; elevated amount of cH2AX foci/nucleus, attenuation of survivin expression [23]; increased the NO level [42]
Microenviroment	Reduced the number of Treg [124], increased the proportion of IFN-γ/I-4, reduced PGE2, inhibited the produce of NO and cytokines (IL-1-b, IL-6, TNF-α, VEGF) [125]