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Br J Cancer. 2010 Jun 29;103(1):43-51. doi: 10.1038/sj.bjc.6605715. Epub 2010 Jun 1.

Betulinic acid induces apoptosis and inhibits hedgehog signalling in rhabdomyosarcoma.

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  • 1Department of Paediatric Surgery, Dr. von Hauner Children's Hospital, Ludwig-Maximilians-University Munich, Lindwurmstrasse 4, Munich 80337, Federal Republic of Germany.

Abstract

BACKGROUND:

Rhabdomyosarcoma (RMS) is the most common soft-tissue sarcoma in childhood with the ability to resist apoptosis by the activation of survival promoting and anti-apoptotic proteins.

METHODS:

Efficacy of the apoptosis-inducing agent betulinic acid (BA) was determined in RMS cell cultures and in vivo by measuring cell viability, survival, apoptosis, hedgehog signalling activity, and neovascularisation.

RESULTS:

Betulinic acid had a strong cytotoxic effect on RMS cells in a dose-dependent manner. The BA treatment caused a massive induction of apoptosis mediated by the intrinsic mitochondrial pathway, which could be inhibited by the broad-range caspase inhibitor zVAD.fmk. Exposure of hedgehog-activated RMS-13 cells to BA resulted in a strong decrease in GLI1, GLI2, PTCH1, and IGF2 expression as well as hedgehog-responsive luciferase activity. Intraperitoneal injection of 20 mg BA per kg per day significantly retarded growth of RMS-13 xenografts in association with markedly higher counts of apoptotic cells and down-regulation of GLI1 expression compared with control tumours, while leaving microvascular density, cell proliferation, and myogenic differentiation unaffected.

CONCLUSION:

Our data show that induction of apoptosis and inhibition of hedgehog signalling are important features of the anti-tumourigenic effect of BA in RMS and advices this compound for the use in a multimodal therapy of this highly aggressive paediatric tumour.

PMID:
20517313
[PubMed - indexed for MEDLINE]
PMCID:
PMC2905279
Free PMC Article
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