Pharmacological inhibition of Bcl-xL sensitizes osteosarcoma to doxorubicin.

Abstract

High-grade conventional osteosarcoma is the most common primary bone tumor. Prognosis for osteosarcoma patients is poor and resistance to chemotherapy is common. We performed an siRNA screen targeting members of the Bcl-2 family in human osteosarcoma cell lines to identify critical regulators of osteosarcoma cell survival. Silencing the anti-apoptotic family member Bcl-xL but also the pro-apoptotic member Bak using a SMARTpool of siRNAs as well as 4/4 individual siRNAs caused loss of viability. Loss of Bak impaired cell cycle progression and triggered autophagy. Instead, silencing Bcl-xL induced apoptotic cell death. Bcl-xL was expressed in clinical osteosarcoma samples but mRNA or protein levels did not significantly correlate with therapy response or survival. Nevertheless, pharmacological inhibition of a range of Bcl-2 family members showed that inhibitors targeting Bcl-xL synergistically enhanced the response to the chemotherapeutic agent, doxorubicin. Indeed, in osteosarcoma cells strongly expressing Bcl-xL, the Bcl-xL-selective BH3 mimetic, WEHI-539 potently enhanced apoptosis in the presence of low doses of doxorubicin. Our results identify Bcl-xL as a candidate drug target for sensitization to chemotherapy in patients with osteosarcoma.

• Authors: Zuzanna Baranski, Yvonne de Jong, Trayana Ilkova, Elisabeth F P Peterse, Anne-Marie Cleton-Jansen, Bob van de Water, Pancras C W Hogendoorn, Judith V M G Bovée, Erik H J Danen
• Journal: Oncotarget (Oncotarget) Vol. 6 Issue 34 Pg. 36113-25 (Nov 03 2015) ISSN: 1949-2553 [Electronic] United States
• PMID: 26416351 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• ABT-737
• BCL2L1 protein, human
• Benzopyrans
• Biphenyl Compounds
• Enzyme Inhibitors
• Nitriles
• Nitrophenols
• Piperazines
• Sulfonamides
• bcl-X Protein
• ethyl 2-amino-6-bromo-4-(1-cyano-2-ethoxy-2-oxoethyl)-4H-chromene-3-carboxylate
• Doxorubicin

Topics

• Antineoplastic Combined Chemotherapy Protocols (pharmacology)
• Apoptosis (drug effects)
• Benzopyrans (pharmacology)
• Biphenyl Compounds (pharmacology)
• Bone Neoplasms (drug therapy, pathology)
• Cell Line, Tumor
• Cohort Studies
• Doxorubicin (administration & dosage, pharmacology)
• Drug Synergism
• Enzyme Inhibitors (administration & dosage, pharmacology)
• Humans
• Immunohistochemistry
• Lung Neoplasms (secondary)
• Nitriles (pharmacology)
• Nitrophenols (pharmacology)
• Osteosarcoma (drug therapy, pathology)
• Piperazines (pharmacology)
• Sulfonamides (pharmacology)
• Tissue Array Analysis
• Transfection
• bcl-X Protein (antagonists & inhibitors, biosynthesis, genetics)