title: Targeting CDKs with Roscovitine Increases Sensitivity to DNA Damaging Drugs of Human Osteosarcoma Cells.
abstract: Cyclin-dependent kinase 2 (CDK2) has been reported to be essential for cell proliferation in several human tumours and it has been suggested as an appropriate target to be considered in order to enhance the efficacy of treatment regimens based on the use of DNA damaging drugs. We evaluated the clinical impact of CDK2 overexpression on a series of 21 high-grade osteosarcoma (OS) samples profiled by using cDNA microarrays. We also assessed the in vitro efficacy of the CDKs inhibitor roscovitine in a panel of drug-sensitive and drug-resistant human OS cell lines. OS tumour samples showed an inherent overexpression of CDK2, and high expression levels at diagnosis of this kinase appeared to negatively impact on clinical outcome. CDK2 expression also proved to be relevant for in vitro OS cells growth. These findings indicated CDK2 as a promising candidate therapeutic marker for OS and therefore we assessed the efficacy of the CDKs-inhibitor roscovitine in both drug-sensitive and -resistant OS cell lines. All cell lines resulted to be responsive to roscovitine, which was also able to increase the activity of cisplatin and doxorubicin, the two most active DNA damaging drugs used in OS chemotherapy. Our results indicated that combined treatment with conventional OS chemotherapeutic drugs and roscovitine may represent a new candidate intervention approach, which may be considered to enhance tumour cell sensitivity to DNA damaging drugs.
authors.affiliation: Laboratory of Experimental Oncology, Orthopaedic Rizzoli Institute, Italy.
authors.forename: Serena
authors.initials: S
authors.lastname: Vella
authors.affiliation: Laboratory of Experimental Oncology, Orthopaedic Rizzoli Institute, Italy.
authors.forename: Elisa
authors.initials: E
authors.lastname: Tavanti
authors.affiliation: Laboratory of Experimental Oncology, Orthopaedic Rizzoli Institute, Italy.
authors.forename: Claudia Maria
authors.initials: CM
authors.lastname: Hattinger
authors.affiliation: Laboratory of Experimental Oncology, Orthopaedic Rizzoli Institute, Italy.
authors.forename: Marilù
authors.initials: M
authors.lastname: Fanelli
authors.affiliation: Department of Human Genetics, Academic Medical Center, University of Amsterdam, The Netherlands.
authors.forename: Rogier
authors.initials: R
authors.lastname: Versteeg
authors.affiliation: Department of Oncogenomics, Academic Medical Center, University of Amsterdam, The Netherlands.
authors.forename: Jan
authors.initials: J
authors.lastname: Koster
authors.affiliation: Laboratory of Experimental Oncology, Orthopaedic Rizzoli Institute, Italy.
authors.forename: Piero
authors.initials: P
authors.lastname: Picci
authors.affiliation: Laboratory of Experimental Oncology, Orthopaedic Rizzoli Institute, Italy.
authors.forename: Massimo
authors.identifier: http://orcid.org/0000-0003-0742-1177
authors.initials: M
authors.lastname: Serra
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D051357:Cyclin-Dependent Kinase 2 / Q000037:antagonists & inhibitors* / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D004249:DNA Damage; D004317:Doxorubicin / Q000494:pharmacology; D004357:Drug Synergism; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D020868:Gene Silencing; D006801:Humans; D058990:Molecular Targeted Therapy; D012516:Osteosarcoma / Q000473:pathology*; D011687:Purines / Q000494:pharmacology*; D000077546:Roscovitine
chemical_list: D000970:Antineoplastic Agents; D011687:Purines; D000077546:Roscovitine; D004317:Doxorubicin; D051357:Cyclin-Dependent Kinase 2