Advertisement

Investigational New Drugs

, Volume 32, Issue 1, pp 60–67 | Cite as

Antitumor activity of semisynthetic derivatives of Aconitum alkaloids

  • Ainura Chodoeva
  • Jean-Jacques Bosc
  • Lydia Lartigue
  • Jean Guillon
  • Céline Auzanneau
  • Pierre Costet
  • Ashiraly Zurdinov
  • Christian Jarry
  • Jacques RobertEmail author
PRECLINICAL STUDIES

Summary

We recently synthesized from aconitine a series of drugs with in vitro and in vivo antitumor properties, among which bis[O-(14-benzoylaconine-8-yl)]suberate (BBAS) was the most active (Eur J Med Chem 2012; 54: 343). In the present work, we used the NCI panel of 60 human tumor cell lines to identify the most sensitive cell lines and drugs with comparable cytotoxicity profiles. GI50 values of BBAS ranged between 0.12 and 6.5 μM. Activity was higher than average for leukemia and melanoma cell lines, especially SK-MEL-5 and SK-MEL-28, for the COLO-205 and HT-29 (colorectal) and MDA-MB-468 (breast) cancer cell lines. We evaluated the correlation between the GI50 of BBAS and those of 125 antiproliferative compounds with various mechanisms of action, using Bonferroni correction for multiple testing, and we observed a highly significant correlation with the GI50s of nitrosoureas. Interestingly, BBAS cytotoxicity was inversely correlated with the expression levels of MGMT (p = 0.009), an enzyme involved in the repair of nitrosourea-induced DNA damage. However, no correlation was found with the expression of 102 other genes involved in DNA repair. Antitumor activity was tested on immunodeficient mice with subcutaneously xenografted COLO-205, HT-29, MDA-MB-468, SK-MEL-5 and SK-MEL-28 cell lines. At 10 mg/kg, there was a significant reduction in tumor size with T/C values of 41 % and 43 % for COLO-205 and SK-MEL-28 cell lines, respectively. The drug was less active on HT-29 and SK-MEL-5 and inactive on MDA-MB-468 xenografts. Cell cycle studies showed an accumulation of BBAS-treated cells in G2/M phase after treatment at 20 μM. Together, our results allowed the identification of a potentially new class of anticancer agent displaying a mechanism of action related to that of nitrosoureas.

Keywords

Aconitum alkaloids Antiproliferative activity Tumor models NCI-60 panel Nitrosoureas 

Notes

Acknowledgments

This work was supported by funds from Conseil Régional d’Aquitaine and from the Ligue Nationale contre le Cancer (Comité des Landes). We thank Dr Jean-Luc Chagnaud, Dr Carlos Larraya and Dr Jacques Susperregui, from Aquitaine Science Transfert, for their support and Dr Philippe Pourquier for brushing up the manuscript.

Ethical standards

Experiments were performed in accordance with the European Community Standards on the Care and Use of Laboratory Animals and were approved by the Animal Care and Use Committee of University Bordeaux Segalen.

Conflicts of interest

None of the authors has a financial relationship with the organization that sponsored the research.

References

  1. 1.
    Chodoeva A, Bosc JJ, Guillon J, Decendit A, Petraud M, Absalon C, Vitry IC, Jarry C, Robert J (2005) 8-O-azeloyl-14-benzoylaconine: a new alkaloid from the roots of Aconitum karacolicum Rapcs, and its antiproliferative activities. Bioorg Med Chem 13:6493–6501CrossRefPubMedGoogle Scholar
  2. 2.
    Chodoeva A, Bosc JJ, Guillon J, Costet P, Decendit A, Mérillon JM, Léger JM, Jarry C, Robert J (2012) Hemisynthesis and antiproliferative properties of mono-[O-(14-benzoylaconine-8-yl)]esters and bis-[O-(14-benzoylaconine-8-yl)]esters. Eur J Med Chem 54:343–351CrossRefPubMedGoogle Scholar
  3. 3.
    Shoemaker RH (2006) The NCI60 human tumour cell line anticancer drug screen. Nat Rev Cancer 6:813–823CrossRefPubMedGoogle Scholar
  4. 4.
    Paull KD, Shoemaker RH, Hodes L, Monks A, Scudiero DA, Rubinstein L, Plowman J, Boyd MR (1989) Display and analysis of patterns of differential activity of drugs against human tumor cell lines: development of mean graph and COMPARE algorithm. J Natl Cancer Inst 81:1088–1092CrossRefPubMedGoogle Scholar
  5. 5.
    Fojo T, Farrell N, Ortuzar W, Tanimura H, Weinstein J, Myers TG (2005) Identification of non-cross-resistant platinum compounds with novel cytotoxicity profiles using the NCI anticancer drug screen and clustered image map visualizations. Crit Rev Oncol Hematol 53:25–34CrossRefPubMedGoogle Scholar
  6. 6.
    Huang R, Wallqvist A, Covell DG (2006) Assessment of in vitro and in vivo activities in the National Cancer Institute’s anticancer screen with respect to chemical structure, target specificity, and mechanism of action. J Med Chem 49:1964–1979CrossRefPubMedGoogle Scholar
  7. 7.
    Türk D, Hall MD, Chu BF, Ludwig JA, Fales HM, Gottesman MM, Szakács G (2009) Identification of compounds selectively killing multidrug-resistant cancer cells. Cancer Res 69:8293–8301PubMedCentralCrossRefPubMedGoogle Scholar
  8. 8.
    Carmichael J, DeGraff WG, Gazdar AF, Minna JD, Mitchell JB (1987) Evaluation of a tetrazolium-based semi-automated colorimetric assay: assessment of chemosensitivity testing. Cancer Res 47:936–942PubMedGoogle Scholar
  9. 9.
    Teicher BA, Andrews PA (2004) Anticancer drug development guide: preclinical screening, clinical trials and approval. Humana Press, TotowaCrossRefGoogle Scholar
  10. 10.
    Johnston TP, Montgomery JA (1986) Relationship of structure to anticancer activity and toxicity of the nitrosoureas in animal systems. Cancer Treat Rep 70:13–30PubMedGoogle Scholar
  11. 11.
    Pieper RO (1997) Understanding and manipulating O6-methylguanine-DNA methyltransferase expression. Pharmacol Ther 74:285–297CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  • Ainura Chodoeva
    • 1
    • 2
  • Jean-Jacques Bosc
    • 3
  • Lydia Lartigue
    • 1
  • Jean Guillon
    • 3
  • Céline Auzanneau
    • 1
  • Pierre Costet
    • 4
  • Ashiraly Zurdinov
    • 2
  • Christian Jarry
    • 3
  • Jacques Robert
    • 1
    Email author
  1. 1.Institut Bergonié, INSERM U916Université Bordeaux SegalenBordeauxFrance
  2. 2.Department of Basic and Clinical PharmacologyKyrgyz State Medical AcademyBishkekKyrgyzstan
  3. 3.FRE CNRS 3396 - PharmacochimieUniversité Bordeaux SegalenBordeauxFrance
  4. 4.Animalerie spécialiséeUniversité Bordeaux SegalenBordeauxFrance

Personalised recommendations