| Title |
Combined treatment with metformin and gefitinib overcomes primary resistance to EGFR-TKIs with EGFR mutation via targeting IGF-1R signaling pathway
|
|---|---|
| Published in |
Biologics: Targets & Therapy, August 2018
|
| DOI | 10.2147/btt.s166867 |
| Pubmed ID | |
| Authors |
Yong-hong Pan, Lin Jiao, Cai-yu Lin, Cong-hua Lu, Li Li, Heng-yi Chen, Yu-bo Wang, Yong He |
| Abstract |
Although EGFR tyrosine kinase inhibitors (TKIs) have shown dramatic effects against sensitizing EGFR mutations in non-small cell lung cancer (NSCLC), ~20%-30% of NSCLC patients with EGFR-sensitive mutation exhibit intrinsic resistance to EGFR-TKIs. The purpose of the current study was to investigate the enhanced antitumor effect of metformin (Met), a biguanide drug, in combination with gefitinib (Gef) in primary resistant human lung cancer cells and the associated molecular mechanism. H1975 cell line was treated with Met and/or Gef to examine the inhibition of cell growth and potential mechanism of action by using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), Ki67 incorporation assay, flow cytometry analysis, small interfering RNA technology, Western blot analysis and xenograft implantation. Insulin-like growth factor-1 receptor (IGF-1R) signaling pathway was markedly activated in EGFR-TKI primary resistant H1975 cells as compared to EGFR-TKI acquired resistance cells (PC-9GR, H1650-M3) and EGFR-TKI sensitivity cells (PC-9, HCC827). Inhibition of IGF-1R activity by AG-1024 (a small molecule of IGF-1R inhibitor), as well as downregulation of IGF-1R by siRNA, significantly enhanced the ability of Gef to suppress proliferation and induce apoptosis in H1975 cells via the inhibition of AKT activation and subsequent upregulation of Bcl-2-interacting mediator of cell death (BIM). Interestingly, the observation showed that Met combined with Gef treatment had similar tumor growth suppression effects in comparison with the addition of AG-1024 to therapy with Gef. A clear synergistic antiproliferative interaction between Met and Gef was observed with a combination index (CI) value of 0.65. Notably, IGF-1R silencing mediated by RNA interference (RNAi) attenuated anticancer effects of Met without obviously resensitizing H1975 cells to Gef. Finally, Met-based combinatorial therapy effectively blocked tumor growth in the xenograft with TKI primary resistant lung cancer cells. Our findings demonstrated that Met combined with Gef would be a promising strategy to overcome EGFR-TKI primary resistance via suppressing IGF-1R signaling pathway in NSCLC. |
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 % |
|---|---|---|
| Serbia | 1 | 50% |
| Unknown | 1 | 50% |
Demographic breakdown
| Type | Count | As % |
|---|---|---|
| Members of the public | 1 | 50% |
| Science communicators (journalists, bloggers, editors) | 1 | 50% |
Mendeley readers
The data shown below were compiled from readership statistics for 28 Mendeley readers of this research output. Click here to see the associated Mendeley record.
Geographical breakdown
| Country | Count | As % |
|---|---|---|
| Unknown | 28 | 100% |
Demographic breakdown
| Readers by professional status | Count | As % |
|---|---|---|
| Student > Master | 5 | 18% |
| Student > Ph. D. Student | 4 | 14% |
| Researcher | 3 | 11% |
| Student > Bachelor | 1 | 4% |
| Other | 1 | 4% |
| Other | 2 | 7% |
| Unknown | 12 | 43% |
| Readers by discipline | Count | As % |
|---|---|---|
| Biochemistry, Genetics and Molecular Biology | 6 | 21% |
| Pharmacology, Toxicology and Pharmaceutical Science | 5 | 18% |
| Agricultural and Biological Sciences | 1 | 4% |
| Medicine and Dentistry | 1 | 4% |
| Neuroscience | 1 | 4% |
| Other | 1 | 4% |
| Unknown | 13 | 46% |
Attention Score in Context
This research output has an Altmetric Attention Score of 3. 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 28 August 2021.
All research outputs
#14,467,433
of 25,498,750 outputs
Outputs from Biologics: Targets & Therapy
#155
of 285 outputs
Outputs of similar age
#165,902
of 342,157 outputs
Outputs of similar age from Biologics: Targets & Therapy
#2
of 3 outputs
Altmetric has tracked 25,498,750 research outputs across all sources so far. This one is in the 42nd percentile – i.e., 42% of other outputs scored the same or lower than it.
So far Altmetric has tracked 285 research outputs from this source. They typically receive a little more attention than average, with a mean Attention Score of 6.2. This one is in the 45th percentile – i.e., 45% of its peers scored the same or lower than it.
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We're also able to compare this research output to 3 others from the same source and published within six weeks on either side of this one.