Evaluation of the antitumor activity of NOV202, a novel microtubule targeting and vascular disrupting agent
| Autor: | Marita Högberg, Linda Rickardson, Marko J. Kallio, Emma Kutvonen, Stefan Rehnmark, Satu Orasniemi |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2017 |
| Předmět: |
Male
Cell Pharmaceutical Science Antineoplastic Agents 030204 cardiovascular system & hematology ta3111 Microtubules 03 medical and health sciences chemistry.chemical_compound Mice Structure-Activity Relationship 0302 clinical medicine In vivo multidrug resistance Drug Discovery medicine Vascular-targeting agent Tumor Cells Cultured Animals Humans NOV202 Original Research Cell Proliferation Pharmacology Tube formation Ovarian Neoplasms microtubule-targeting agent Drug Design Development and Therapy biology Dose-Response Relationship Drug Neovascularization Pathologic Cell growth ta1184 vascular disruption Neoplasms Experimental Cell cycle Mice Inbred C57BL Tubulin medicine.anatomical_structure ovarian cancer Paclitaxel chemistry biology.protein Cancer research Female Drug Screening Assays Antitumor M phase arrest 030217 neurology & neurosurgery |
| Zdroj: | Drug Design, Development and Therapy |
| ISSN: | 1177-8881 |
| Popis: | Linda Rickardson,1 Emma Kutvonen,2 Satu Orasniemi,2 Marita Högberg,1 Marko J Kallio,2,3 Stefan Rehnmark1 1Noviga Research AB, Södertälje, Sweden; 2Department of Physiology, Institute of Biomedicine, University of Turku, 3Centre for Biotechnology, University of Turku, Turku, Finland Purpose: Overall, ~65% of patients diagnosed with advanced ovarian cancer (OC) will relapse after primary surgery and adjuvant first-line platinum- and taxane-based chemotherapy. Significant improvements in the treatment of OC are expected from the development of novel compounds having combined cytotoxic and antiangiogenic properties that make them effective on refractory tumors. Methods: Permeability of NOV202 was determined with Caco-2 monolayer assay. The compound’s pharmacokinetic profile and plasma:brain distribution were assessed in male C57Bl/6 mice. The compound’s impacts on tubulin, microtubules and cell cycle were investigated by using invitro tubulin polymerization assay, cell-based immunofluorescence and live cell microscopy. The IC50 concentrations of NOV202 were assessed in a panel of eight cancer cell lines. Impact of the compound on vascular tube formation was determined using the StemKit and Chick chorioallantoic membrane assays. The in vivo efficacy of the compound was analyzed with an OC xenograft mouse model. Results: NOV202 was found to suppress cancer cell proliferation at low nanomolar concentrations (IC50 2.3–12.0 nM) and showed equal efficacy between OC cell line A2780 (IC50 2.4nM) and its multidrug-resistant subline A2780/Adr (IC50 2.3 nM). Mechanistically, NOV202 targeted tubulin polymerization in vitro in a dose-dependent manner and in cells induced an M phase arrest. In vivo, NOV202 caused a dose-dependent reduction of tumor mass in an A2780 xenograft model, which at the highest dose (40 mg/kg) was comparable to the effect of paclitaxel (24 mg/kg). Interestingly, NOV202 exhibited vascular disrupting properties that were similar to the effects of Combretastatin A4. Conclusion: NOV202 is a novel tubulin and vascular targeting agent that shows strong anticancer efficacy in cells and OC xenograft models. The finding that the compound induced significantly more cell death in Pgp/MDR1 overexpressing OC cells compared to vincristine and paclitaxel warrants further development of the compound as a new therapy for OC patients with treatment refractory tumors and/or relapsing disease. Keywords: ovarian cancer, NOV202, microtubule-targeting agent, vascular disruption, Mphase arrest, multidrug resistance |
| Databáze: | OpenAIRE |
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