volasertib and Neuroblastoma

Polo-like kinase 1 (PLK1) controls the main cell-cycle checkpoints, suggesting utility of its inhibition for cancer treatment, including of highly proliferative pediatric cancer. This preclinical study explored the selective PLK1 inhibitor volasertib (BI 6727) alone and combined with chemotherapy in pediatric malignancies.. Inhibition of proliferation was explored in vitro using dimethylthiazol carboxymethoxyphenyl sulfophenyl tetrazolium (MTS) assay. Mice bearing human xenografts were treated with weekly intravenous injections of volasertib.. Volasertib inhibited proliferation in all 40 cell lines tested, with a mean half-maximal growth inhibitory concentration of 313 nmol/l (range: 4-5000 nmol/l). Volasertib was highly active against RMS-1 alveolar rhabdomyosarcoma xenografts, resulting in 100% tumor regression. Activity was associated with complete and prolonged G2/M arrest and subsequent apoptotic cell death. Volasertib showed synergistic activity with vincristine but antagonistic effects with etoposide.. These findings support the further exploration of volasertib for pediatric malignancies, particularly alveolar rhabdomyosarcoma, and its combination with mitotic spindle poison.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Blotting, Western; Bone Neoplasms; Cell Cycle; Cell Cycle Proteins; Cell Proliferation; Child; Drug Synergism; Female; Flow Cytometry; Humans; Medulloblastoma; Mice; Mice, Nude; Neoplasms; Neuroblastoma; Polo-Like Kinase 1; Protein Serine-Threonine Kinases; Proto-Oncogene Proteins; Pteridines; Rhabdomyosarcoma; Sarcoma, Ewing; Tumor Cells, Cultured; Vincristine; Xenograft Model Antitumor Assays

MYCN amplification in human cancers predicts poor prognosis and resistance to therapy. However, pharmacological strategies that directly target N-Myc, the protein encoded by MYCN, remain elusive. Here, we identify a molecular mechanism responsible for reciprocal activation between Polo-like kinase-1 (PLK1) and N-Myc. PLK1 specifically binds to the SCF

Topics: Animals; Antineoplastic Agents; Brain Neoplasms; Bridged Bicyclo Compounds, Heterocyclic; Cell Cycle Proteins; Cell Line, Tumor; Drug Synergism; F-Box Proteins; F-Box-WD Repeat-Containing Protein 7; Feedback, Physiological; Gene Expression Regulation, Neoplastic; Humans; Mice, Nude; N-Myc Proto-Oncogene Protein; Neuroblastoma; Neurons; Polo-Like Kinase 1; Protein Serine-Threonine Kinases; Proto-Oncogene Proteins; Proto-Oncogene Proteins c-bcl-2; Pteridines; RNA, Small Interfering; Signal Transduction; Sulfonamides; Survival Analysis; Transcription, Genetic; Tumor Burden; Ubiquitin-Protein Ligases; Xenograft Model Antitumor Assays