TY - JOUR
T1 - Polo-like Kinase Inhibitor Volasertib Exhibits Antitumor Activity and Synergy with Vincristine in Pediatric Malignancies
AU - within the ITCC Biology and Preclinical Evaluation Committee
AU - Abbou, Samuel
AU - Lanvers-Kaminsky, Claudia
AU - Daudigeos-Dubus, Estelle
AU - LE Dret, Ludivine
AU - Laplace-Builhe, Corinne
AU - Molenaar, Jan
AU - Vassal, Gilles
AU - Geoerger, Birgit
N1 - Publisher Copyright:
Copyright© 2016 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.
PY - 2016/2/1
Y1 - 2016/2/1
N2 - BACKGROUND: 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.MATERIALS AND METHODS: 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.RESULTS: 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.CONCLUSION: These findings support the further exploration of volasertib for pediatric malignancies, particularly alveolar rhabdomyosarcoma, and its combination with mitotic spindle poison.
AB - BACKGROUND: 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.MATERIALS AND METHODS: 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.RESULTS: 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.CONCLUSION: These findings support the further exploration of volasertib for pediatric malignancies, particularly alveolar rhabdomyosarcoma, and its combination with mitotic spindle poison.
KW - Cell-cycle checkpoint
KW - childhood tumors
KW - neuroblastoma
KW - polo-like kinase 1 combination
KW - rhabdomyosarcoma
UR - http://www.scopus.com/inward/record.url?scp=84975230889&partnerID=8YFLogxK
M3 - Article
C2 - 26851014
AN - SCOPUS:84975230889
SN - 0250-7005
VL - 36
SP - 599
EP - 609
JO - Anticancer Research
JF - Anticancer Research
IS - 2
ER -