Cyclin-dependent kinase inhibitor, P276-00 induces apoptosis in multiple myeloma cells by inhibition of Cdk9-T1 and RNA polymerase II-dependent transcription

• Published in: Leukemia research Vol. 35; no. 6; pp. 821 - 830
• Main Authors: Manohar, Sonal M, Rathos, Maggie J, Sonawane, Vinay, Rao, Shalini V, Joshi, Kalpana S
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01.06.2011
• Subjects: Animals; Apoptosis - drug effects; Apoptosis Regulatory Proteins - metabolism; Blotting, Western; Cdk9; Cell Cycle - drug effects; Cell Cycle Proteins - metabolism; Cell Line, Tumor; Cell Survival - drug effects; Cyclin-Dependent Kinase 9 - antagonists & inhibitors; Cyclin-Dependent Kinase 9 - genetics; Cyclin-Dependent Kinase 9 - metabolism; Cyclin-Dependent Kinases - antagonists & inhibitors; Cyclin-Dependent Kinases - genetics; Cyclin-Dependent Kinases - metabolism; Dose-Response Relationship, Drug; Flavones - pharmacology; Hematology, Oncology and Palliative Medicine; Humans; Mcl-1; Mice; Mice, SCID; Microscopy, Confocal; Multiple myeloma; Multiple Myeloma - drug therapy; Multiple Myeloma - genetics; Multiple Myeloma - pathology; Myeloid Cell Leukemia Sequence 1 Protein; P276-00; Proto-Oncogene Proteins c-bcl-2 - genetics; Proto-Oncogene Proteins c-bcl-2 - metabolism; Reverse Transcriptase Polymerase Chain Reaction; RNA Interference; RNA Polymerase II - metabolism; Time Factors; Transcription, Genetic - drug effects; Xenograft Model Antitumor Assays; Cdk9; Mcl-1; P276-00; Multiple myeloma
• ISSN: 0145-2126; 1873-5835
• DOI: 10.1016/j.leukres.2010.12.010

Abstract P276-00 is a novel cyclin-dependent kinase inhibitor especially potent for Cdk9-T1, Cdk4-D1 and Cdk1-B. Multiple myeloma (MM) is a B-cell malignancy characterized by the accumulation of malignant plasma cells. Treatment of MM cell lines with P276-00 resulted in apoptosis that correlated with transcription inhibition and a significant decline in Mcl-1 protein levels with the appearance of cleaved PARP in these cells. In vivo studies of P276-00 confirmed antitumor activity in RPMI-8226 xenograft. These results suggest that P276-00 causes multiple myeloma cell death by disrupting the balance between cell survival and apoptosis through inhibition of transcription and downregulation of Mcl-1.