Growth inhibition and apoptosis of myeloma cells by the CDK inhibitor flavopiridol.
Although myeloma shows responsiveness in intensive chemotherapy, overall survival remains less than 40% at 2 years. Since myeloma appears to be dependent on cytokines, such as IL-6, we hypothesized that targeting signal transduction molecules could effectively treat myeloma. Two myeloma cell lines U266 and RPMI-8226 and CD38+ myeloma cells were studied by immune complex kinase assay or anti-phosphotyrosine blot for evidence of constitutive activation of tyrosine kinases. Growth arrest and apoptosis were evaluated in these two cell lines following their treatment with specific kinase inhibitors. We found that a variety of Src and Janus kinases were present and constitutively active in U266 and RPMI-8226 cells. Inhibitors of both Src and Janus kinases were inferior to the cyclin-dependent kinase inhibitor, flavopiridol, in inducing both growth arrest with GI50 of 100 nM and apoptosis in both cell lines and CD38+ myeloma cells. Although, flavopiridol did not affect cyclin D1 and cyclin A levels, it inhibited Mcl-1 and Bcl-2 protein levels and cyclin-dependent kinase 2 activity. Flavopiridol is a well-tolerated drug, currently in phase I-II trials for a variety of tumors. A clinical trial using flavopiridol should be performed in patients with myeloma. Its mechanism of action may involve targets other than the cyclin-dependent kinases.
Semenov
Igor
I
Department of Pediatrics (Hematology-Oncology), Children's Hospital of Pittsburgh, 3705 Fifth Avenue, Pittsburgh, PA 15213, USA.
Akyuz
Canan
C
Roginskaya
Vera
V
Chauhan
Dharminder
D
Corey
Seth J
SJ
D036541:ADP-ribosyl Cyclase; D051997:ADP-ribosyl Cyclase 1; D000911:Antibodies, Monoclonal; D015703:Antigens, CD / Q000032:analysis; D000943:Antigens, Differentiation / Q000032:analysis; D000970:Antineoplastic Agents / Q000633:toxicity*; D017209:Apoptosis / Q000187:drug effects*; D001854:Bone Marrow Cells / Q000473:pathology; D002455:Cell Division / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors*; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000633:toxicity; D005419:Flavonoids / Q000633:toxicity*; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases; D008562:Membrane Glycoproteins; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors; D009101:Multiple Myeloma / Q000473:pathology*; D009244:NAD+ Nucleosidase / Q000032:analysis; D019000:Phosphotyrosine / Q000032:analysis; D010880:Piperidines / Q000633:toxicity*; D014407:Tumor Cells, Cultured; D019061:src-Family Kinases / Q000037:antagonists & inhibitors
D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D000943:Antigens, Differentiation; D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D005419:Flavonoids; D008562:Membrane Glycoproteins; D010880:Piperidines; D019000:Phosphotyrosine; C077990:alvocidib; D019061:src-Family Kinases; D018844:Cyclin-Dependent Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D036541:ADP-ribosyl Cyclase; C498154:CD38 protein, human; D009244:NAD+ Nucleosidase; D051997:ADP-ribosyl Cyclase 1