siRNA-based targeting of antiapoptotic genes can reverse chemoresistance in P-glycoprotein expressing chondrosarcoma cells.
BACKGROUND
High expression of P-glycoprotein is one of the well-known mechanisms of chemoresistance in chondrosarcomas. However, the role of antiapoptotic proteins, a common mechanism responsible for chemoresistance in other tumors, has not been well studied in chondrosarcomas. We examined the importance of P-glycoprotein and antiapoptotic proteins in the chemoresistance to doxorubicin of two Grade II chondrosarcoma cell lines, JJ012 and SW1353.


RESULTS
We confirmed that both chondrosarcoma cell types expressed P-glycoprotein and antiapoptotic proteins (Bcl-2, Bcl-xL and XIAP). siRNA knockdown as well as pharmacologic inhibitors of cell survival proteins (Bcl-2, Bcl-xL and XIAP) enhanced apoptosis of chemoresistant chondrosarcoma cells by up to 5.5 fold at 0.1 micromol and 5.5 fold at 1 micromol doxorubicin. These chemosensitizing effects were comparable to those of P-glycoprotein inhibition by siRNA or pharmacologic inhibitor.


CONCLUSIONS
These findings suggest that antiapoptotic proteins play a significant role in the chemoresistance of chondrosarcoma cells independent of P-glycoprotein. Based on the results, a new siRNA-based therapeutic strategy targeting antiapoptotic genes can be designed to overcome the chemoresistance of chondrosarcomas which is often conferred by P-glycoprotein.
Kim
Dae Won
DW
Department of Orthopaedic Surgery, The Center for Orthopaedic Research, Columbia University, New York, NY 10032, USA.kimdw1031@yahoo.com
Kim
Kyung-Ok
KO
Shin
Mike J
MJ
Ha
Jung Hee
JH
Seo
Sung Wook
SW
Yang
Jay
J
Lee
Francis Y
FY
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000096:biosynthesis*; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000235:genetics*; D001859:Bone Neoplasms / Q000235:genetics* / Q000378:metabolism; D045744:Cell Line, Tumor; D002813:Chondrosarcoma / Q000235:genetics* / Q000378:metabolism; D004317:Doxorubicin / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D005434:Flow Cytometry; D020868:Gene Silencing; D019254:Genes, bcl-2; D006801:Humans; D015151:Immunoblotting; D034741:RNA, Small Interfering; D020133:Reverse Transcriptase Polymerase Chain Reaction; D051636:X-Linked Inhibitor of Apoptosis Protein / Q000235:genetics / Q000378:metabolism; D051020:bcl-X Protein / Q000235:genetics / Q000378:metabolism
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000970:Antineoplastic Agents; D034741:RNA, Small Interfering; D051636:X-Linked Inhibitor of Apoptosis Protein; D051020:bcl-X Protein; D004317:Doxorubicin