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Nilotinib does not significantly reduce imatinib OCT-1 activity in either cell lines or primary CML cells

Leukemia volume 24, pages 855–857 (2010)Cite this article

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The recently published study by Davies et al.,1 confirms previous data from our laboratory indicating that nilotinib, unlike imatinib, does not require the human organic cation transporter-1 (hOCT-1) for active transport into leukaemic cells.2 This study also confirms our own recent data that show the predominantly passive nature of nilotinib uptake in which maximum intracellular concentrations of between 300 and 400 ng of 14C-nilotinib per 200 000 cells are reached within the first 2 min of incubation. This peak is then followed by a rapid, temperature-sensitive, ATP-dependent decrease. Davies et al. suggest that the reduction in the intracellular concentration of imatinib in the presence of nilotinib is mediated through inhibition of the function of the OCT-1 protein.3 This finding could have significant implications for imatinib/nilotinib combination therapies and may adversely affect the action of concomitantly administered medications transported by OCT-1 (for example, metformin). We have previously shown in primary cells and cell lines that the addition of nilotinib to 14C-imatinib (IM) in the intracellular uptake and retention (IUR) assay resulted in a reduction in intracellular IM; however, this failed to reach statistical significance.4 For this study, we have performed a series of combination IUR2 and OCT-1 Activity assays3 to assess the effect of nilotinib on OCT-1 Activity, a measure previously shown to be highly predictive of patient response.3

To further investigate this, we also recapitulated the experiments of Davies et al., which suggested that higher concentrations of nilotinib (4 μM) reduced the uptake of the hOCT-1 substrate, Tetraethylammonium Bromide (TEA), and abolished imatinib uptake. However, we were unable to show any significant effects of 4 μM nilotinib on the intracellular concentrations of imatinib in either KCL22 or K562 cells (n=3) (Table 1a). Similarly, 4 μM nilotinib also had no significant effect on the uptake of TEA (5 μM; n=4 and 10 μM; n=2) in K562 cells (Table 1b).

Table 1a IUR of imatinib (IM) in K562 and KCL22 cells in the absence or presence of 4 μM nilotinib (NIL)
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Table 1b IUR of the OCT-1 substrate Tetraethylammonium Bromide (TEA) (5 and 10 μM) in K562 cells in the absence or presence of 4 μM nilotinib (NIL) over a period of 120 min
Full size table

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References

  1. Davies A, Jordanides NE, Giannoudis A, Lucas CM, Hatziieremia S, Harris RJ et al. Nilotinib concentration in cell lines and primary CD34(+) chronic myeloid leukemia cells is not mediated by active uptake or efflux by major drug transporters. Leukemia 2009; 23: 1999–2006.

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  2. White DL, Saunders VA, Dang P, Engler J, Zannettino AC, Cambareri AC et al. OCT-1-mediated influx is a key determinant of the intracellular uptake of imatinib but not nilotinib (AMN107): reduced OCT-1 activity is the cause of low in vitro sensitivity to imatinib. Blood 2006; 108: 697–704.

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  3. White DL, Saunders VA, Dang P, Engler J, Venables A, Zrim S et al. Most CML patients who have a suboptimal response to imatinib have low OCT-1 activity: higher doses of imatinib may overcome the negative impact of low OCT-1 activity. Blood 2007; 110: 4064–4072.

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  4. White DL, Saunders VA, Quinn SR, Manley PW, Hughes TP . Imatinib increases the intracellular concentration of nilotinib, which may explain the observed synergy between these drugs. Blood 2007; 109: 3609–3610.

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Acknowledgements

This research was supported by the Leukaemia Foundation of Australia. Special thanks to Novartis Pharmaceuticals for the provision of imatinib and nilotinib.

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Authors and Affiliations

  1. Department of Haematology, SA Pathology, Adelaide, South Australia, Australia

    L Eadie, T P Hughes & D L White

  2. Department of Medicine, University of Adelaide, Adelaide, South Australia, Australia

    L Eadie, T P Hughes & D L White

  3. Centre for Cancer Biology, SA Pathology, Adelaide, South Australia, Australia,

    T P Hughes & D L White

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  1. L Eadie
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  2. T P Hughes
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Correspondence to D L White.

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Competing interests

Deborah White and Timothy Hughes receive honoraria and research funds from Novartis Pharmaceuticals, and are members of the Advisory Boards for Novartis. However, Novartis had no role in the design of the study, collection and analysis of data nor the decision to publish. Laura Eadie has no conflict of interest to disclose.

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Eadie, L., Hughes, T. & White, D. Nilotinib does not significantly reduce imatinib OCT-1 activity in either cell lines or primary CML cells. Leukemia 24, 855–857 (2010). https://doi.org/10.1038/leu.2010.7

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