Role of the ABCG2 drug transporter in the resistance and oral bioavailability of a potent cyclin-dependent kinase/Aurora kinase inhibitor

Seamon, Jennifer A.; Rugg, Catherine A.; Emanuel, Stuart L.; Calcagno, Anna Maria; Ambudkar, Suresh V.; Middleton, Steven A.; Butler, Jeannene; Borowski, Virna; Greenberger, Lee M.

doi:10.1158/1535-7163.mct-06-0339

Cited by 55 publications

(31 citation statements)

References 28 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…32 For example, BCRP was shown to confer resistance to the cyclin-dependent kinase and Aurora kinase inhibitor, JNJ-7706621, in cells propagated in the presence of the drug. 33 Interestingly, both BCRP expression and resistance to JNJ-7706621 were fully reversed following drug withdrawal, 33 indicating that BRCP-mediated resistance does not require a genomic alteration. Activation of nuclear hormone receptors 34 and promoter methylation 35 have been demonstrated to control the transcription of BCRP.…”

Section: Discussionmentioning

confidence: 99%

Identification of genes that confer tumor cell resistance to the Aurora B kinase inhibitor, AZD1152

et al. 2009

View full text Add to dashboard Cite

Section: Discussionmentioning

confidence: 99%

Identification of genes that confer tumor cell resistance to the Aurora B kinase inhibitor, AZD1152

et al. 2009

View full text Add to dashboard Cite

“…ABCG2 mRNA expression was higher compared to other efflux transporter in the human small intestine, which is a rate-limiting barrier to oral drug absorption [64] . The important impact of ABCG2 on the intestinal absorption was further supported by several knockout mice research, which have indicated that ABCG2 affects the pharmacological and toxicological behavior of many drugs [65][66][67] . Also, polymorphisms might influence the role of ABCG2 in intestinal absorption.…”

Section: Breast Cancer Resistance Proteinmentioning

confidence: 89%

How to overcome ATP-binding cassette drug efflux transporter-mediated drug resistance?

Jaramillo¹,

Saig²,

Cloos³

et al. 2018

CDR

View full text Add to dashboard Cite

P-glycoprotein (ABCB1), multidrug resistance protein-1 (ABCC1) and breast cancer resistance protein (ABCG2) belong to the ATP-binding cassette (ABC) superfamily of proteins that play an important physiological role in protection of the body from toxic xenobiotics and endogenous metabolites. Beyond this, these transporters determine the toxicity profile of many drugs, and confer multidrug resistance (MDR) in cancer cells associated with a poor treatment outcome of cancer patients.It has long been hypothesized that inhibition of ABC drug efflux transporters will increase drug accumulation and thereby overcome MDR, but until now no approved inhibitor of these transporters is available in the clinic. In this review we present molecular strategies to overcome this type of drug resistance and discuss for each of these strategies their promising value or indicate underlying reasons for their limited success.

show abstract

“…Several researchers have reported high levels of ABCG2 in the digestive tract (47), suggesting a role for ABCG2 in the oral bioavailability of substrate drugs. This has been reported even for drugs currently in clinical development (48). To increase oral bioavailability, coadministration of ABCG2 substrate drugs with ABCG2 inhibitors has been suggested.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of ABCG2-mediated transport by protein kinase inhibitors with a bisindolylmaleimide or indolocarbazole structure

Robey

Shukla

Steadman³

et al. 2007

Molecular Cancer Therapeutics

Self Cite

View full text Add to dashboard Cite

ABCG2 is a transporter with potential importance in cancer drug resistance, drug oral absorption, and stem cell biology. In an effort to identify novel inhibitors of ABCG2, we examined the ability of commercially available bisindolylmaleimides (BIM) and indolocarbazole protein kinase inhibitors (PKI) to inhibit ABCG2, given the previous demonstration that the indolocarbazole PKI UCN-01 interacted with the transporter. At a concentration of 10 Mmol/L, all of the compounds tested increased intracellular fluorescence of the ABCG2-specific substrate pheophorbide a in ABCG2-transfected HEK-293 cells by 1.3-to 6-fold as measured by flow cytometry; the ABCG2-specific inhibitor fumitremorgin C increased intracellular fluorescence by 6.6-fold. In 4-day cytotoxicity assays, wild-type ABCG2-transfected cells were not more than 2-fold resistant to any of the compounds, suggesting that the PKIs are not significantly transported by ABCG2. BIMs I, II, III, IV, and V, K252c, and arcyriaflavin A were also able to inhibit [ 125 I]iodoarylazidoprazosin labeling of ABCG2 by 65% to 80% at 20 Mmol/L, compared with a 50% to 70% reduction by 20 Mmol/L fumitremorgin C. K252c and arcyriaflavin A were the most potent compounds, with IC 50 values for inhibition of [ 125 I]iodoarylazidoprazosin labeling of 0.37 and 0.23 Mmol/L, respectively. K252c and arcyriaflavin A did not have any effect on the ATPase activity of ABCG2. Four minimally toxic compounds-BIM IV, BIM V, arcyriaflavin A, and K252c-reduced the relative resistance of ABCG2-transfected cells to SN-38 in cytotoxicity assays. We find that indolocarbazole and BIM PKIs directly interact with the ABCG2 protein and may thus increase oral bioavailability of ABCG2 substrates.

show abstract

Role of the ABCG2 drug transporter in the resistance and oral bioavailability of a potent cyclin-dependent kinase/Aurora kinase inhibitor

Cited by 55 publications

References 28 publications

Identification of genes that confer tumor cell resistance to the Aurora B kinase inhibitor, AZD1152

Identification of genes that confer tumor cell resistance to the Aurora B kinase inhibitor, AZD1152

How to overcome ATP-binding cassette drug efflux transporter-mediated drug resistance?

Inhibition of ABCG2-mediated transport by protein kinase inhibitors with a bisindolylmaleimide or indolocarbazole structure

Contact Info

Product

Resources

About