Abstract
Although rare, osteosarcoma is an aggressive cancer that often metastasizes to the lungs. Toward the goal of developing new treatment options for osteosarcoma, we show that the cyclin-dependent kinase (CDK) inhibitor SCH 727965 (SCH) induces the apoptosis of several osteosarcoma cell lines including those resistant to doxorubicin and dasatinib. Cell lines prepared in our laboratory from patients who had received adjuvant chemotherapy and explants derived from a human osteosarcoma xenograft in mice were also responsive to SCH. Apoptosis occurred at low nanomolar concentrations of SCH, as did CDK inhibition, and was p53-independent. SCH activated the mitochondrial pathway of apoptosis as evidenced by caspase-9 cleavage and accumulation of cytoplasmic cytochrome c. Amounts of the apoptotic proteins Bax and Bim increased in mitochondria, whereas amounts of the antiapoptotic proteins Mcl-1 and Bcl-x(L) declined. Osteosarcoma cells apoptosed when codepleted of CDK1 and CDK2 but not when depleted of other CDK combinations. We suggest that SCH triggers the apoptosis of osteosarcoma cells by inactivating CDK1 and CDK2 and that SCH may be useful for treatment of drug-resistant osteosarcomas. SCH also induced the apoptosis of other sarcoma types but not of normal quiescent osteoblasts or fibroblasts.
MeSH terms
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Animals
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Apoptosis / drug effects*
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Apoptosis Regulatory Proteins / metabolism
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Bcl-2-Like Protein 11
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Bone Neoplasms / drug therapy*
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Bone Neoplasms / enzymology*
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Bone Neoplasms / pathology
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Bridged Bicyclo Compounds, Heterocyclic / pharmacology*
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CDC2 Protein Kinase / antagonists & inhibitors
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CDC2 Protein Kinase / metabolism
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Caspase 9 / metabolism
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Cell Line, Tumor
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Cyclic N-Oxides
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Cyclin-Dependent Kinase 2 / antagonists & inhibitors
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Cyclin-Dependent Kinase 2 / metabolism
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Cytochromes c / metabolism
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Drug Resistance, Neoplasm / drug effects
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Humans
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Indolizines
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Membrane Proteins / metabolism
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Mice
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Mitochondria / metabolism
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Osteosarcoma / drug therapy*
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Osteosarcoma / enzymology*
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Osteosarcoma / pathology
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Phosphorylation
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Proto-Oncogene Proteins / metabolism
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Proto-Oncogene Proteins c-bcl-2 / metabolism
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Pyridinium Compounds / pharmacology*
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Tumor Suppressor Protein p53 / metabolism
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Xenograft Model Antitumor Assays
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bcl-2-Associated X Protein / metabolism
Substances
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Apoptosis Regulatory Proteins
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BAX protein, human
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BCL2L11 protein, human
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Bcl-2-Like Protein 11
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Bcl2l11 protein, mouse
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Bridged Bicyclo Compounds, Heterocyclic
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Cyclic N-Oxides
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Indolizines
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Membrane Proteins
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Proto-Oncogene Proteins
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Proto-Oncogene Proteins c-bcl-2
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Pyridinium Compounds
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Tumor Suppressor Protein p53
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bcl-2-Associated X Protein
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dinaciclib
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Cytochromes c
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CDC2 Protein Kinase
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Cyclin-Dependent Kinase 2
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Caspase 9