Evidence map›Paper›PMID 24178759›Full record

ArticleBritish journal of cancer2014

Synergistic interaction of novel lactate dehydrogenase inhibitors with gemcitabine against pancreatic cancer cells in hypoxia.

M Maftouh, A Avan, R Sciarrillo, C Granchi, L G Leon, R Rani, N Funel, K Smid, R Honeywell, U Boggi and 3 more

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

Article in British journal of cancer, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 96 papers, 2 of them syntheses that pooled it.

0numbers the graph read from it
0cells of the map it votes in
96citing papers in PubMed, 2 pooled it
2.8field-weighted citation impact, top 10% 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

96 citing papers in PubMed, 2 syntheses or guidelines pooled it, 175 citations in OpenAlex.

  1. Pooled it
  2. Glucose metabolic phenotype of pancreatic cancer.World journal of gastroenterology · 2016
    Pooled it
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36 more citing papers are in PubMed but not listed here.

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

13 authors at 2 institutions in 2 countries.

M MaftouhDepartment of Medical Oncology, VU University Medical Center, De Boelelaan 1117, 1081HV, Amsterdam, Netherlands.
A AvanDepartment of Medical Oncology, VU University Medical Center, De Boelelaan 1117, 1081HV, Amsterdam, Netherlands.
R SciarrilloDepartment of Medical Oncology, VU University Medical Center, De Boelelaan 1117, 1081HV, Amsterdam, Netherlands.
C GranchiDepartment of Pharmacy, University of Pisa, Pisa, Italy.
L G LeonCenter for Biomedical Research of the Canary Islands, Instituto de Tecnologias Biomedicas, University of La Laguna, La Laguna, Spain.
R RaniDepartment of Pharmacy, University of Pisa, Pisa, Italy.
N FunelDepartment of Surgery, University of Pisa, Pisa, Italy.
K SmidDepartment of Medical Oncology, VU University Medical Center, De Boelelaan 1117, 1081HV, Amsterdam, Netherlands.
R HoneywellDepartment of Medical Oncology, VU University Medical Center, De Boelelaan 1117, 1081HV, Amsterdam, Netherlands.
U BoggiDepartment of Surgery, University of Pisa, Pisa, Italy.
F MinutoloDepartment of Pharmacy, University of Pisa, Pisa, Italy.
G J PetersDepartment of Medical Oncology, VU University Medical Center, De Boelelaan 1117, 1081HV, Amsterdam, Netherlands.
E GiovannettiDepartment of Medical Oncology, VU University Medical Center, De Boelelaan 1117, 1081HV, Amsterdam, Netherlands.
University of Pisa · ITUniversidad de La Laguna · ES

Funding

No grant is acknowledged in the PubMed record.

6 · The paper itself

Abstract

backgroundHypoxia is a driving force in pancreatic-ductal-adenocarcinoma (PDAC) growth, metastasis and chemoresistance. The muscle-isoform of lactate dehydrogenase (LDH-A) constitutes a major checkpoint for the switch to anaerobic glycolysis, ensuring supply of energy and anabolites in hypoxic-environments. Therefore, we investigated the molecular mechanisms underlying the pharmacological interaction of novel LDH-A inhibitors in combination with gemcitabine in PDAC cells.

methodsLactate dehydrogenase A levels were studied by quantitative RT-PCR, western blot, immunofluorescence and activity assays in 14 PDAC cells, including primary-cell-cultures and spheroids, in normoxic and hypoxic conditions. Cell proliferation, migration and key determinants of drug activity were evaluated by sulforhodamine-B-assay, wound-healing assay, PCR and LC-MS/MS.

resultsLactate dehydrogenase A was significantly increased under hypoxic conditions (1% O2), where the novel LDH-A inhibitors proved to be particularly effective (e.g., with IC50 values of 0.9 vs 16.3 μM for NHI-1 in LPC006 in hypoxia vs normoxia, respectively). These compounds induced apoptosis, affected invasiveness and spheroid-growth, reducing expression of metalloproteinases and cancer-stem-like-cells markers (CD133+). Their synergistic interaction with gemcitabine, with combination index values <0.4 in hypoxia, might also be attributed to modulation of gemcitabine metabolism, overcoming the reduced synthesis of phosphorylated metabolites.

conclusionLactate dehydrogenase A is a viable target in PDAC, and novel LDH-A inhibitors display synergistic cytotoxic activity with gemcitabine, offering an innovative tool in hypoxic tumours.

Indexed as

AC133 AntigenAnimalsAntigens, CDAntineoplastic Combined Chemotherapy ProtocolsCarcinoma, Pancreatic DuctalCell HypoxiaCell Line, TumorCell MovementDeoxycytidineDown-RegulationDrug SynergismEnhancer of Zeste Homolog 2 ProteinEnzyme InhibitorsGemcitabineGlycoproteinsIsoenzymesAC133 AntigenAntigens, CDDeoxycytidineEnhancer of Zeste Homolog 2 ProteinEnzyme InhibitorsEZH2 protein, humanGemcitabineGlycoproteinsIsoenzymesLactate Dehydrogenase 5L-Lactate DehydrogenaseMetalloproteasesPeptidesPolycomb Repressive Complex 2PROM1 protein, humanRNA, Messenger

Identifiers

PMID24178759
PMCPMC3887288
OpenAlexW1967673331

What OpenQuestion holds

Textmetadata
LicenceCC BY-NC-SA
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.