Evidence map›Paper›PMID 27821815›Full record

ArticleOncotarget2016

Everolimus (RAD001) sensitizes prostate cancer cells to docetaxel by down-regulation of HIF-1α and sphingosine kinase 1.

Heba Alshaker, Qi Wang, Yoshiaki Kawano, Tawfiq Arafat, Torsten Böhler, Mathias Winkler, Colin Cooper, Dmitri Pchejetski

Open access · diamondAbstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Oncotarget, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 24 papers.

0numbers the graph read from it
0cells of the map it votes in
24citing papers in PubMed
3.0field-weighted citation impact, top 9% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

24 citing papers in PubMed, 35 citations in OpenAlex.

  1. Article
  2. Review
  3. Review
  4. Review
  5. Review
  6. Review
  7. Review
  8. Review
  9. Review
  10. Review
  11. Review
  12. Review
  13. Article
  14. Article
  15. Article
  16. Article
  17. Article
  18. Article
  19. Article
  20. Article
4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

8 authors at 3 institutions in 2 countries.

Heba AlshakerSchool of Medicine, University of East Anglia, Norwich, UK.
Qi WangSchool of Medicine, University of East Anglia, Norwich, UK.
Yoshiaki KawanoDepartment of Urology, University of Kumamoto, Kumamoto, Japan.
Tawfiq ArafatDepartment of Pharmaceutical Medicinal Chemistry and Pharmacognosy, Faculty of Pharmacy and Medical Sciences, University of Petra, Amman, Jordan.
Torsten BöhlerDepartment of Surgery and Cancer, Imperial College London, London, UK.
Mathias WinklerDepartment of Surgery and Cancer, Imperial College London, London, UK.
Colin CooperSchool of Medicine, University of East Anglia, Norwich, UK.
Dmitri PchejetskiSchool of Medicine, University of East Anglia, Norwich, UK.
University of East Anglia · GBImperial College London · GBPetra University · JO

Funding

No grant is acknowledged in the PubMed record.

6 · The paper itself

Abstract

Resistance to docetaxel is a key problem in current prostate cancer management. Sphingosine kinase 1 (SK1) and phosphoinositide 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) pathways have been implicated in prostate cancer chemoresistance. Here we investigated whether their combined targeting may re-sensitize prostate cancer cells to docetaxel.In hormone-insensitive PC-3 and DU145 prostate cancer cells the mTOR inhibitor everolimus (RAD001) alone did not lead to significant cell death, however, it strongly sensitized cells to low levels (5 nM) of docetaxel. We show that mTOR inhibition has led to a decrease in hypoxia-inducible factor-1α (HIF-1α) protein levels and SK1 mRNA. HIF-1α accumulation induced by CoCl2 has led to a partial chemoresistance to RAD001/docetaxel combination. SK1 overexpression has completely protected prostate cancer cells from RAD001/docetaxel effects. Using gene knockdown and CoCl2 treatment we showed that SK1 mRNA expression is downstream of HIF-1α. In a human xenograft model in nude mice single RAD001 and docetaxel therapies induced 23% and 15% reduction in prostate tumor volume, respectively, while their combination led to a 58% reduction. RAD001 alone or in combination with docetaxel has suppressed intratumoral mTOR and SK1 signaling, however as evidenced by tumor size, it required docetaxel for clinical efficacy. Combination therapy was well tolerated and had similar levels of toxicity to docetaxel alone.Overall, our data demonstrate a new mechanism of docetaxel sensitization in prostate cancer. This provides a mechanistic basis for further clinical application of RAD001/docetaxel combination in prostate cancer therapy.

Indexed as

AnimalsAntineoplastic Combined Chemotherapy ProtocolsCell Line, TumorCell SurvivalCobaltDocetaxelDose-Response Relationship, DrugDown-RegulationDrug Resistance, NeoplasmDrug SynergismEverolimusGene Expression Regulation, EnzymologicGene Expression Regulation, NeoplasticHumansHypoxia-Inducible Factor 1, alpha SubunitMaleCobaltcobaltous chlorideDocetaxelEverolimusHIF1A protein, humanHypoxia-Inducible Factor 1, alpha SubunitMTOR protein, humanPhosphotransferases (Alcohol Group Acceptor)Sphingosine KinaseTaxoidsTOR Serine-Threonine Kinaseschemosensitizationdocetaxeleverolimus (RAD001)mTORprostate cancer

Identifiers

PMID27821815
PMCPMC5348367
OpenAlexW2546515194

What OpenQuestion holds

Textmetadata
LicenceCC BY
Read underepoch 390

Registered trials

None linked

Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.