The antimalarial agent artesunate possesses anticancer properties that can be enhanced by combination strategies.
Artemisinins are a class of compounds that are first-line treatment options for malaria. They also have potent antiproliferative activity, which makes them potential anticancer drugs. We have previously demonstrated anticancer activity of a number of these compounds in vitro; however, cytotoxic activities were compromised by drug-induced cell cycle arrests. In this study, we have explored further the activity of the clinical lead artemisinin-drug artesunate (ART), used either alone or in combination with established chemotherapy. Also, by using a cell line expressing polyploidy character, have also explored the impact of cell cycle arrest in determining overall drug activity. Results showed that ART caused dose-dependent decreases in cell number, which were associated with either increased cytotoxicity or cytostasis. Cytostasis appeared to be a consequence of a simultaneous arrest at all phases of the cell cycle, a deduction that was supported by molecular profiling, which showed reductions in cell cycle transit proteins. ART appeared to maintain cells in this arrested state; however, reculturing these treated cells in drug-free medium resulted in significant reductions in viabilities. We also showed that ART maintained activity in polyploidy cells, and that an impressive enhancement to its activity was achievable through a combination with the immunomodulatory drug lenalidomide. Taken together, these observations indicate ART and its related compounds may be effective for the treatment of tumours, and that activity is related to schedule. Therefore, it is important to carefully select the most appropriate schedule to maximise ART efficacy.
Liu
Wai M
WM
Department of Oncology, Division of Clinical Sciences, St George's, University of London, Jenner Wing, London SW17, United Kingdom. w.liu@sgul.ac.uk
Gravett
Andrew M
AM
Dalgleish
Angus G
AG
D000962:Antimalarials / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D037621:Artemisinins / Q000627:therapeutic use*; D000077332:Artesunate; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000473:pathology; D049109:Cell Proliferation / Q000187:drug effects*; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000473:pathology; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D000077269:Lenalidomide; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000473:pathology; D009944:Organoplatinum Compounds / Q000008:administration & dosage; D000077150:Oxaliplatin; D013792:Thalidomide / Q000008:administration & dosage / Q000031:analogs & derivatives; D014407:Tumor Cells, Cultured; D000093542:Gemcitabine
D000962:Antimalarials; D037621:Artemisinins; D009944:Organoplatinum Compounds; D000077150:Oxaliplatin; D003841:Deoxycytidine; D013792:Thalidomide; D000077332:Artesunate; D000077269:Lenalidomide; D000093542:Gemcitabine