In vitro study of the anti-cancer effects of artemisone alone or in combination with other chemotherapeutic agents.
OBJECTIVE
Artemisinins are now established drugs for treatment of malaria. These agents have been shown to possess impressive anti-cancer properties. We have investigated the role of artemisone (ATM), a novel derivative of artemisinin (ART) in a cancer setting both alone and in combination with established chemotherapeutic agents.


METHODS
The anti-proliferative effects of ART and ATM were tested on a panel of human cancer cells in vitro using the methylthiazoletetrazolium assay, and the effect on cell cycling established by flow cytometry. Immunoblot analyses were performed to determine effects at the molecular level. Finally, ART and ATM were combined with the common anti-cancer agents oxaliplatin, gemcitabine and thalidomide.


RESULTS
ART and ATM caused dose dependent decreases in cell number. ATM was consistently superior to ART, with IC50 s significantly lower in the former. Neither drug caused significant changes to the cell viability (%viable cells >95%), but arrested cell cycling. Blockade was either exclusively at the level of G1, or at all phases of the cell cycle, and associated with reductions in cyclin D1, CDK4 and pRb. Combination studies showed the anti-proliferative effect of ATM was often enhanced by addition of the other drugs, whilst ART exhibited antagonistic properties.


CONCLUSIONS
ART and ATM are active in cancer cell lines, with ATM displaying the greater anti-proliferative effect when used alone. ATM also enhances the effects of the above drugs, with ART being less likely to improve activities. Taken together, ATM should be thought of as the ART-derived compound next in line for further study.
Gravett
Andrew M
AM
Department of Oncology, Division of Cellular and Molecular Medicine, St George's, University of London, London, UK. agravett@sgul.ac.uk
Liu
Wai M
WM
Krishna
Sanjeev
S
Chan
Wing-Chi
WC
Haynes
Richard K
RK
Wilson
Natalie L
NL
Dalgleish
Angus G
AG
D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D037621:Artemisinins / Q000008:administration & dosage / Q000494:pharmacology*; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005434:Flow Cytometry; D006801:Humans; D015151:Immunoblotting; D020128:Inhibitory Concentration 50; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology; D009944:Organoplatinum Compounds / Q000008:administration & dosage / Q000494:pharmacology; D000077150:Oxaliplatin; D013792:Thalidomide / Q000008:administration & dosage / Q000494:pharmacology; D000093542:Gemcitabine
D000970:Antineoplastic Agents; D037621:Artemisinins; D009944:Organoplatinum Compounds; D000077150:Oxaliplatin; D003841:Deoxycytidine; D013792:Thalidomide; C514498:artemisone; C031327:artemisinin; D000093542:Gemcitabine