Tyrosine kinase inhibitors as modulators of ATP binding cassette multidrug transporters: substrates, chemosensitizers or inducers of acquired multidrug resistance?
116
Citation
190
Reference
10
Related Paper
Citation Trend
Abstract:
Anticancer tyrosine kinase inhibitors (TKIs) are small molecule hydrophobic compounds designed to arrest aberrant signaling pathways in malignant cells. Multidrug resistance (MDR) ATP binding cassette (ABC) transporters have recently been recognized as important determinants of the general ADME-Tox (absorption, distribution, metabolism, excretion, toxicity) properties of small molecule TKIs, as well as key factors of resistance against targeted anticancer therapeutics.The article summarizes MDR-related ABC transporter interactions with imatinib, nilotinib, dasatinib, gefitinib, erlotinib, lapatinib, sunitinib and sorafenib, including in vitro and in vivo observations. An array of methods developed to study such interactions is presented. Transporter-TKI interactions relevant to the ADME-Tox properties of TKI drugs, primary or acquired cancer TKI resistance, and drug-drug interactions are also reviewed.Based on the concept presented in this review, TKI anticancer drugs are considered as compounds recognized by the cellular mechanisms handling xenobiotics. Accordingly, novel anticancer therapies should equally focus on the effectiveness of target inhibition and exploration of potential interactions of the designed molecules by membrane transporters. Thus, targeted hydrophobic small molecule compounds should also be screened to evade xenobiotic-sensing cellular mechanisms.Keywords:
Lapatinib
ADME
Abcg2
ABCC1
Multidrug resistance (MDR) mediated by ATP-binding cassette (ABC) transporters through efflux of antineoplastic agents from cancer cells is a major obstacle to successful cancer chemotherapy. The inhibition of these ABC transporters is thus a logical approach to circumvent MDR. There has been intensive research effort to design and develop novel inhibitors for the ABC transporters to achieve this goal. In the present study, we evaluated the ability of UMMS-4 to modulate P-glycoprotein (P-gp/ABCB1)-, breast cancer resistance protein (BCRP/ABCG2)- and multidrug resistance protein (MRP1/ABCC1)-mediated MDR in cancer cells. Our findings showed that UMMS-4, at non-cytotoxic concentrations, apparently circumvents resistance to ABCB1 substrate anticancer drugs in ABCB1-overexpressing cells. When used at a concentration of 20 μmol/L, UMMS-4 produced a 17.53-fold reversal of MDR, but showed no effect on the sensitivity of drug-sensitive parental cells. UMMS-4, however, did not significantly alter the sensitivity of non-ABCB1 substrates in all cells and was unable to reverse ABCG2- and ABCC1-mediated MDR. Additionally, UMMS-4 profoundly inhibited the transport of rhodamine 123 (Rho 123) and doxorubicin (Dox) by the ABCB1 transporter. Furthermore, UMMS-4 did not alter the expression of ABCB1 at the mRNA and protein levels. In addition, the results of ATPase assays showed that UMMS-4 stimulated the ATPase activity of ABCB1. Taken together, we conclude that UMMS-4 antagonizes ABCB1-mediated MDR in cancer cells through direct inhibition of the drug efflux function of ABCB1. These findings may be useful for the development of safer and more effective MDR modulator.
ABCC1
Abcg2
Efflux
P-glycoprotein
Rhodamine 123
Multidrug Resistance-Associated Proteins
Cite
Citations (13)
Abcg2
ABCC1
P-glycoprotein
Efflux
Cite
Citations (8)
This chapter contains sections titled: Introduction P-glycoprotein (P-gp) ABCB1 Breast cancer resistance protein (BCRP) ABCG2 Multidrug resistance associated protein (MRP1) ABCC1 Multidrug resistance associated protein (MRP1) ABCC3 ABCA3 Future perspectives References
Abcg2
ABCC1
P-glycoprotein
Acute myeloblastic leukemia
Multidrug Resistance-Associated Proteins
Cite
Citations (0)
Imatinib and nilotinib interact with ABCB1 and ABCG2. However, whether they are substrates or inhibitors is a source of conjecture. Here, in vitro, Bcr-Abl kinase inhibition was used to elucidate the impact of ABCB1/ABCG2 overexpression on imatinib and nilotinib transport. High levels of ABCB1 protein in K562-Dox cells resulted in a significantly increased 50% inhibitory concentration (IC(50)) compared with parental K562 cells for imatinib (IC(50)(IM); 9 µM to 19 µM, p = 0.002) and nilotinib (IC(50)(NIL); 345 nM to 620 nM, p = 0.013). This difference was abrogated by ABCB1 inhibitors. However, overexpression of ABCG2 did not significantly increase IC(50)(IM) or IC(50)(NIL) or significantly decrease IC(50) upon ABCG2 inhibition. Inhibition of ABCB1 but not ABCG2 resulted in a substantial increase in intracellular nilotinib when used at 150 nM but no increase when used at 2 µM. Imatinib and nilotinib appear to be transported by ABCB1 but do not interact strongly with ABCG2. Furthermore, ABCB1 efflux of nilotinib may be concentration-dependent with transport occurring at clinically relevant concentrations.
