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Br J Cancer. 2016 May 24;114(11):1219-26. doi: 10.1038/bjc.2016.117. Epub 2016 May 3.

Inhibition of Bcl-2 family members sensitises soft tissue leiomyosarcomas to chemotherapy.

Author information

1
Department of Pathology, Leiden University Medical Center, Albinusdreef 2, Leiden 2333 ZA, The Netherlands.
2
Department of Medical Oncology, Leiden University Medical Center, Albinusdreef 2, Leiden 2333 ZA, The Netherlands.
3
Department of Molecular Pathology, Institut Bergonie, 229 cours de l'Argonne, 33076, Bordeaux Cedex, France.
4
Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, 75 Francis Street, Boston, MA, 02115, USA.

Abstract

BACKGROUND:

Leiomyosarcoma is an aggressive soft tissue sarcoma with a 5-year survival rate of 15 to 60%. Treatment options for inoperable or metastatic patients are limited owing to frequent resistance of tumours to chemotherapy and radiation. In this study, we hypothesised that antiapoptotic Bcl-2 family proteins might contribute to leiomyosarcoma chemoresistance and therefore inhibition of Bcl-2 family proteins might sensitise leiomyosarcomas to conventional chemotherapy.

METHODS:

Expression of the Bcl-2 family proteins Bcl-xL, Bcl-w and Bcl-2 was investigated using immunohistochemistry on a tissue microarray containing 43 leiomyosarcomas. Furthermore, we investigated whether ABT-737, a potent BH3 mimetic, sensitises leiomyosarcoma cells to doxorubicin treatment in vitro.

RESULTS:

Seventy-seven per cent, 84% and 42% of leiomyosarcomas demonstrated high expression of Bcl-2, Bcl-xL and Bcl-w, respectively. Single-agent treatment with ABT-737 resulted in a minor reduction of cell viability. However, combination treatment of ABT-737 and doxorubicin revealed synergism in all four cell lines, by inducing apoptosis.

CONCLUSIONS:

In conclusion, Bcl-2 family proteins contribute to soft tissue leiomyosarcoma chemoresistance. Antiapoptotic proteins are highly expressed in leiomyosarcoma of soft tissue, and inhibition of these proteins using a BH3 mimetic increases leiomyosarcoma sensitivity to doxorubicin.

PMID:
27140314
PMCID:
PMC4891502
DOI:
10.1038/bjc.2016.117
[Indexed for MEDLINE]
Free PMC Article

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