Comparison of ATP-Binding Cassette Transporter Interactions with the Tyrosine Kinase Inhibitors Imatinib, Nilotinib, and Dasatinib

Dohse, Marius; Scharenberg, Christian; Shukla, Suneet; Robey, Robert W.; Volkmann, Thorsten; Deeken, John F.; Brendel, Cornelia; Ambudkar, Suresh V.; Neubauer, Andreas; Bates, Susan E.

doi:10.1124/dmd.109.031302

Cited by 199 publications

(173 citation statements)

References 40 publications

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“…Nilotinib inhibited ABCB1-mediated Rhodamine-123 efflux in K562-Dox cells (Online Supplementary Figure S2A and B) which is consistent with previously published findings 18,19 and increases dasatinib IUR in K562-Dox cells. Figure S2C).…”

supporting

confidence: 81%

“…Dhose et al suggested that dasatinib is an ABCB1 inhibitor, but only at a very high concentration (10 mM) which is not achievable at therapeutic dosing schedule and, therefore, probably not clinically relevant. 19 Understanding these interactions can be clinically relevant for monitoring the drug level, dosing schedule and drugdrug interactions.…”

Section: Dasatinib Does Not Block Efflux Of Abcb1 Substratesmentioning

confidence: 99%

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Dasatinib targets chronic myeloid leukemia-CD34+ progenitors as effectively as it targets mature cells

et al. 2012

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supporting

confidence: 81%

Section: Dasatinib Does Not Block Efflux Of Abcb1 Substratesmentioning

confidence: 99%

Dasatinib targets chronic myeloid leukemia-CD34+ progenitors as effectively as it targets mature cells

et al. 2012

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“…It is assumed that uptake of nilotinib into K562/IM cells is reduced via P-gp compared to that into K562 cells when the incubation period was longer. Several previous studies have demonstrated that the cytotoxic effect of nilotinib in K562 cells overexpressing P-gp is decreased compared with that in the parent K562 cells, [30][31][32][33] and P-gp overexpression is one of the factors responsible for the development of nilotinib resistance.…”

Section: Discussionmentioning

confidence: 99%

Distinct Interaction of Nilotinib and Imatinib with P-Glycoprotein in Intracellular Accumulation and Cytotoxicity in CML Cell Line K562 Cells

Yamakawa

Hamada²,

Uchida

et al. 2014

Biological & Pharmaceutical Bulletin

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Nilotinib, a second-generation tyrosine kinase inhibitor (TKI), has been approved for first-line chronic myeloid leukemia (CML) treatment. The improved clinical response of nilotinib over that of the first generation TKI, imatinib, has been thought to be a result of its high potency of inhibition of BCR-ABL kinase. This study aimed to characterize differences between nilotinib and imatinib in the intracellular accumulation and cytotoxic effect on the CML cell line K562. Accumulation of nilotinib in K562 cells was from 4.7-to 9.0-fold higher than that of imatinib. The cytotoxic effect of nilotinib on K562 cells was 14.2-fold higher than that of imatinib. Inhibition experiments in K562 cells, and examination of the cellular uptake using influx transporter-transfected human embryonic kidney (HEK) 293 cells, suggested that the influx transporters OCT1 and OATP1A2, which have been reported to mediate accumulation of imatinib in CML cells, contributed little to the uptake of nilotinib. Nilotinib was found to accumulate in imatinib-resistant K562 (K562/ IM) cells overexpressing the efflux transporter P-glycoprotein (P-gp), although cytotoxic assays showed that K562/IM cells displayed 20000-fold greater resistance to nilotinib over the parent K562 cells. In conclusion, the present findings suggest that intracellular accumulation of nilotinib in CML cells contributes to its clinical response and efficacy in CML patients. Although nilotinib has been reported to be effective against imatinib-resistant ABL kinase mutants, the drug could not overcome imatinib resistance acquired by P-gpoverexpression. These results imply that classification of mechanisms of drug resistance is important for suitable strategies to treat imatinib-resistant CML patients.

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“…Similarly, it has been shown that sunitinib is an inhibitor of BCRP and can reverse chemoresistance to co-administered chemotherapeutics in BCRP over-expressing cells [16]. Others have shown that dasatinib, nilotinib, and imatinib are competitive inhibitors of P-glycoprotein and BCRP, meaning that they are substrates at low concentrations, while they inhibit transport function at high concentrations [24]. Although these data indicate the potential for kinase inhibitors to be used as tools to overcome chemoresistance through ABC efflux transporter inhibition in vitro, several clinical trials employing kinase inhibitors for mitigation of chemoresistance have been unable to definitively demonstrate improvements in progression free survival and/or overall survival of patients [25][26][27][28].…”

Section: Introductionmentioning

confidence: 99%

Tyrosine and aurora kinase inhibitors diminish transport function of multidrug resistance-associated protein (MRP) 4 and breast cancer resistance protein (BCRP)

et al. 2016

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Tyrosine and aurora kinases are important effectors in signal transduction pathways that are often involved in aberrant cancer cell growth. Tyrosine (TKI) and aurora (AKI) kinase inhibitors are anti-cancer MRP4: alisertib, danusertib, erlotinib, lapatinib, neratinib, nilotinib, pazopanib, sorafenib, and tozasertib. The potentially clinically relevant inhibition of BCRP was much more extensive and included alisertib, barasertib, danusertib, enzastaurin, erlotinib, gefitinib, imatinib, neratinib, nilotinib, pazopanib, selumetinib, sorafenib, sunitinib, tozasertib, and vandetanib Keywords ABC transporters; transport inhibition ADMET & DMPK 4(4) (2016) 302-313TKIs and AKIs diminish transport of function of MRP4 and BCRP

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Comparison of ATP-Binding Cassette Transporter Interactions with the Tyrosine Kinase Inhibitors Imatinib, Nilotinib, and Dasatinib

Cited by 199 publications

References 40 publications

Dasatinib targets chronic myeloid leukemia-CD34+ progenitors as effectively as it targets mature cells

Dasatinib targets chronic myeloid leukemia-CD34+ progenitors as effectively as it targets mature cells

Distinct Interaction of Nilotinib and Imatinib with P-Glycoprotein in Intracellular Accumulation and Cytotoxicity in CML Cell Line K562 Cells

Tyrosine and aurora kinase inhibitors diminish transport function of multidrug resistance-associated protein (MRP) 4 and breast cancer resistance protein (BCRP)

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