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.