Purpose: Artemisinin is a prominent anti-malarial drug in the clinic with remarkable therapeutic effect and low toxicity. Artemisinin and its derivative dihydroartemisinin (DHA) also demonstrate interesting anticancer activity against a wide range of tumor cell lines. In the current project, a series of DHA dimers have been synthesized to explore their emerging biological properties. The goal of this study is to evaluate the anticancer activity of DHA dimers in comparison with artemisinin and DHA.
Methods: Tumor cells were seeded in 96-well plates and treated with DHA dimers (0.01–100 μM) in triplicates. DMSO was used to solubilize DHA dimers to prepare original stock solutions, which were subsequently diluted in DMEM media. The DMSO concentration in all treated cells was kept below 0.5% (v/v). Human and murine cancer cells of various tissue origins, including lung, breast, pancreas, ovary, and colon were used in this study. After incubation under 5% CO2 at 37 oC for 72–96 h, tumor cells were fixed with 1% glutaraldehyde, stained with 0.1% crystal violet, dissolved in 10% acetic acid, and then analyzed for absorbance at 595 nm using microplate reader. The relative cell viability was calculated as percentage of absorbance of the treated vs. the untreated wells.
Results: Several DHA dimers were identified to possess potent anticancer activity with IC50s ranging from 0.1–1 μM in human and murine cancer cell lines. In contrast, IC50 of DHA was 10–35 μM. These results clearly indicate the dimerization greatly enhances the anticancer activity of DHA. The anticancer activity of DHA dimers is highly dependent on the linker structures. Chemical structure of one such dimer is shown below as Fig. 1.
Conclusion: DHA dimers demonstrate great promises as novel anticancer agents. Further evaluation of DHA dimers in animal models is warranted.