Inhibition of Bcl-2 family members sensitizes mesenchymal chondrosarcoma to conventional chemotherapy: report on a novel mesenchymal chondrosarcoma cell line.
Mesenchymal chondrosarcomas are rare and highly aggressive sarcomas occurring in bone and soft tissue, with poor overall survival. Bcl-2 expression was previously shown to be upregulated in mesenchymal chondrosarcomas. We here report on a newly derived mesenchymal chondrosarcoma cell line, MCS170, in which we investigated treatment with the BH3 mimetic ABT-737 alone or in combination with conventional chemotherapy as a possible new therapeutic strategy. The presence of the characteristic HEY1-NCOA2 fusion was confirmed in the MCS170 cell line using FISH, RT-PCR, and sequencing. The MCS170 cell line was treated with ABT-737 alone or in combination with doxorubicin or cisplatin. Cell viability and proliferation was determined using WST-1 viability assays and the xCELLigence system. Expression of Bcl-2 family members was studied using immunohistochemistry. Apoptosis was determined using the caspase-glo 3/7 assay and western blot for PARP cleavage. The MCS170 cell line was sensitive to doxorubicin treatment with an IC50 of 0.09 μM after 72 h, but more resistant to cisplatin treatment with an IC50 of 4.5 μM after 72 h. Cells showed little sensitivity toward ABT-737 with an IC50 of 1.8 μM after 72 h. Combination treatments demonstrated ABT-737 synergism with cisplatin as well as doxorubicin as shown by induction of apoptosis and reduction in cell proliferation. Restoration of the apoptotic machinery by inhibition of Bcl-2 family members sensitizes MCS170 mesenchymal chondrosarcoma cells to conventional chemotherapy. This indicates that combining the inhibition of Bcl-2 family members with conventional chemotherapy can be a possible therapeutic strategy for patients with mesenchymal chondrosarcoma.
Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands.
Yvonne
Y
de Jong
Department of Medical Oncology, Leiden University Medical Center, Leiden, The Netherlands.
Annemiek M
AM
van Maldegem
Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
Adrian
A
Marino-Enriquez
Department of Molecular Cell Biology, Leiden University Medical Center, Leiden, The Netherlands.
Danielle
D
de Jong
Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands.
Johnny
J
Suijker
Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands.
Inge H
IH
Briaire-de Bruijn
Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands.
Alwine B
AB
Kruisselbrink
Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands.
Anne-Marie
AM
Cleton-Jansen
Department of Molecular Cell Biology, Leiden University Medical Center, Leiden, The Netherlands.
Karoly
K
Szuhai
Department of Medical Oncology, Leiden University Medical Center, Leiden, The Netherlands.
Hans
H
Gelderblom
Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
Jonathan A
JA
Fletcher
Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands.
Judith V M G
JV
Bovée
D000328:Adult; D000970:Antineoplastic Agents; D001713:Biphenyl Compounds; D045744:Cell Line, Tumor / Q000187:drug effects*; D018211:Chondrosarcoma, Mesenchymal; D002945:Cisplatin; D004317:Doxorubicin; D019008:Drug Resistance, Neoplasm; D006801:Humans; D008297:Male; D009596:Nitrophenols; D010879:Piperazines; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000037:antagonists & inhibitors*; D013449:Sulfonamides
C501332:ABT-737; D000970:Antineoplastic Agents; D001713:Biphenyl Compounds; D009596:Nitrophenols; D010879:Piperazines; D019253:Proto-Oncogene Proteins c-bcl-2; D013449:Sulfonamides; D004317:Doxorubicin; D002945:Cisplatin