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A drug screening assay on cancer cells chronically adapted to acidosis

Overview of attention for article published in Cancer Cell International, September 2018
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5 tweeters

Citations

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3 Dimensions

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21 Mendeley
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Title
A drug screening assay on cancer cells chronically adapted to acidosis
Published in
Cancer Cell International, September 2018
DOI 10.1186/s12935-018-0645-5
Pubmed ID
Authors

Paola Pellegrini, Jason T. Serviss, Thomas Lundbäck, Nicolo Bancaro, Magdalena Mazurkiewicz, Iryna Kolosenko, Di Yu, Martin Haraldsson, Padraig D’Arcy, Stig Linder, Angelo De Milito

Abstract

Drug screening for the identification of compounds with anticancer activity is commonly performed using cell lines cultured under normal oxygen pressure and physiological pH. However, solid tumors are characterized by a microenvironment with limited access to nutrients, reduced oxygen supply and acidosis. Tumor hypoxia and acidosis have been identified as important drivers of malignant progression and contribute to multicellular resistance to different forms of therapy. Tumor acidosis represents an important mechanism mediating drug resistance thus the identification of drugs active on acid-adapted cells may improve the efficacy of cancer therapy. Here, we characterized human colon carcinoma cells (HCT116) chronically adapted to grow at pH 6.8 and used them to screen the Prestwick drug library for cytotoxic compounds. Analysis of gene expression profiles in parental and low pH-adapted cells showed several differences relating to cell cycle, metabolism and autophagy. The screen led to the identification of several compounds which were further selected for their preferential cytotoxicity towards acid-adapted cells. Amongst 11 confirmed hits, we primarily focused our investigation on the benzoporphyrin derivative Verteporfin (VP). VP significantly reduced viability in low pH-adapted HCT116 cells as compared to parental HCT116 cells and normal immortalized epithelial cells. The cytotoxic activity of VP was enhanced by light activation and acidic pH culture conditions, likely via increased acid-dependent drug uptake. VP displayed the unique property to cause light-dependent cross-linking of proteins and resulted in accumulation of polyubiquitinated proteins without inducing inhibition of the proteasome. Our study provides an example and a tool to identify anticancer drugs targeting acid-adapted cancer cells.

Twitter Demographics

The data shown below were collected from the profiles of 5 tweeters 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 21 Mendeley readers of this research output. Click here to see the associated Mendeley record.

Geographical breakdown

Country Count As %
Unknown 21 100%

Demographic breakdown

Readers by professional status Count As %
Student > Bachelor 7 33%
Student > Master 6 29%
Student > Ph. D. Student 4 19%
Unknown 4 19%
Readers by discipline Count As %
Biochemistry, Genetics and Molecular Biology 8 38%
Medicine and Dentistry 4 19%
Earth and Planetary Sciences 1 5%
Immunology and Microbiology 1 5%
Agricultural and Biological Sciences 1 5%
Other 1 5%
Unknown 5 24%

Attention Score in Context

This research output has an Altmetric Attention Score of 2. 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 29 September 2018.
All research outputs
#7,825,026
of 13,571,692 outputs
Outputs from Cancer Cell International
#138
of 572 outputs
Outputs of similar age
#138,484
of 265,109 outputs
Outputs of similar age from Cancer Cell International
#1
of 1 outputs
Altmetric has tracked 13,571,692 research outputs across all sources so far. This one is in the 40th percentile – i.e., 40% of other outputs scored the same or lower than it.
So far Altmetric has tracked 572 research outputs from this source. They receive a mean Attention Score of 2.6. This one has gotten more attention than average, scoring higher than 73% of its peers.
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 265,109 tracked outputs that were published within six weeks on either side of this one in any source. This one is in the 44th percentile – i.e., 44% of its contemporaries scored the same or lower than it.
We're also able to compare this research output to 1 others from the same source and published within six weeks on either side of this one. This one has scored higher than all of them