Scientific reports, 2020-04, Vol.10 (1), p.6524-6524, Article 6524
2020
Details
- Autor(en) / Beteiligte
- Titel
- Enhancing Brain Retention of a KIF11 Inhibitor Significantly Improves its Efficacy in a Mouse Model of Glioblastoma
- Ist Teil von
- Scientific reports, 2020-04, Vol.10 (1), p.6524-6524, Article 6524
- Ort / Verlag
- England: Nature Publishing Group
- Erscheinungsjahr
- 2020
- Link zum Volltext
- Quelle
- Free E-Journal (出版社公開部分のみ）
- Beschreibungen/Notizen
- Glioblastoma, the most lethal primary brain cancer, is extremely proliferative and invasive. Tumor cells at tumor/brain-interface often exist behind a functionally intact blood-brain barrier (BBB), and so are shielded from exposure to therapeutic drug concentrations. An ideal glioblastoma treatment needs to engage targets that drive proliferation as well as invasion, with brain penetrant therapies. One such target is the mitotic kinesin KIF11, which can be inhibited with ispinesib, a potent molecularly-targeted drug. Although, achieving durable brain exposures of ispinesib is critical for adequate tumor cell engagement during mitosis, when tumor cells are vulnerable, for efficacy. Our results demonstrate that the delivery of ispinesib is restricted by P-gp and Bcrp efflux at BBB. Thereby, ispinesib distribution is heterogeneous with concentrations substantially lower in invasive tumor rim (intact BBB) compared to glioblastoma core (disrupted BBB). We further find that elacridar-a P-gp and Bcrp inhibitor-improves brain accumulation of ispinesib, resulting in remarkably reduced tumor growth and extended survival in a rodent model of glioblastoma. Such observations show the benefits and feasibility of pairing a potentially ideal treatment with a compound that improves its brain accumulation, and supports use of this strategy in clinical exploration of cell cycle-targeting therapies in brain cancers.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 2045-2322eISSN: 2045-2322DOI: 10.1038/s41598-020-63494-7Titel-ID: cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_7162859
- Format
- –
- Schlagworte
- Acridines - chemistry, Acridines - pharmacology, Animals, ATP Binding Cassette Transporter, Subfamily B - antagonists & inhibitors, ATP Binding Cassette Transporter, Subfamily B - genetics, ATP Binding Cassette Transporter, Subfamily G, Member 2 - antagonists & inhibitors, ATP Binding Cassette Transporter, Subfamily G, Member 2 - genetics, Benzamides - pharmacology, Blood-brain barrier, Blood-Brain Barrier - drug effects, Brain, Brain cancer, Brain tumors, Cell cycle, Cell Line, Tumor, Cell Proliferation - drug effects, Disease Models, Animal, Glioblastoma, Glioblastoma - genetics, Glioblastoma - pathology, Humans, Invasiveness, Kinesin, Kinesin - antagonists & inhibitors, Kinesin - genetics, Mice, Mitosis, Molecular Targeted Therapy, Neoplasm Invasiveness - genetics, Neoplasm Invasiveness - pathology, Neoplasm Proteins - antagonists & inhibitors, Neoplasm Proteins - genetics, Quinazolines - pharmacology, Tetrahydroisoquinolines - chemistry, Tetrahydroisoquinolines - pharmacology, Tumor cells, Xenograft Model Antitumor Assays