| Title |
The plant alkaloid and anti-leukemia drug homoharringtonine sensitizes resistant human colorectal carcinoma cells to TRAIL-induced apoptosis via multiple mechanisms
|
|---|---|
| Published in |
Apoptosis, March 2013
|
| DOI | 10.1007/s10495-013-0823-9 |
| Pubmed ID | |
| Authors |
Lenka Beranova, Antonio R. Pombinho, Jarmila Spegarova, Michal Koc, Magdalena Klanova, Jan Molinsky, Pavel Klener, Petr Bartunek, Ladislav Andera |
| Abstract |
TNF-related apoptosis-inducing ligand (TRAIL) is a pro-apoptotic ligand from the TNF-alpha family that is under consideration, along with agonistic anti-TRAIL receptor antibodies, as a potential anti-tumor agent. However, most primary human tumors are resistant to monotherapy with TRAIL apoptogens, and thus the potential applicability of TRAIL in anti-tumor therapy ultimately depends on its rational combination with drugs targeting these resistances. In our high-throughput screening for novel agents/drugs that could sensitize TRAIL-resistant colorectal cancer cells to TRAIL-induced apoptosis, we found homoharringtonine (HHT), a cephalotaxus alkaloid and tested anti-leukemia drug, to be a very effective, low nanomolar enhancer of TRAIL-mediated apoptosis/growth suppression of these resistant cells. Co-treatment of TRAIL-resistant RKO or HT-29 cells with HHT and TRAIL led to the effective induction of apoptosis and the complete elimination of the treated cells. HHT suppressed the expression of the anti-apoptotic proteins Mcl-1 and cFLIP and enhanced the TRAIL-triggered activation of JNK and p38 kinases. The shRNA-mediated down-regulation of cFLIP or Mcl-1 in HT-29 or RKO cells variably enhanced their TRAIL-induced apoptosis but it did not markedly sensitize them to TRAIL-mediated growth suppression. However, with the notable exception of RKO/sh cFLIP cells, the downregulation of cFLIP or Mcl-1 significantly lowered the effective concentration of HHT in HHT + TRAIL co-treatment. Combined HHT + TRAIL therapy also led to the strong suppression of HT-29 tumors implanted into immunodeficient mice. Thus, HHT represents a very efficient enhancer of TRAIL-induced apoptosis with potential application in TRAIL-based, anti-cancer combination therapy. |
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 % |
|---|---|---|
| Czechia | 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 27 Mendeley readers of this research output. Click here to see the associated Mendeley record.
Geographical breakdown
| Country | Count | As % |
|---|---|---|
| United States | 2 | 7% |
| Czechia | 1 | 4% |
| Unknown | 24 | 89% |
Demographic breakdown
| Readers by professional status | Count | As % |
|---|---|---|
| Student > Ph. D. Student | 5 | 19% |
| Other | 4 | 15% |
| Researcher | 4 | 15% |
| Student > Doctoral Student | 3 | 11% |
| Student > Master | 3 | 11% |
| Other | 4 | 15% |
| Unknown | 4 | 15% |
| Readers by discipline | Count | As % |
|---|---|---|
| Agricultural and Biological Sciences | 9 | 33% |
| Biochemistry, Genetics and Molecular Biology | 6 | 22% |
| Medicine and Dentistry | 6 | 22% |
| Chemistry | 2 | 7% |
| Business, Management and Accounting | 1 | 4% |
| Other | 0 | 0% |
| Unknown | 3 | 11% |
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 18 July 2013.
All research outputs
#14,755,656
of 22,714,025 outputs
Outputs from Apoptosis
#446
of 802 outputs
Outputs of similar age
#117,161
of 193,968 outputs
Outputs of similar age from Apoptosis
#2
of 9 outputs
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So far Altmetric has tracked 802 research outputs from this source. They receive a mean Attention Score of 3.6. This one is in the 41st percentile – i.e., 41% of its peers scored the same or lower than it.
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