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

Darby, Richard AJ, Unsworth, Amanda ORCID: https://orcid.org/0000-0003-3809-5984, Knapp, Stefan, Kerr, Ian D and Callaghan, Richard (2015) Overcoming ABCG2-mediated drug resistance with imidazo-[1,2-b]-pyridazine-based Pim1 kinase inhibitors. Cancer Chemotherapy and Pharmacology, 76 (4). pp. 853-864. ISSN 0344-5704

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Official URL: https://link.springer.com/article/10.1007%2Fs00280...

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.

Item Type:	Article
Peer-reviewed:	Yes
Date Deposited:	04 Apr 2019 10:08
Publisher:	Springer
Additional Information:	This is an Author Accepted Manuscript of an article in the journal Cancer Chemotherapy and Pharmacology, published by Springer.
Divisions:	Faculties > Science and Engineering
Subject terms:	Science & Technology, Life Sciences & Biomedicine, Oncology, Pharmacology & Pharmacy, Multidrug resistance, BCRP, ABCG2, Pim1 kinase, Cancer chemotherapy, HUMAN MULTIDRUG TRANSPORTER, CELL-SURFACE EXPRESSION, BREAST-CANCER CELLS, PROSTATE-CANCER, IN-VITRO, SUBSTRATE-SPECIFICITY, STRUCTURAL-ANALYSIS, PLASMA-MEMBRANE, PROTEIN-KINASE, Cell Line, Tumor, Humans, Imidazoles, Pyridazines, ATP-Binding Cassette Transporters, Neoplasm Proteins, Recombinant Proteins, Antineoplastic Agents, Drugs, Investigational, Protein Kinase Inhibitors, Inhibitory Concentration 50, Drug Resistance, Multiple, Cell Proliferation, Cell Survival, Down-Regulation, Biological Transport, Protein Transport, Drug Synergism, Drug Resistance, Neoplasm, Kinetics, Proto-Oncogene Proteins c-pim-1, ATP Binding Cassette Transporter, Sub-Family G, Member 2, ABCG2, BCRP, Cancer chemotherapy, Multidrug resistance, Pim1 kinase, ATP Binding Cassette Transporter, Subfamily G, Member 2, ATP-Binding Cassette Transporters, Antineoplastic Agents, Biological Transport, Cell Line, Tumor, Cell Proliferation, Cell Survival, Down-Regulation, Drug Resistance, Multiple, Drug Resistance, Neoplasm, Drug Synergism, Drugs, Investigational, Humans, Imidazoles, Inhibitory Concentration 50, Kinetics, Neoplasm Proteins, Protein Kinase Inhibitors, Protein Transport, Proto-Oncogene Proteins c-pim-1, Pyridazines, Recombinant Proteins, Science & Technology, Life Sciences & Biomedicine, Oncology, Pharmacology & Pharmacy, Multidrug resistance, BCRP, ABCG2, Pim1 kinase, Cancer chemotherapy, HUMAN MULTIDRUG TRANSPORTER, CELL-SURFACE EXPRESSION, BREAST-CANCER CELLS, PROSTATE-CANCER, IN-VITRO, SUBSTRATE-SPECIFICITY, STRUCTURAL-ANALYSIS, PLASMA-MEMBRANE, PROTEIN-KINASE, 1115 Pharmacology and Pharmaceutical Sciences, Oncology & Carcinogenesis
URI:	https://e-space.mmu.ac.uk/id/eprint/622749
DOI:	https://doi.org/10.1007/s00280-015-2858-9
ISSN	0344-5704
e-ISSN	1432-0843

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