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In vitro study of the anti-cancer effects of artemisone alone or in combination with other chemotherapeutic agents

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Abstract

Purpose

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.

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Acknowledgments

The authors would like to thank Dr. John Copier for helpful discussions and critical reading of the manuscript. The authors would also like to thank Celgene Corps. for supplying thalidomide. Work at the Hong Kong University of Science and Technology was carried out in the Open Laboratory of Chemical Biology of the Institute of Molecular Technology for Drug Discovery and Synthesis with financial support from the Government of the HKSAR University Grants Committee Areas of Excellence Fund, Projects No. AoE P/10-01/01-02-I, AOE/P-10/01-2-II and the University Grants Council Grants No. HKUST 6493/06 M and 600507. Professor Krishna is funded by the European Commission projects ANTIMAL (Grant No. 018834) and MALSIG (Grant No. 223044). This work was funded by the cancer vaccine institute (http://www.cancervaccine.org.uk).

Conflict of interest statement

The authors have no conflicts of interest to declare.

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Authors and Affiliations

  1. Department of Oncology, Division of Cellular and Molecular Medicine, St George’s, University of London, 2nd Floor, Jenner Wing, London, SW17 0RE, UK

    Andrew M. Gravett, Wai M. Liu, Natalie L. Wilson & Angus G. Dalgleish

  2. Centre for Infection, Division of Cellular and Molecular Medicine, St George’s, University of London, London, UK

    Sanjeev Krishna

  3. Department of Chemistry, Open Laboratory of Chemical Biology, Institute of Molecular Technology for Drug Discovery and Synthesis, The Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong, People’s Republic of China

    Wing-Chi Chan & Richard K. Haynes

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  1. Andrew M. Gravett
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  2. Wai M. Liu
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  3. Sanjeev Krishna
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  4. Wing-Chi Chan
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  5. Richard K. Haynes
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  7. Angus G. Dalgleish
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Correspondence to Andrew M. Gravett or Wai M. Liu.

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Gravett, A.M., Liu, W.M., Krishna, S. et al. In vitro study of the anti-cancer effects of artemisone alone or in combination with other chemotherapeutic agents. Cancer Chemother Pharmacol 67, 569–577 (2011). https://doi.org/10.1007/s00280-010-1355-4

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  • DOI: https://doi.org/10.1007/s00280-010-1355-4

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