Two major obstacles for successful
cancer treatment are the toxicity of
cytostatics and the development of drug resistance in
cancer cells during
chemotherapy. Acquired or intrinsic drug resistance is responsible for almost 90% of treatment failure. For this reason, there is an urgent need for new anticancer drugs with improved efficacy against
cancer cells, and with less toxicity on normal cells. There are impressive examples demonstrating the success of natural plant compounds to fight
cancer, such as
Vinca alkaloids,
taxanes, and
anthracyclines.
Artesunic acid (ARTA), a drug for
malaria treatment, also exerts cytotoxic activity towards
cancer cells. Multidrug resistance often results from drug efflux pumps (
ABC-transporters) that reduce intracellular drug levels. Hence, it would be interesting to know, whether ARTA could overcome drug resistance of
tumor cells, and in what way
ABC-transporters are involved. Different derivatives showing improved features concerning cytotoxicity and pharmacokinetic behavior have been developed. Considering both drug sensitivity and resistance, we chose a sensitive and a
doxorubicin-resistant
leukemia cell line and determined the killing effect of ARTA on these cells. Molecular docking and
doxorubicin efflux assays were performed to investigate the interaction of the derivatives with
P-glycoprotein. Using single-cell gel electrophoresis (alkaline comet assay), we showed that the derivatives of ARTA induce
DNA breakage and accordingly programmed cell death, which represents a promising strategy in
cancer treatment. ARTA activated apoptosis in
cancer cells by the
iron-mediated generation of
reactive oxygen species (ROS). In conclusion, ARTA derivatives may bear the potential to be further developed as anticancer drugs.