| Title |
The redox antimalarial dihydroartemisinin targets human metastatic melanoma cells but not primary melanocytes with induction of NOXA-dependent apoptosis
|
|---|---|
| Published in |
Investigational New Drugs, May 2011
|
| DOI | 10.1007/s10637-011-9676-7 |
| Pubmed ID | |
| Authors |
Christopher M. Cabello, Sarah D. Lamore, Warner B. Bair, Shuxi Qiao, Sara Azimian, Jessica L. Lesson, Georg T. Wondrak |
| Abstract |
Recent research suggests that altered redox control of melanoma cell survival, proliferation, and invasiveness represents a chemical vulnerability that can be targeted by pharmacological modulation of cellular oxidative stress. The endoperoxide artemisinin and semisynthetic artemisinin-derivatives including dihydroartemisinin (DHA) constitute a major class of antimalarials that kill plasmodium parasites through induction of iron-dependent oxidative stress. Here, we demonstrate that DHA may serve as a redox chemotherapeutic that selectively induces melanoma cell apoptosis without compromising viability of primary human melanocytes. Cultured human metastatic melanoma cells (A375, G361, LOX) were sensitive to DHA-induced apoptosis with upregulation of cellular oxidative stress, phosphatidylserine externalization, and activational cleavage of procaspase 3. Expression array analysis revealed DHA-induced upregulation of oxidative and genotoxic stress response genes (GADD45A, GADD153, CDKN1A, PMAIP1, HMOX1, EGR1) in A375 cells. DHA exposure caused early upregulation of the BH3-only protein NOXA, a proapototic member of the Bcl2 family encoded by PMAIP1, and genetic antagonism (siRNA targeting PMAIP1) rescued melanoma cells from apoptosis indicating a causative role of NOXA-upregulation in DHA-induced melanoma cell death. Comet analysis revealed early DHA-induction of genotoxic stress accompanied by p53 activational phosphorylation (Ser 15). In primary human epidermal melanocytes, viability was not compromised by DHA, and oxidative stress, comet tail moment, and PMAIP1 (NOXA) expression remained unaltered. Taken together, these data demonstrate that metastatic melanoma cells display a specific vulnerability to DHA-induced NOXA-dependent apoptosis and suggest feasibility of future anti-melanoma intervention using artemisinin-derived clinical redox antimalarials. |
Mendeley readers
The data shown below were compiled from readership statistics for 58 Mendeley readers of this research output. Click here to see the associated Mendeley record.
Geographical breakdown
| Country | Count | As % |
|---|---|---|
| United Kingdom | 1 | 2% |
| Unknown | 57 | 98% |
Demographic breakdown
| Readers by professional status | Count | As % |
|---|---|---|
| Student > Ph. D. Student | 15 | 26% |
| Researcher | 10 | 17% |
| Student > Master | 7 | 12% |
| Other | 4 | 7% |
| Student > Doctoral Student | 3 | 5% |
| Other | 11 | 19% |
| Unknown | 8 | 14% |
| Readers by discipline | Count | As % |
|---|---|---|
| Agricultural and Biological Sciences | 15 | 26% |
| Medicine and Dentistry | 11 | 19% |
| Chemistry | 9 | 16% |
| Biochemistry, Genetics and Molecular Biology | 6 | 10% |
| Unspecified | 2 | 3% |
| Other | 5 | 9% |
| Unknown | 10 | 17% |
Attention Score in Context
This research output has an Altmetric Attention Score of 6. 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 05 December 2020.
All research outputs
#4,803,389
of 23,202,641 outputs
Outputs from Investigational New Drugs
#168
of 1,179 outputs
Outputs of similar age
#24,251
of 111,263 outputs
Outputs of similar age from Investigational New Drugs
#5
of 22 outputs
Altmetric has tracked 23,202,641 research outputs across all sources so far. Compared to these this one has done well and is in the 76th percentile: it's in the top 25% of all research outputs ever tracked by Altmetric.
So far Altmetric has tracked 1,179 research outputs from this source. They receive a mean Attention Score of 4.7. This one has done well, scoring higher than 79% 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 111,263 tracked outputs that were published within six weeks on either side of this one in any source. This one has gotten more attention than average, scoring higher than 72% of its contemporaries.
We're also able to compare this research output to 22 others from the same source and published within six weeks on either side of this one. This one has gotten more attention than average, scoring higher than 72% of its contemporaries.