title: 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.affiliation: Division of Toxicology, Leiden/Academic Center for Drug Research, Leiden University, 2300 RA Leiden, The Netherlands.
authors.forename: Zuzanna
authors.initials: Z
authors.lastname: Baranski
authors.affiliation: Department of Pathology, Leiden University Medical Center, 2300 RC Leiden, The Netherlands.
authors.forename: Yvonne
authors.initials: Y
authors.lastname: de Jong
authors.affiliation: Division of Toxicology, Leiden/Academic Center for Drug Research, Leiden University, 2300 RA Leiden, The Netherlands.
authors.forename: Trayana
authors.initials: T
authors.lastname: Ilkova
authors.affiliation: Department of Pathology, Leiden University Medical Center, 2300 RC Leiden, The Netherlands.
authors.forename: Elisabeth F P
authors.initials: EF
authors.lastname: Peterse
authors.affiliation: Department of Pathology, Leiden University Medical Center, 2300 RC Leiden, The Netherlands.
authors.forename: Anne-Marie
authors.initials: AM
authors.lastname: Cleton-Jansen
authors.affiliation: Division of Toxicology, Leiden/Academic Center for Drug Research, Leiden University, 2300 RA Leiden, The Netherlands.
authors.forename: Bob
authors.initials: B
authors.lastname: van de Water
authors.affiliation: Department of Pathology, Leiden University Medical Center, 2300 RC Leiden, The Netherlands.
authors.forename: Pancras C W
authors.initials: PC
authors.lastname: Hogendoorn
authors.affiliation: Department of Pathology, Leiden University Medical Center, 2300 RC Leiden, The Netherlands.
authors.forename: Judith V M G
authors.initials: JV
authors.lastname: Bovée
authors.affiliation: Division of Toxicology, Leiden/Academic Center for Drug Research, Leiden University, 2300 RA Leiden, The Netherlands.
authors.forename: Erik H J
authors.initials: EH
authors.lastname: Danen
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001578:Benzopyrans / Q000494:pharmacology; D001713:Biphenyl Compounds / Q000494:pharmacology; D001859:Bone Neoplasms / Q000188:drug therapy* / Q000473:pathology; D045744:Cell Line, Tumor; D015331:Cohort Studies; D004317:Doxorubicin / Q000008:administration & dosage / Q000494:pharmacology*; D004357:Drug Synergism; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D006801:Humans; D007150:Immunohistochemistry; D008175:Lung Neoplasms / Q000556:secondary; D009570:Nitriles / Q000494:pharmacology; D009596:Nitrophenols / Q000494:pharmacology; D012516:Osteosarcoma / Q000188:drug therapy* / Q000473:pathology; D010879:Piperazines / Q000494:pharmacology; D013449:Sulfonamides / Q000494:pharmacology; D046888:Tissue Array Analysis; D014162:Transfection; D051020:bcl-X Protein / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics
chemical_list: C501332:ABT-737; C494811:BCL2L1 protein, human; D001578:Benzopyrans; D001713:Biphenyl Compounds; D004791:Enzyme Inhibitors; D009570:Nitriles; D009596:Nitrophenols; D010879:Piperazines; D013449:Sulfonamides; D051020:bcl-X Protein; C456800:ethyl 2-amino-6-bromo-4-(1-cyano-2-ethoxy-2-oxoethyl)-4H-chromene-3-carboxylate; D004317:Doxorubicin
keywords: Bcl-xL; apoptosis; autophagy; doxorubicin; osteosarcoma