Comparison of imatinib, dasatinib, nilotinib and INNO-406 in imatinib-resistant cell lines

Deguchi, Yasuyuki; Kimura, Shinya; Ashihara, Eishi; Niwa, Takeo; Hodohara, Keiko; Fujiyama, Yoshihide; Maekawa, Taira

doi:10.1016/j.leukres.2007.11.008

Cited by 77 publications

(41 citation statements)

References 7 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…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: 97%

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

View full text Add to dashboard Cite

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.

show abstract

Section: Discussionmentioning

confidence: 97%

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

View full text Add to dashboard Cite

show abstract

“…35 Using the same mouse model as described before, dasatinib administered at 40 mg/kg IP daily in concurrent combination with ESKM resulted in the clinical For personal use only. on May 12, 2018.…”

Section: Eskm Therapy With the Second-generation Tki Dasatinibmentioning

confidence: 99%

A TCR-mimic antibody to WT1 bypasses tyrosine kinase inhibitor resistance in human BCR-ABL+ leukemias

Dubrovsky

Pankov

Brea

et al. 2014

Blood

View full text Add to dashboard Cite

show abstract

“…BaF3 cells expressing the random mutagenesis of BCR-ABL were kindly provided by Dr James D Griffin (Dana-Farber Cancer Institute, Boston, MA, USA) (Ray et al, 2007). BaF3 cells expressing WT BCR-ABL and mutant forms of BCR-ABL (M244V, G250E, Q252H, Y253F, T315A, T315I, F317L, F317V, M351T and H396P) were described previously (Deguchi et al, 2008). These cell lines were cultured in RPMI1640 (Life Technology, Inc., Carlsbad, CA, USA) supplemented with 10% fetal calf serum (Hyclone Laboratories, Logan, UT, USA).…”

Section: Cells and Cell Culturementioning

confidence: 99%

Combined effects of novel heat shock protein 90 inhibitor NVP-AUY922 and nilotinib in a random mutagenesis screen

et al. 2011

View full text Add to dashboard Cite

To overcome imatinib resistance, more potent ABL tyrosine kinase inhibitors (TKIs), such as nilotinib and dasatinib have been developed, with demonstrable preclinical activity against most imatinib-resistant BCR-ABL kinase domain mutations, with the exception of T315I. However, imatinib-resistant patients already harboring mutations have a higher likelihood of developing further mutations under the selective pressure of potent ABL TKIs. NVP-AUY922 (Novartis) is a novel 4,5-diaryloxazole adenosine triphosphate-binding site heat shock protein 90 (HSP90) inhibitor, which has been shown to inhibit the chaperone function of HSP90 and deplete the levels of HSP90 client protein including BCR-ABL. In this study, we investigated the combined effects of AUY922 and nilotinib on random mutagenesis for BCR-ABL mutation (Blood, 109; 5011, 2007). Compared with single agents, combination with AUY922 and nilotinib was more effective at reducing the outgrowth of resistant cell clones. No outgrowth was observed in the presence of 2 lM of nilotinib and 20 nM of AUY922. The observed data from the isobologram indicated the synergistic effect of simultaneous exposure to AUY922 and nilotinib even in BaF3 cells expressing BCR-ABL mutants including T315I. In vivo studies also demonstrated that the combination of AUY922 and nilotinib prolonged the survival of mice transplanted with mixture of BaF3 cells expressing wild-type BCR-ABL and mutant forms. Taken together, this study shows that the combination of AUY922 and nilotinib exhibits a desirable therapeutic index that can reduce the in vivo growth of mutant forms of BCR-ABL-expressing cells.

show abstract

Comparison of imatinib, dasatinib, nilotinib and INNO-406 in imatinib-resistant cell lines

Cited by 77 publications

References 7 publications

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

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

A TCR-mimic antibody to WT1 bypasses tyrosine kinase inhibitor resistance in human BCR-ABL+ leukemias

Combined effects of novel heat shock protein 90 inhibitor NVP-AUY922 and nilotinib in a random mutagenesis screen

Contact Info

Product

Resources

About