| Title |
Versatile inhibitory effects of the flavonoid‐derived PI3K/Akt inhibitor, LY294002, on ATP‐binding cassette transporters that characterize stem cells
|
|---|---|
| Published in |
Clinical and Translational Medicine, October 2012
|
| DOI | 10.1186/2001-1326-1-24 |
| Pubmed ID | |
| Authors |
Yasuo Imai, Hidetsugu Yamagishi, Yuko Ono, Yoshihiko Ueda |
| Abstract |
Stem cells are undifferentiated cells capable of proliferation, self-renewal, and production of a large number of differentiated progeny. Stem cells exist even in malignancies. They are called cancer stem cells, which may represent the origin of these tumors and may be one of the reasons of chemoresistance. The phosphatidylinositol-3-kinase (PI3K)/Akt pathway is important for the maintenance of pluripotency in stem cells. Flow cytometry assay for identifying stem cells defines a side population of cells that displays low fluorescent dye and is highly enriched for stem cells. The dye efflux is attributed to expression of ATP-binding cassette transporters such as P-glycoprotein and breast cancer resistance protein (BCRP)/ABCG2, which also transport a variety of anticancer drugs. The PI3K/Akt pathway can modulate functions of ABC transporters through various mechanisms. Reportedly, inhibition of the PI3K/Akt pathway caused BCRP translocation in hematopoietic stem cells and glioma stem-like cells. On the other hand, a PI3K inhibitor, LY294002, reversed multidrug resistance in cancer cells that overexpress BCRP not by affecting BCRP translocation but putatively as a competitive inhibitor. Other PI3K inhibitors, wortmannin and PI-103, did not reverse BCRP-mediated drug resistance. Since LY294002 is a derivative of quercetin that is a naturally occurring flavonoid, its chemical structure is similar to those of a group of flavonoids but those of wortmannin and PI-103 are quite different. It is known that many flavonoids are inhibitors of BCRP and PI3K. LY294002 has also been reported to exert inhibitory effects on multidrug resistance-associated protein 1 (MRP1) function via dual mechanisms, competitive block of substrate transport and modulation of expression. Furthermore, LY294002 has been found to antagonize transport activity of P-glycoprotein without influencing its expression. Taken together, LY294002 can inhibit all BCRP, P-glycoprotein, and MRP1, which are three major ABC transporters that are highly expressed in stem cells and cause multidrug resistance. Due to its versatile effects, LY294002 could be a lead compound for developing more effective and tolerable reagents for cancer treatment. |
X Demographics
The data shown below were collected from the profile of 1 X user who shared this research output. Click here to find out more about how the information was compiled.
Geographical breakdown
| Country | Count | As % |
|---|---|---|
| United States | 1 | 100% |
Demographic breakdown
| Type | Count | As % |
|---|---|---|
| Members of the public | 1 | 100% |
Mendeley readers
The data shown below were compiled from readership statistics for 39 Mendeley readers of this research output. Click here to see the associated Mendeley record.
Geographical breakdown
| Country | Count | As % |
|---|---|---|
| India | 1 | 3% |
| Unknown | 38 | 97% |
Demographic breakdown
| Readers by professional status | Count | As % |
|---|---|---|
| Student > Ph. D. Student | 12 | 31% |
| Student > Master | 10 | 26% |
| Student > Bachelor | 5 | 13% |
| Researcher | 2 | 5% |
| Other | 1 | 3% |
| Other | 3 | 8% |
| Unknown | 6 | 15% |
| Readers by discipline | Count | As % |
|---|---|---|
| Agricultural and Biological Sciences | 13 | 33% |
| Biochemistry, Genetics and Molecular Biology | 7 | 18% |
| Medicine and Dentistry | 5 | 13% |
| Chemistry | 3 | 8% |
| Mathematics | 1 | 3% |
| Other | 5 | 13% |
| Unknown | 5 | 13% |
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 03 February 2013.
All research outputs
#19,942,887
of 25,371,288 outputs
Outputs from Clinical and Translational Medicine
#712
of 1,060 outputs
Outputs of similar age
#144,535
of 192,746 outputs
Outputs of similar age from Clinical and Translational Medicine
#4
of 9 outputs
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