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

Cancer Chemotherapy and Pharmacology
Richard A J DarbyRichard Callaghan

Abstract

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. 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. 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 [(3)H]-mitoxantrone, suggesting direct impairment of the transporter. However, prolonged pre-incubation with the studied inhibitors greatly enhanced the effect on mitoxantrone accumulation....Continue Reading

References

Nov 15, 1993·Proceedings of the National Academy of Sciences of the United States of America·T MöröyK U Hartmann
Jan 1, 1997·Biochemistry and Cell Biology = Biochimie Et Biologie Cellulaire·C K PalatyS L Pelech
Jun 13, 1998·Journal of the National Cancer Institute·D A ScudieroE A Sausville
Nov 11, 1998·Molecular Cell·J D LeversonS A Ness
Dec 23, 1998·Proceedings of the National Academy of Sciences of the United States of America·L A DoyleD D Ross
Jul 5, 2001·Biochemical and Biophysical Research Communications·C OzvegyB Sarkadi
Jul 10, 2003·The Journal of Biological Chemistry·Masaki MogiKenneth Walsh
Jul 21, 2004·Biochemistry·Orsolya PolgarSusan E Bates
Nov 5, 2004·The Journal of Biological Chemistry·Kevin C QianBennett Farmer
Feb 8, 2005·The International Journal of Biochemistry & Cell Biology·Malte Bachmann, Tarik Möröy
Apr 22, 2005·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Tappei TakadaYuichi Sugiyama
Aug 19, 2005·The Journal of Biological Chemistry·Ulla HenriksenUlrik Gether
Oct 18, 2005·The Journal of Biological Chemistry·Alex N BullockBenjamin E Turk
Nov 14, 2006·Structure·Christopher A McDevittRichard Callaghan
Feb 27, 2007·Cancer Metastasis Reviews·Robert W RobeySusan E Bates
Dec 25, 2007·Journal of Clinical Pharmacology·Richard CallaghanIan D Kerr
Aug 22, 2008·European Journal of Cancer : Official Journal for European Organization for Research and Treatment of Cancer (EORTC) [and] European Association for Cancer Research (EACR)·Nilesh ShahManuel Salto-Tellez
Oct 7, 2008·European Journal of Pharmacology·Francesca RiversRichard Callaghan
Dec 15, 2010·Journal of Experimental & Clinical Cancer Research : CR·Shengjie GuoShaopeng Qiu
May 24, 2011·Drug Resistance Updates : Reviews and Commentaries in Antimicrobial and Anticancer Chemotherapy·Methvin IsaacJan Jongstra
Jul 23, 2011·Current Drug Targets·Ronan SwordsFrancis Giles

❮ Previous
Next ❯

Citations

Mar 9, 2018·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Rebecca R CrawfordJohn D Schuetz
Feb 11, 2021·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Bruno OyallonCaroline Denevault-Sabourin
May 15, 2020·Journal of Chemical Information and Modeling·Gudong LiYu Zhou

❮ Previous
Next ❯

Related Concepts

Related Feeds

Antimicrobial Resistance (ASM)

Antimicrobial resistance poses a significant threat to the continued successful use of antimicrobial agents for the treatment of bacterial infections.

Antimicrobial Resistance

Antimicrobial resistance poses a significant threat to the continued successful use of antimicrobial agents for the treatment of bacterial infections.