Influence of multidrug resistance on (18)F-FCH cellular uptake in a glioblastoma model.
OBJECTIVE
Multidrug resistance, aggressiveness and accelerated choline metabolism are hallmarks of malignancy and have motivated the development of new PET tracers like (18)F-FCH, an analogue of choline. Our aim was to study the relationship of multidrug resistance of cultured glioma cell lines and (18)F-FCH tracer uptake.


METHODS
We used an in vitro multidrug-resistant (MDR) glioma model composed of sensitive parental U87MG and derived resistant cells U87MG-CIS and U87MG-DOX. Aggressiveness, choline metabolism and transport were studied, particularly the expression of choline kinase (CK) and high-affinity choline transporter (CHT1). FCH transport studies were assessed in our glioblastoma model.


RESULTS
As expected, the resistant cell lines express P-glycoprotein (Pgp), multidrug resistance-associated protein isoform 1 (MRP1) and elevated glutathione (GSH) content and are also more mobile and more invasive than the sensitive U87MG cells. Our results show an overexpression of CK and CHT1 in the resistant cell lines compared to the sensitive cell lines. We found an increased uptake of FCH (in % of uptake per 200,000 cells) in the resistant cells compared to the sensitive ones (U87MG: 0.89 +/- 0.14; U87MG-CIS: 1.27 +/- 0.18; U87MG-DOX: 1.33 +/- 0.13) in line with accelerated choline metabolism and aggressive phenotype.


CONCLUSIONS
FCH uptake is not influenced by the two ATP-dependant efflux pumps: Pgp and MRP1. FCH would be an interesting probe for glioma imaging which would not be effluxed from the resistant cells by the classic MDR ABC transporters. Our results clearly show that FCH uptake reflects accelerated choline metabolism and is related to tumour aggressiveness and drug resistance.
Vanpouille
Claire
C
Université de Lyon, Université Jean Monnet-Cancer Research Group IFRESIS 143, 42023, Saint-Etienne, France.
Le Jeune
Nathalie
N
Kryza
David
D
Clotagatide
Anthony
A
Janier
Marc
M
Dubois
Francis
F
Perek
Nathalie
N
D000818:Animals; D001692:Biological Transport; D045744:Cell Line, Tumor; D002794:Choline / Q000031:analogs & derivatives* / Q000378:metabolism; D002797:Choline Kinase / Q000378:metabolism; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D015972:Gene Expression Regulation, Neoplastic; D005909:Glioblastoma / Q000175:diagnosis / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D010641:Phenotype; D027981:Symporters / Q000378:metabolism
C510731:SLC5A7 protein, human; D027981:Symporters; C514960:fluorocholine; D002797:Choline Kinase; D002794:Choline