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27-10-2016 | Chronic myeloid leukaemia | News | Article

MATE1 protein crucial for imatinib uptake

medwireNews: Cellular uptake of the tyrosine kinase inhibitor (TKI) imatinib may be regulated by the multidrug and toxin extrusion protein (MATE)1, suggests research published in Blood Cancer Journal.

The study investigators compared the imatinib transport capacity of MATE1 in cells with that of other possible transporters, including the organic cation transporter (OCT)1, which has previously been linked to imatinib uptake in patients with chronic myeloid leukaemia (CML).

They calculated that MATE1 binds to imatinib with a strong affinity when exposed to a plasma level that would be achieved by a clinically relevant daily dose of 400 mg or 600 mg. The OCT2 transporter binds to imatinib with a lower affinity but still within a clinically relevant concentration, whereas OCT1 did not.

The researchers showed that imatinib uptake occurs as an active process rather than by passive diffusion by comparing uptake at different temperatures and found that selective inhibition of MATE1 significantly reduced imatinib uptake in peripheral blood mononuclear cells whereas blocking OCT1 and OCT2 had no significant impact.

Gene knockdown of MATE1 in the K562 CML cell line confirmed that lack of the transporter led to almost complete inhibition of imatinib uptake, say Giuliano Ciarimboli, from Universitätsklinikum Münster in Germany, and co-workers.

“These results clearly show that MATE1 is the major transporter for imatinib uptake in K562 cells and is probably crucial for its intracellular therapeutic effects”, they write.

Transporter profiling of bone marrow samples from CML patients indicated that OCT1 messenger (m)RNA levels did not significantly differ between patients who did and did not respond to imatinib therapy. By contrast, MATE1 mRNA expression was significantly higher in patients who responded to imatinib than those who did not.

 Indeed, the team found that MATE1 mRNA levels in bone marrow cells significantly correlated with clinical response to imatinib, “suggesting that MATE1 levels might […] predict whether CML patients are likely to respond to imatinib therapy”.

The authors conclude that MATE1 expression or MATE1 mutation analysis may have potential as a screening tool for clinicians prescribing TKIs to individual patients, helping them to “choose the best, safest and economically reasonable therapy.”

By Lynda Williams

medwireNews is an independent medical news service provided by Springer Healthcare Limited. © Springer Healthcare Ltd; 2016

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