Polo-like Kinase Inhibitor Volasertib Exhibits Antitumor Activity and Synergy with Vincristine in Pediatric Malignancies

• Published in: Anticancer research Vol. 36; no. 2; p. 599
• Main Authors: Abbou, Samuel, Lanvers-Kaminsky, Claudia, Daudigeos-Dubus, Estelle, LE Dret, Ludivine, Laplace-Builhe, Corinne, Molenaar, Jan, Vassal, Gilles, Geoerger, Birgit
• Format: Journal Article
• Language: English
• Published: Greece 01-02-2016
• Subjects: Animals; Antineoplastic Combined Chemotherapy Protocols - pharmacology; Apoptosis - drug effects; Blotting, Western; Bone Neoplasms - drug therapy; Bone Neoplasms - enzymology; Bone Neoplasms - pathology; Cell Cycle - drug effects; Cell Cycle Proteins - antagonists & inhibitors; Cell Cycle Proteins - metabolism; Cell Proliferation - drug effects; Child; Drug Synergism; Female; Flow Cytometry; Humans; Medulloblastoma - drug therapy; Medulloblastoma - enzymology; Medulloblastoma - pathology; Mice; Mice, Nude; Neoplasms - drug therapy; Neoplasms - enzymology; Neoplasms - pathology; Neuroblastoma - drug therapy; Neuroblastoma - enzymology; Neuroblastoma - pathology; Polo-Like Kinase 1; Protein Serine-Threonine Kinases - antagonists & inhibitors; Protein Serine-Threonine Kinases - metabolism; Proto-Oncogene Proteins - antagonists & inhibitors; Proto-Oncogene Proteins - metabolism; Pteridines - administration & dosage; Rhabdomyosarcoma - drug therapy; Rhabdomyosarcoma - enzymology; Rhabdomyosarcoma - pathology; Sarcoma, Ewing - drug therapy; Sarcoma, Ewing - enzymology; Sarcoma, Ewing - pathology; Tumor Cells, Cultured; Vincristine - administration & dosage; Xenograft Model Antitumor Assays; neuroblastoma; childhood tumors; Cell-cycle checkpoint; polo-like kinase 1 combination; rhabdomyosarcoma
• ISSN: 1791-7530

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.