title: Roscovitine, a small molecule CDK inhibitor induces apoptosis in multidrug-resistant human multiple myeloma cells.
abstract: Small molecule inhibitors of cyclin-dependent kinases (CDKs) show high therapeutic potential against rapidly dividing cancers and malignancies, characterized by the accumulation of transformed cells due to deregulation of apoptosis, such as multiple myeloma. In the present study we addressed the possibility that pharmacological CDK inhibitors like Roscovitine (ROSC) may be effective against human multiple myeloma cells that have acquired resistance to doxorubicin (DOX). For this purpose we selected an experimental model of human multiple myeloma-sensitive (RPMI-8226s) and doxorubicin-resistant (RPMI-8226(DOX40)) cell lines. Exposure of RPMI-8826 cells to ROSC markedly increased the proportion of hypoploid cells, representing cells undergoing apoptosis, in both sensitive and resistant cells. Unlike ROSC, DOX at high dosage did not elevate the apoptosis rate in the RPMI-8226(DOX40) cell line. Our results show that ROSC has the capacity to induce apoptosis in the RPMI-8226(DOX40) cells overexpressing the P-gp glycoprotein. Since ROSC not only inhibits cell cycle-related CDKs but also negatively regulates kinases involved in the regulation of transcription, its administration to quiescent multidrug-resistant cells might be advantageous. Inhibition of transcription of pro-survival genes such as BCL2 and MCL-1 as well as destabilization of survivin seems to improve its therapeutic efficacy.
authors.affiliation: Cell Cycle Regulation Group, Division, Institute of Cancer Research, Department of Medicine I, Medical University of Vienna, Borschkegasse 8a, 1090 Vienna, Austria.
authors.forename: Oxane
authors.initials: O
authors.lastname: Komina
authors.forename: Ellen
authors.initials: E
authors.lastname: Nosske
authors.forename: Margarita
authors.initials: M
authors.lastname: Maurer
authors.forename: Jozefa
authors.initials: J
authors.lastname: Wesierska-Gadek
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors*; D004317:Doxorubicin / Q000494:pharmacology; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D005434:Flow Cytometry; D006801:Humans; D015151:Immunoblotting; D009101:Multiple Myeloma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology*; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D011687:Purines / Q000627:therapeutic use*; D000077546:Roscovitine; D014407:Tumor Cells, Cultured
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000903:Antibiotics, Antineoplastic; D047428:Protein Kinase Inhibitors; D011687:Purines; D000077546:Roscovitine; D004317:Doxorubicin; D018844:Cyclin-Dependent Kinases