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Discovery and characterization of Isofistularin-3, a marine brominated alkaloid, as a new DNA demethylating agent inducing cell cycle arrest and sensitization to TRAIL in cancer cells

Overview of attention for article published in Oncotarget, March 2016
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Title
Discovery and characterization of Isofistularin-3, a marine brominated alkaloid, as a new DNA demethylating agent inducing cell cycle arrest and sensitization to TRAIL in cancer cells
Published in
Oncotarget, March 2016
DOI 10.18632/oncotarget.8210
Pubmed ID
Authors

Florean, Cristina, Schnekenburger, Michael, Lee, Jin-Young, Kim, Kyung Rok, Mazumder, Aloran, Song, Sungmi, Kim, Jae-Myun, Grandjenette, Cindy, Kim, Jeoung-Gyun, Yoon, Ah-Young, Dicato, Mario, Kim, Kyu-Won, Christov, Christo, Han, Byung-Woo, Proksch, Peter, Diederich, Marc

Abstract

We characterized the brominated alkaloid Isofistularin-3 (Iso-3), from the marine sponge Aplysina aerophoba, as a new DNA methyltransferase (DNMT)1 inhibitor. Docking analysis confirmed our in vitro DNMT inhibition data and revealed binding of Iso-3 within the DNA binding site of DNMT1. Subsequent increased expression of tumor suppressor gene aryl hydrocarbon receptor (AHR) could be correlated to decreased methylation of CpG sites within the essential Sp1 regulatory region of its promoter. Iso-3 induced growth arrest of cancer cells in G0/G1 concomitant with increased p21 and p27 expression and reduced cyclin E1, PCNA and c-myc levels. Reduced proliferation was accompanied by morphological changes typical of autophagy revealed by fluorescent and transmission electron microscopy and validated by LC3I-II conversion. Furthermore, Iso-3 strongly synergized with tumor-necrosis-factor related apoptosis inducing ligand (TRAIL) in RAJI [combination index (CI) = 0.22] and U-937 cells (CI = 0.21) and increased TRAIL-induced apoptosis via a mechanism involving reduction of survivin expression but not of Bcl-2 family proteins nor X-linked inhibitor of apoptosis protein (XIAP). Iso-3 treatment decreased FLIPL expression and triggered activation of endoplasmatic reticulum (ER) stress with increased GRP78 expression, eventually inducing TRAIL receptor death receptor (DR)5 surface expression. Importantly, as a potential candidate for further anticancer drug development, Iso-3 reduced the viability, colony and in vivo tumor forming potential without affecting the viability of PBMCs from healthy donors or zebrafish development.

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Mendeley readers

The data shown below were compiled from readership statistics for 27 Mendeley readers of this research output. Click here to see the associated Mendeley record.

Geographical breakdown

Country Count As %
Unknown 27 100%

Demographic breakdown

Readers by professional status Count As %
Student > Ph. D. Student 5 19%
Unspecified 4 15%
Student > Bachelor 4 15%
Librarian 2 7%
Student > Master 2 7%
Other 10 37%
Readers by discipline Count As %
Biochemistry, Genetics and Molecular Biology 8 30%
Unspecified 7 26%
Medicine and Dentistry 4 15%
Chemistry 3 11%
Pharmacology, Toxicology and Pharmaceutical Science 2 7%
Other 3 11%

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 24 March 2016.
All research outputs
#5,626,705
of 7,435,912 outputs
Outputs from Oncotarget
#3,449
of 6,698 outputs
Outputs of similar age
#193,604
of 275,323 outputs
Outputs of similar age from Oncotarget
#212
of 367 outputs
Altmetric has tracked 7,435,912 research outputs across all sources so far. This one is in the 13th percentile – i.e., 13% of other outputs scored the same or lower than it.
So far Altmetric has tracked 6,698 research outputs from this source. They receive a mean Attention Score of 2.9. This one is in the 26th percentile – i.e., 26% of its peers scored the same or lower than it.
Older research outputs will score higher simply because they've had more time to accumulate mentions. To account for age we can compare this Altmetric Attention Score to the 275,323 tracked outputs that were published within six weeks on either side of this one in any source. This one is in the 15th percentile – i.e., 15% of its contemporaries scored the same or lower than it.
We're also able to compare this research output to 367 others from the same source and published within six weeks on either side of this one. This one is in the 12th percentile – i.e., 12% of its contemporaries scored the same or lower than it.