The artemisinin class of anticancer compounds is well known for oxidative 
DNA-damage-mediated growth arrest, followed by cell death. However, the nature 
of this genotoxic stress for cancer therapeutics remains elusive. Here we show 
that artesunate (Art), a water-soluble artemisinin analog, triggers inducible 
anticancer responses directly implicated in the DNA-damage-intended therapy. We 
observed that the level of the antiviral enzyme APOBEC3C (apolipoprotein-B 
mRNA-editing catalytic polypeptide-like 3C (A3C)) preferentially increased upon 
the treatment with Art against tumor xenografts of p53-deficient H1299 cells. 
Using gain-of-function experiments, A3C could improve the therapeutic efficacy 
of Art, as determined by cell proliferation and colony formation assays. 
Furthermore, elevated A3C provoked a minor accumulation of γH2AX foci and the 
phosphorylation of RPA32 and Chk1, which strongly sensitized H1299 cells to Art. 
The employment of A3C also caused an increase in the synergistic interaction 
between Art and Chk1 inhibition. Besides, A3C overexpression delayed the cell 
cycle at the S phase, accompanied by attenuated G2/M arrest in the presence of 
Art. The enzymatic inactivation of A3C by the mutation of zinc-coordinating 
residues (C97S and C100S) indicated that A3C sensitized Art in a 
deaminase-dependent manner. Furthermore, we showed that using small interfering 
RNA against A3C can induce the chemoresistance of Art. These studies combine to 
suggest that upregulated A3C is involved in the Art-induced DNA damage response 
as a consequent event to improve the overall cytotoxic responses of Art.