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Microenvironmental effects limit efficacy of thymoquinone treatment in a mouse model of ovarian cancer

Overview of attention for article published in Molecular Cancer, November 2015
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Title
Microenvironmental effects limit efficacy of thymoquinone treatment in a mouse model of ovarian cancer
Published in
Molecular Cancer, November 2015
DOI 10.1186/s12943-015-0463-5
Pubmed ID
Authors

Andrew J. Wilson, Jeanette Saskowski, Whitney Barham, Dineo Khabele, Fiona Yull

Abstract

Ovarian cancer is the most lethal gynecologic malignancy, with limited treatment options for chemoresistant disease. An important link between inflammation and peritoneal spread of ovarian cancer is NF-κB signaling. Thymoquinone (TQ) exerts multiple anti-tumorigenic cellular effects, including NF-κB inhibition. We aimed to investigate the therapeutic potential of TQ in an established murine syngeneic model of ovarian cancer. ID8-NGL mouse ovarian cancer cells stably expressing an NF-κB reporter transgene were injected intra-peritoneally into C57BL/6 mice, and mice were treated with TQ or vehicle for 10 or 30 days. TQ was combined with the macrophage depleting drug, liposomal clodronate, in selected experiments. Effects on peritoneal tumor burden were measured by volume of ascites, number of peritoneal implants and mesenteric tumor mass. NF-κB reporter activity and markers of proliferation and apoptosis were measured in tumors and in confirmatory in vitro experiments. Protein or mRNA expression of M1 (anti-tumor) and M2 (pro-tumor) macrophage markers, and soluble cytokine profiles, were examined from harvested ascites fluid, peritoneal lavages and/or tumor sections. 2-tailed Mann-Whitney tests were used for measuring differences between groups in in vivo experiments. Consistent with its effects in vitro, TQ reduced proliferation and increased apoptosis in ID8-NGL tumors after 10 and 30 day treatment. Prolonged TQ treatment did not significantly alter tumor number or mass compared to vehicle, but rather exerted an overall deleterious effect by stimulating ascites formation. Increased ascites was accompanied by elevated NF-κB activity in tumors and macrophages, increased pro-tumor M2 macrophages and expression of pro-tumorigenic soluble factors such as VEGF in ascites fluid, and increased tumor infiltration of M2 macrophages. In contrast, a 10 day exposure to TQ produced no ascites, and reduced tumor NF-κB activity, M2 macrophages and soluble VEGF levels. Peritoneal macrophage depletion by clodronate significantly reduced tumor burden. However, TQ-stimulated ascites was further enhanced by co-treatment with clodronate, with macrophages present overwhelmingly of the M2 phenotype. Our findings show that pro-tumorigenic microenvironmental effects limited the efficacy of TQ in a syngeneic mouse model of ovarian cancer, and provide caution regarding its potential use in clinical trials in ovarian cancer patients.

Twitter Demographics

The data shown below were collected from the profile of 1 tweeter who shared this research output. Click here to find out more about how the information was compiled.

Mendeley readers

The data shown below were compiled from readership statistics for 41 Mendeley readers of this research output. Click here to see the associated Mendeley record.

Geographical breakdown

Country Count As %
United Kingdom 1 2%
Unknown 40 98%

Demographic breakdown

Readers by professional status Count As %
Student > Doctoral Student 7 17%
Student > Ph. D. Student 6 15%
Student > Master 6 15%
Researcher 5 12%
Lecturer 3 7%
Other 8 20%
Unknown 6 15%
Readers by discipline Count As %
Medicine and Dentistry 14 34%
Biochemistry, Genetics and Molecular Biology 7 17%
Agricultural and Biological Sciences 4 10%
Pharmacology, Toxicology and Pharmaceutical Science 2 5%
Immunology and Microbiology 1 2%
Other 2 5%
Unknown 11 27%

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 11 November 2015.
All research outputs
#5,595,736
of 6,559,289 outputs
Outputs from Molecular Cancer
#561
of 656 outputs
Outputs of similar age
#166,728
of 209,272 outputs
Outputs of similar age from Molecular Cancer
#35
of 43 outputs
Altmetric has tracked 6,559,289 research outputs across all sources so far. This one is in the 1st percentile – i.e., 1% of other outputs scored the same or lower than it.
So far Altmetric has tracked 656 research outputs from this source. They receive a mean Attention Score of 2.6. This one is in the 1st percentile – i.e., 1% of its peers scored the same or lower than it.
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We're also able to compare this research output to 43 others from the same source and published within six weeks on either side of this one. This one is in the 1st percentile – i.e., 1% of its contemporaries scored the same or lower than it.