| Title |
Evaluation of the antitumor activity of NOV202, a novel microtubule targeting and vascular disrupting agent
|
|---|---|
| Published in |
Drug Design, Development and Therapy, April 2017
|
| DOI | 10.2147/dddt.s133189 |
| Pubmed ID | |
| Authors |
Linda Rickardson, Emma Kutvonen, Satu Orasniemi, Marita Högberg, Marko J Kallio, Stefan Rehnmark |
| Abstract |
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. 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 in vitro 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. 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 2.4 nM) 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. 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. |
X Demographics
The data shown below were collected from the profiles of 2 X users who shared this research output. Click here to find out more about how the information was compiled.
Geographical breakdown
| Country | Count | As % |
|---|---|---|
| Portugal | 1 | 50% |
| Unknown | 1 | 50% |
Demographic breakdown
| Type | Count | As % |
|---|---|---|
| Members of the public | 2 | 100% |
Mendeley readers
The data shown below were compiled from readership statistics for 18 Mendeley readers of this research output. Click here to see the associated Mendeley record.
Geographical breakdown
| Country | Count | As % |
|---|---|---|
| Unknown | 18 | 100% |
Demographic breakdown
| Readers by professional status | Count | As % |
|---|---|---|
| Student > Bachelor | 5 | 28% |
| Other | 1 | 6% |
| Student > Postgraduate | 1 | 6% |
| Student > Master | 1 | 6% |
| Unknown | 10 | 56% |
| Readers by discipline | Count | As % |
|---|---|---|
| Medicine and Dentistry | 5 | 28% |
| Pharmacology, Toxicology and Pharmaceutical Science | 2 | 11% |
| Neuroscience | 1 | 6% |
| Biochemistry, Genetics and Molecular Biology | 1 | 6% |
| Unknown | 9 | 50% |
Attention Score in Context
This research output has an Altmetric Attention Score of 1. This is our high-level measure of the quality and quantity of online attention that it has received. This Attention Score, as well as the ranking and number of research outputs shown below, was calculated when the research output was last mentioned on 13 May 2017.
All research outputs
#20,660,571
of 25,382,440 outputs
Outputs from Drug Design, Development and Therapy
#1,436
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Outputs of similar age
#249,416
of 323,961 outputs
Outputs of similar age from Drug Design, Development and Therapy
#44
of 59 outputs
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