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Overcoming ABCG2-mediated drug resistance with imidazo-[1,2-b]-pyridazine-based Pim1 kinase inhibitors

Darby, Richard A.J.; Kerr, Ian; Unsworth, Amanda; Knapp, Stefan; Callaghan, Richard

Authors

Richard A.J. Darby

IAN KERR ian.kerr@nottingham.ac.uk
Associate Professor

Amanda Unsworth

Stefan Knapp

Richard Callaghan



Abstract

Purpose

Multidrug efflux pumps such as ABCG2 confer drug resistance to a number of cancer types, leading to poor prognosis and outcome. To date, the strategy of directly inhibiting multidrug efflux pumps in order to overcome drug resistance in cancer has been unsuccessful. An alternative strategy is to target proteins involved in the regulation of multidrug efflux pump activity or expression. Pim1 kinase has been demonstrated to phosphorylate ABCG2, promote its oligomerisation and contribute to its ability to confer drug resistance.

Methods

In the present manuscript, imidazo-pyridazine-based inhibitors of Pim1 were examined for their ability to overcome ABCG2-mediated drug resistance. Drug efficacy was measured as a cytotoxic response or an effect on transport by ABCG2. Protein expression patterns were assessed using western immuno-blotting.

Results

The two Pim1 inhibitors increased the potency of flavopiridol, mitoxantrone, topotecan and doxorubicin, specifically in ABCG2-expressing cells. This effect was associated with an increase in the cellular accumulation of [3H]-mitoxantrone, suggesting direct impairment of the transporter. However, prolonged pre-incubation with the studied inhibitors greatly enhanced the effect on mitoxantrone accumulation. The inhibitors caused a significant time-dependent reduction in the expression of ABCG2 in the resistant cells, an effect that would improve drug efficacy.

Conclusion

Consequently, it appears that the Pim1 inhibitors display a dual-mode effect on ABCG2-expressing cancer cells. This may provide a powerful new strategy in overcoming drug resistance by targeting proteins that regulate expression of efflux pumps.

Citation

Darby, R. A., Kerr, I., Unsworth, A., Knapp, S., & Callaghan, R. (2015). Overcoming ABCG2-mediated drug resistance with imidazo-[1,2-b]-pyridazine-based Pim1 kinase inhibitors. Cancer Chemotherapy and Pharmacology, 76(4), 853-864. doi:10.1007/s00280-015-2858-9

Journal Article Type Article
Acceptance Date Aug 25, 2015
Publication Date Oct 1, 2015
Deposit Date Sep 29, 2017
Publicly Available Date Mar 29, 2024
Print ISSN 0344-5704
Electronic ISSN 1432-0843
Publisher BMC
Peer Reviewed Peer Reviewed
Volume 76
Issue 4
Pages 853-864
DOI https://doi.org/10.1007/s00280-015-2858-9
Public URL https://nottingham-repository.worktribe.com/output/1107701
Publisher URL https://link.springer.com/article/10.1007%2Fs00280-015-2858-9
PMID 00036149
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