Human dihydrofolate reductase influences the sensitivity of the malaria parasite Plasmodium falciparum to ketotifen - A cautionary tale in screening transgenic parasites.

Phuong N Tran, Cameron J Tate, Melanie C Ridgway, Kevin J Saliba, Kiaran Kirk, Alexander G Maier

Open access · goldAbstract read

In one paragraph

Article in International journal for parasitology. Drugs and drug resistance, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 4 papers.

0numbers the graph read from it

0cells of the map it votes in

4citing papers in PubMed

–field-weighted citation impact, top 87% 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

4 citing papers in PubMed, 5 citations in OpenAlex.

Development of QSAR Models and Web Applications for Predicting hDHFR Inhibitor Bioactivity Using Machine Learning.Molecules (Basel, Switzerland) · 2025
Article
Single- and duplex TaqMan-quantitative PCR for determining the copy numbers of integrated selection markers during site-specific mutagenesis in Toxoplasma gondii by CRISPR-Cas9.PloS one · 2022
Article
Incomptine A Induces Apoptosis, ROS Production and a Differential Protein Expression on Non-Hodgkin's Lymphoma Cells.International journal of molecular sciences · 2021
Article
In Silico Study Identified Methotrexate Analog as Potential Inhibitor of Drug Resistant Human Dihydrofolate Reductase for Cancer Therapeutics.Molecules (Basel, Switzerland) · 2020
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

6 authors at 1 institution in 1 country.

Phuong N TranResearch School of Biology, The Australian National University, Canberra, ACT, 2601, Australia.

Cameron J TateResearch School of Biology, The Australian National University, Canberra, ACT, 2601, Australia.

Melanie C RidgwayResearch School of Biology, The Australian National University, Canberra, ACT, 2601, Australia.

Kevin J SalibaResearch School of Biology, The Australian National University, Canberra, ACT, 2601, Australia; Medical School, The Australian National University, Canberra, ACT, 2601, Australia.

Kiaran KirkResearch School of Biology, The Australian National University, Canberra, ACT, 2601, Australia.

Alexander G MaierResearch School of Biology, The Australian National University, Canberra, ACT, 2601, Australia. Electronic address: alex.maier@anu.edu.au.

Australian National University · AU

Funding

No grant is acknowledged in the PubMed record.

6 · The paper itself

Abstract

Ketotifen has recently been reported to inhibit the growth of both asexual and sexual malaria parasites. A parasite transporter, PfgABCG2, has been implicated in its mechanism of action. Human dihydrofolate reductase (hDHFR) is the most commonly used selectable marker to create transgenic Plasmodium falciparum cell lines. Growth assays using transgenic P. falciparum parasites with different selectable markers revealed that the presence of hDHFR rather than the absence of PfgABCG2 is responsible for a shift in the parasite's sensitivity to ketotifen. Employing a range of in vitro assays and liquid chromatography-mass spectrometry we show that ketotifen influences hDHFR activity, but it is not metabolised by the enzyme. Our data also highlights potential pitfalls when functionally characterising transgenic parasites.

Indexed as

AntimalarialsDrug Evaluation, PreclinicalGene ExpressionHumansKetotifenParasitic Sensitivity TestsPlasmodium falciparumRecombinant ProteinsTetrahydrofolate DehydrogenaseAntimalarialsKetotifenRecombinant ProteinsTetrahydrofolate DehydrogenaseFolatehDHFRKetotifen fumarateMalariaPlasmodium falciparumSelectable markerTransfection

Identifiers

PMID27705841

DOI10.1016/j.ijpddr.2016.09.003

PMCPMC5050295

OpenAlexW2521296486

What OpenQuestion holds

Textmetadata

LicenceCC BY-NC-ND

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.