Abcg2
IC50
K562 cells
Cite
Citations (26)
2300 Multidrug resistance (MDR) is a major obstacle in the successful application of chemotherapy. The overexpression of ABC transporters, Pgp/ABCB1, MRP1/ABCC1, and BCRP/ABCG2, has been a well-known indicator of MDR. However, the importance of ABC transporters in MDR, and the mechanism of their upregulation have not been fully elucidated. The aim of this study is to examine the role of Notch1 in the expression of the multidrug resistance protein, MRP1/ABCC1. Notch1 is an enzymatic cleavable type I transmembrane protein, which is also known as an intracellular transcriptional regulator involved in regulating cell fate, apoptosis, proliferation and migration. We evaluated the levels of transmembrane Notch1 (N1 TM ) in cancer cell lines, such as CEM/VLB 100 , CEM/VM1-5, and BeWo known to overexpress the ABC transporters, Pgp, MRP1 and BCRP, respectively. Interestingly, we found an inverse relationship between the expression of Notch1 and MRP1/ABCC1 in the etoposide (VP16)-resistant CEM/VM1-5 cells and parental CEM cells. To investigate whether this inverse expression of N1 TM and MRP1 is associated with etoposide resistance, we used another cell model, VP-16-resistant MCF7/VP and its drug sensitive parents, MCF7/WT, and observed the same inverse relationship: low N1 TM but high MRP1 in the resistant MCF7/VP cells, compared to the parental cells. We hypothesize that Notch1 is one of the biological factors involved in MRP1 expression in the drug resistant cells. To understand the mechanism by which Notch1 may regulate MRP1, we measured the level and activity of intracellular Notch1 (ICN1) in MCF7/WT and MCF7/VP. As opposed to N1 TM , there were no detectable differences in the levels of ICN1 between MCF7/WT and MCF7/VP. However, the activity of ICN1 in MCF7/VP was about 1.5-times higher than MCF7/WT, as measured by CBF1 promoter assay. To further verify the effect of ICN1 on MRP1 expression, we blocked the generation of ICN1 in MCF7/WT and MCF7/VP with DAPT, a gama-secretase inhibitor (GSI). We observed a dose-dependent reduction of both ICN1 and MRP1 expression in the MCF7/VP cells but not in the parental cells, suggesting a possible role for ICN1 in the overexpression of MRP1 in drug resistant cells. We next measured the level of presenilin 1 (PSEN1), which is a main proteolytic enzyme involved in the generation of ICN1, and observed increased levels of PSEN1 in MCF7/VP. We conclude that etoposide-resistant cells show faster processing of ICN1, possibly via PSEN1 overexpression, and that this is associated with MRP1 upregulation. This MRP1 upregulation can be blocked by GSI, suggesting a therapeutic possibility to prevent the development of MDR. (This work was supported in part by grant CA-40570 [to WTB] and in part by the University of Illinois at Chicago)
ABCC1
Abcg2
Multidrug Resistance-Associated Proteins
Rhodamine 123
Cite
Citations (0)
Resistance to antineoplastic drugs is thought to be a major reason for failure to cure malignant diseases today. Multidrug resistance, defined as the development of resistance to a broad spectrum of antineoplastic agents following exposure to a single agent, can arise from a variety of mechanisms, among which is overexpression of members of the ATP-binding cassette (ABC) superfamily of transporter proteins. Notable among ABC transporters are those that cause multidrug resistance by effluxing anticancer agents from cells. P-glycoprotein (Pgp, product of the MDR1 gene and officially designated as ABCB1) and the multidrug resistance protein 1 (MRP1, or ABCC1) are the best studied in this context; however, other members of the MRP (ABCC) family and the recently discovered breast cancer resistance protein (BCRP, officially ABCG2) are also known to efflux anticancer drugs and to confer multdrug resistance to cancer cell lines. The recognition that a self-renewing stem cell compartment exists in AML and the expression of Pgp/ABCB1, BCRP/ABCG2, and perhaps other ABC transporters in these cells points to a need for future research on the contribution of these transporters to drug resistance in this target population.
Abcg2
ABCC1
Efflux
P-glycoprotein
Cite
Citations (1)
P-Glycoprotein (P-gp, ABCB1), multidrug resistance-associated protein 1 (MRP1, ABCC1), and breast cancer resistance protein (BCRP, ABCG2) are the three major ABC transport proteins conferring resistance to many structurally diverse anticancer agents, leading to the phenomenon called multidrug resistance (MDR). Much effort has been put into the development of clinically useful compounds to reverse MDR. Broad-spectrum inhibitors of ABC transport proteins can be of great use in cancers that simultaneously coexpress two or three transporters. In this work, we continued our effort to generate new, potent, nontoxic, and multiply effective inhibitors of the three major ABC transporters. The best compound was active in a very low micromolar concentration range against all three transporters and restored sensitivity toward daunorubicin (P-gp and MRP1) and SN-38 (BCRP) in A2780/ADR (P-gp), H69AR (MRP1), and MDCK II BCRP (BCRP) cells. Additionally, the compound is a noncompetitive inhibitor of daunorubicin (MRP1), calcein AM (P-gp), and pheophorbide A (BCRP) transport.
Abcg2
ABCC1
Daunorubicin
P-glycoprotein
Multidrug Resistance-Associated Proteins
Pheophorbide A
Efflux
Mediated transport
Cite
Citations (56)
ABCC1
Abcg2
Efflux
Daunorubicin
Cite
Citations (27)
Breast cancer resistance protein (BCRP/ABCG2) belongs to the ATP-binding cassette (ABC) transporter superfamily. It is able to efflux a broad range of anti-cancer drugs through the cellular membrane, thus limiting their anti-proliferative effects. Due to its relatively recent discovery in 1998, and in contrast to the other ABC transporters P-glycoprotein (MDR1/ABCB1) and multidrug resistance-associated protein (MRP1/ABCC1), only a few BCRP inhibitors have been reported. This review summarizes the known classes of inhibitors that are either specific for BCRP or also inhibit the other multidrug resistance ABC transporters. Information is presented on structure-activity relationship aspects and how modulators may interact with BCRP.
Abcg2
ABCC1
Efflux
P-glycoprotein
Cite
Citations (84)