TY - JOUR
T1 - Bcl-xl as the most promising Bcl-2 family member in targeted treatment of chondrosarcoma
AU - de Jong, Yvonne
AU - Monderer, David
AU - Brandinelli, Emeline
AU - Monchanin, Morgane
AU - van den Akker, Brendy E.
AU - van Oosterwijk, Jolieke G.
AU - Blay, Jean Yves
AU - Dutour, Aurélie
AU - Bovée, Judith V.M.G.
N1 - Funding Information:
We thank Maayke van Ruler, Inge Briaire-de Bruijn and Pasquale D’Acunzo for technical assistance. We would also like to thank Alexandra Vandermoeten for technical support during the in vivo studies at SCAR. Furthermore we are grateful to Dr JA Block (Rush University Medical Centre, Chicago, IL, USA), who provided us with the JJ012 cell line, to Professor A Llombart Bosch (University of Valencia, Spain) for the CH2879 and CH3573 cell lines, Professor J.A. Fletcher for the MCS-170 cell line and Dr T Ariizumi (Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan) for the cell line NDCS-1. Also we would like to thank Dorien van der Geest for aiding in constructing the conventional chondrosarcoma TMA. This work was financially supported by Servier pharmaceutical company. Support from grant EUROSARC FP7 278742 & LYRIC INCA-DGOS 4664.
Publisher Copyright:
© 2018, The Author(s).
PY - 2018/9/1
Y1 - 2018/9/1
N2 - Chondrosarcomas are malignant cartilage tumors showing relative resistance to conventional chemo- and radiotherapy. Previous studies showed that chondrosarcoma cells could be sensitized to chemotherapy by inhibiting the Bcl-2 family members Bcl-2, Bcl-xl and Bcl-w using ABT-737. In this study we explored the specific role of Bcl-2 family members to identify the most important player in chondrosarcoma cell survival and chemo resistance. Immunohistochemistry was performed on tissue microarrays containing 137 conventional chondrosarcomas of different grades. Selective inhibition of Bcl-2 (S55746) or Bcl-xl (WEHI-539 or A-1155463) and the combination with doxorubicin or cisplatin was investigated in a panel of 8 chondrosarcoma cell lines using presto blue viability assays and caspase 3/7 glo apoptosis assays. In addition Bcl-2 and Bcl-xl inhibition was investigated in an orthotopic Swarm Rat Chondrosarcoma (SRC) model. Bcl-2 and Bcl-xl were most abundantly expressed in the primary tumors, and expression increased with increasing histological grade. A subset of chondrosarcoma cell lines was sensitive to selective inhibition of Bcl-xl, and synergy was observed with doxorubicin or cisplatin in 3 out of 8 chondrosarcoma cell lines resulting in apoptosis. Conversely, selective inhibition of Bcl-2 was not effective in chondrosarcoma cell lines and could not sensitize to chemotherapy. In vivo, selective inhibition of Bcl-xl, but not Bcl-2 resulted in a decrease in tumor growth rate, even though no sensitization to doxorubicin was observed. These results suggest that among the Bcl-2 family members, Bcl-xl is most important for chondrosarcoma survival. Further research is needed to validate whether single or combination treatment with chemotherapy will be beneficial for chondrosarcoma patients.
AB - Chondrosarcomas are malignant cartilage tumors showing relative resistance to conventional chemo- and radiotherapy. Previous studies showed that chondrosarcoma cells could be sensitized to chemotherapy by inhibiting the Bcl-2 family members Bcl-2, Bcl-xl and Bcl-w using ABT-737. In this study we explored the specific role of Bcl-2 family members to identify the most important player in chondrosarcoma cell survival and chemo resistance. Immunohistochemistry was performed on tissue microarrays containing 137 conventional chondrosarcomas of different grades. Selective inhibition of Bcl-2 (S55746) or Bcl-xl (WEHI-539 or A-1155463) and the combination with doxorubicin or cisplatin was investigated in a panel of 8 chondrosarcoma cell lines using presto blue viability assays and caspase 3/7 glo apoptosis assays. In addition Bcl-2 and Bcl-xl inhibition was investigated in an orthotopic Swarm Rat Chondrosarcoma (SRC) model. Bcl-2 and Bcl-xl were most abundantly expressed in the primary tumors, and expression increased with increasing histological grade. A subset of chondrosarcoma cell lines was sensitive to selective inhibition of Bcl-xl, and synergy was observed with doxorubicin or cisplatin in 3 out of 8 chondrosarcoma cell lines resulting in apoptosis. Conversely, selective inhibition of Bcl-2 was not effective in chondrosarcoma cell lines and could not sensitize to chemotherapy. In vivo, selective inhibition of Bcl-xl, but not Bcl-2 resulted in a decrease in tumor growth rate, even though no sensitization to doxorubicin was observed. These results suggest that among the Bcl-2 family members, Bcl-xl is most important for chondrosarcoma survival. Further research is needed to validate whether single or combination treatment with chemotherapy will be beneficial for chondrosarcoma patients.
UR - http://www.scopus.com/inward/record.url?scp=85053698155&partnerID=8YFLogxK
U2 - 10.1038/s41389-018-0084-0
DO - 10.1038/s41389-018-0084-0
M3 - Article
SN - 2157-9024
VL - 7
JO - Oncogenesis
JF - Oncogenesis
IS - 9
M1 - 74
ER -