VMY-1-103 is a novel CDK inhibitor that disrupts chromosome organization and delays metaphase progression in medulloblastoma cells

• Published in: Cancer biology & therapy Vol. 12; no. 9; pp. 818 - 826
• Main Authors: Ringer, Lymor, Sirajuddin, Paul, Heckler, Mary, Ghosh, Anup, Suprynowicz, Frank, Yenugonda, Venkata M., Brown, Milton L., Toretsky, Jeffrey A., Üren, Aykut, Lee, YiChien, MacDonald, Tobey J., Rodriguez, Olga, Glazer, Robert I., Schlegel, Richard, Albanese, Chris
• Format: Journal Article
• Language: English
• Published: United States Taylor & Francis 01.11.2011; Landes Bioscience
• Subjects: Adenine - analogs & derivatives; Adenine - pharmacology; Antineoplastic Agents - pharmacology; Binding; Biology; Bioscience; Calcium; Cancer; CDC2 Protein Kinase - antagonists & inhibitors; Cell; Cell Cycle - drug effects; Cell Line, Tumor; Centrosome - drug effects; Cerebellar Neoplasms - enzymology; Cerebellar Neoplasms - genetics; Cerebellar Neoplasms - metabolism; Chromosomes, Human - drug effects; Cycle; Dansyl Compounds - pharmacology; Humans; Landes; Medulloblastoma - enzymology; Medulloblastoma - genetics; Medulloblastoma - metabolism; Metaphase - drug effects; Mitosis - drug effects; Organogenesis; Protein Kinase Inhibitors - pharmacology; Proteins; Research Paper
• ISSN: 1538-4047; 1555-8576
• DOI: 10.4161/cbt.12.9.17682

Medulloblastoma is the most prevalent of childhood brain malignancies, constituting 25% of childhood brain tumors. Craniospinal radiotherapy is a standard of care, followed by a 12-month regimen of multi-agent chemotherapy. For children less than 3 years of age, irradiation is avoided due to its destructive effects on the developing nervous system. Long-term prognosis is worst for these youngest children and more effective treatment strategies with a better therapeutic index are needed. VMY-1-103, a novel dansylated analog of purvalanol B, was previously shown to inhibit cell cycle progression and proliferation in prostate and breast cancer cells more effectively than purvalanol B. In the current study, we have identified new mechanisms of action by which VMY-1-103 affected cellular proliferation in medulloblastoma cells. VMY-1-103, but not purvalanol B, significantly decreased the proportion of cells in S phase and increased the proportion of cells in G2/M. VMY-1-103 increased the sub G1 fraction of apoptotic cells, induced PARP and caspase-3 cleavage and increased the levels of the Death Receptors DR4 and DR5, Bax and Bad while decreasing the number of viable cells, all supporting apoptosis as a mechanism of cell death. p21CIP1/WAF1 levels were greatly suppressed. Importantly, we found that while both VMY and flavopiridol inhibited intracellular CDK1 catalytic activity, VMY-1-103 was unique in its ability to severely disrupt the mitotic spindle apparatus significantly delaying metaphase and disrupting mitosis. Our data suggest that VMY-1-103 possesses unique antiproliferative capabilities and that this compound may form the basis of a new candidate drug to treat medulloblastoma.