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Investigational New Drugs

, Volume 30, Issue 4, pp 1331–1342 | Cite as

Screening of well-established drugs targeting cancer metabolism: reproducibility of the efficacy of a highly effective drug combination in mice.

  • Mohammad Abolhassani
  • Adeline Guais
  • Edward Sanders
  • Frédéric Campion
  • Iduna Fichtner
  • Jacques Bonte
  • Gianfranco Baronzio
  • Giammaria Fiorentini
  • Maurice Israël
  • Laurent Schwartz
PRECLINICAL STUDIES

Summary

Alterations in metabolic pathways are known to characterize cancer. In order to suppress cancer growth, however, multiple proteins involved in these pathways have to be targeted simultaneously. We have developed a screening method to assess the best drug combination for cancer treatment based on targeting several factors implicated in tumor specific metabolism. Following a review of the literature, we identified those enzymes known to be deregulated in cancer and established a list of sixty-two drugs targeting them. These molecules are used routinely in clinical settings for diseases other than cancer. We screened a first library in vitro against four cell lines and then evaluated the most promising binary combinations in vivo against three murine syngeneic cancer models, (LL/2, Lewis lung carcinoma; B16-F10, melanoma; and MBT-2, bladder cancer). The optimum result was obtained using a combination of α-lipoic acid and hydroxycitrate (METABLOCTM). In this study, a third agent was added by in vivo evaluation of a large number of combinations. The addition of octreotide strongly reduced tumor development (T/C% value of 30.2 to 34.5%; P < 0.001) in the same models and prolonged animal survival (P < 0.001) as compared to cisplatin. These results were confirmed in a different laboratory setting using a human xenograft model (NCI-H69, small cell lung cancer). None of these three molecules are known to target DNA. The effectiveness of this combination in several animal models, as well as the low toxicity of these inexpensive drugs, emphasizes the necessity of rapidly setting up a clinical trial.

Keywords

Lipoic acid Hydroxycitrate Octreotide Metabolic enzymes Screening 

Notes

Acknowledgments

We acknowledge the help of Jean-Marc Steyaert. The mice studies were performed by Nosco Pharmaceuticals (France) and EPO GmbH (Germany). This work was funded by Biorébus. METABLOC is a trade mark of Biorébus. AG is an employee of Biorébus. The other authors declare that they have no competing interests.

Supplementary material

10637_2011_9692_MOESM1_ESM.doc (62 kb)
Esm 1 Describing detailed statistical results for each experiment. (DOC 61 kb)

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Copyright information

© Springer Science+Business Media, LLC 2011

Authors and Affiliations

  • Mohammad Abolhassani
    • 1
  • Adeline Guais
    • 1
  • Edward Sanders
    • 1
  • Frédéric Campion
    • 1
  • Iduna Fichtner
    • 2
  • Jacques Bonte
    • 1
  • Gianfranco Baronzio
    • 3
  • Giammaria Fiorentini
    • 4
  • Maurice Israël
    • 1
    • 5
  • Laurent Schwartz
    • 6
    • 7
  1. 1.BiorébusParisFrance
  2. 2.Experimental Pharmacology & Oncology (EPO) GmbHBerlin BuchGermany
  3. 3.METABLOC Cancer Center, Centro Medico KinesCastano PrimoItaly
  4. 4.Oncology unitS. Giuseppe hospitalEmpoliItaly
  5. 5.Bures sur YvetteFrance
  6. 6.Laboratoire d’InformatiqueEcole PolytechniquePalaiseauFrance
  7. 7.Service d’Oncologie PédiatriqueAP-HP, Hôpital Raymond PoincaréGarchesFrance

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