Dinaciclib, a cyclin-dependent kinase inhibitor, is a substrate of human ABCB1 and ABCG2 and an inhibitor of human ABCC1 in vitro

Cihalova, Daniela; Čečková, Martina; Kučera, Radim; Klimeš, Jiřı́; Štaud, František

doi:10.1016/j.bcp.2015.08.099

Cited by 27 publications

(18 citation statements)

References 40 publications

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“…This mechanism has also recently been reported for the novel anticancer drugs ribociclib and dinaciclib (Cihalova et al, 2015;Sorf et al, 2018), which showed efflux ratios higher than 2 in transport assays across MDCKII parental cells. These compounds show strong affinity for human ABCB1, and as such the results from the MDCKII-ABCB1 cells showed even higher ER values, yielding relative ratios between the ABCB1-overexpressing and parental cells (R r 5 ER ABCB1 /ER parental ) that were higher than 2.…”

Section: Downloaded Fromsupporting

confidence: 73%

Interactions between Maraviroc and the ABCB1, ABCG2, and ABCC2 Transporters: An Important Role in Transplacental Pharmacokinetics

et al. 2019

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Maraviroc is a chemokine receptor 5 (CCR5) inhibitor used in the treatment of human immunodeficiency virus (HIV) that also shows therapeutic potential for several autoimmune, cancer, and inflammatory diseases that can afflict pregnant women. However, only limited information exists on the mechanisms underlying the transplacental transfer of the drug. We aimed to expand the current knowledge base on how maraviroc interacts with several placental ATP-binding cassette (ABC) efflux transporters that have a recognized role in the protection of a developing fetus: P-glycoprotein (ABCB1), breast cancer resistance protein (ABCG2), and multidrug resistance protein 2 (ABCC2). We found that maraviroc does not inhibit any of the three studied ABC transporters and that its permeability is not affected by ABCG2 or ABCC2. However, our in vitro results revealed that maraviroc shows affinity for human ABCB1 and the endogenous canine P-glycoprotein (Abcb1) expressed in Madin-Darby canine kidney II (MDCKII) cells. Perfusion of rat term placenta showed accelerated transport of maraviroc in the fetal-tomaternal direction, which suggests that ABCB1/Abcb1 facilitates in situ maraviroc transport. This transplacental transport was saturable and significantly diminished after the addition of the ABCB1/Abcb1 inhibitors elacridar, zosuquidar, and ritonavir. Our results indicate that neither ABCG2 nor ABCC2 influence maraviroc pharmacokinetic but that ABCB1/Abcb1 may be partly responsible for the decreased transplacental permeability of maraviroc to the fetus. The strong affinity of maraviroc to Abcb1 found in our animal models necessitates studies in human tissue so that maraviroc pharmacokinetics in pregnant women can be fully understood. SIGNIFICANCE STATEMENT Antiretroviral drug maraviroc shows low toxicity and is thus a good candidate for prevention of mother-to-child transmission of human immunodeficiency virus when failure of recommended therapy occurs. Using in vitro cell-based experiments and in situ dually perfused rat term placenta, we examined maraviroc interaction with the placental ABC drug transporters ABCB1, ABCG2, and ABCC2. We demonstrate for the first time that placental ABCB1 significantly reduces mother-to-fetus transport of maraviroc, which suggests that ABCB1 may be responsible for the low cord-blood/maternalblood ratio observed in humans.

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Section: Downloaded Fromsupporting

confidence: 73%

Interactions between Maraviroc and the ABCB1, ABCG2, and ABCC2 Transporters: An Important Role in Transplacental Pharmacokinetics

et al. 2019

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“…This dual activity has attracted considerable interest, and combinations of these new drugs with standard cytostatic agents may be powerful therapeutic options for resistant tumors [19,20]. Our research group recently demonstrated that several cyclin-dependent kinase inhibitors exhibit such dual modes of action [21][22][23][24][25][26][27]. We believe that the synergistic combinations identified in our studies could potentially be translated into more efficient and safe therapies for many oncological patients.…”

Section: Introductionmentioning

confidence: 59%

“…The ABCB1 ATPase assay was performed with minor modifications as described previously [24]. The ATPase activitity was determined using ABCB1 PREDEASY ATPase Kit according to the manufacturer's instructions.…”

Section: Abcb1 Atpase Assaymentioning

confidence: 99%

Ensartinib (X-396) Effectively Modulates Pharmacokinetic Resistance Mediated by ABCB1 and ABCG2 Drug Efflux Transporters and CYP3A4 Biotransformation Enzyme

Vagiannis

Novotná

Skarka

et al. 2020

Cancers

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Ensartinib (X-396) is a promising tyrosine kinase inhibitor currently undergoing advanced clinical evaluation for the treatment of non-small cell lung cancer. In this work, we investigate possible interactions of this promising drug candidate with ATP-binding cassette (ABC) drug efflux transporters and cytochrome P450 biotransformation enzymes (CYPs), which play major roles in multidrug resistance (MDR) and pharmacokinetic drug-drug interactions (DDIs). Accumulation studies showed that ensartinib is a potent inhibitor of ABCB1 and ABCG2 transporters. Additionally, incubation experiments with recombinant CYPs showed that ensartinib significantly inhibits CYP3A4 and CYP2C9. Subsequent molecular docking studies confirmed these findings. Drug combination experiments demonstrated that ensartinib synergistically potentiates the antiproliferative effects of daunorubicin, mitoxantrone, and docetaxel in ABCB1, ABCG2, and CYP3A4-overexpressing cellular models, respectively. Advantageously, ensartinib’s antitumor efficiency was not compromised by the presence of MDR-associated ABC transporters, although it acted as a substrate of ABCB1 in Madin-Darby Canine Kidney II (MDCKII) monolayer transport assays. Finally, we demonstrated that ensartinib had no significant effect on the mRNA-level expression of examined transporters and enzymes in physiological and lung tumor cellular models. In conclusion, ensartinib may perpetrate clinically relevant pharmacokinetic DDIs and modulate ABCB1-, ABCG2-, and CYP3A4-mediated MDR. The in vitro findings presented here will provide a valuable foundation for future in vivo investigations.

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“…The cyclin‐dependent kinase inhibitor dinaciclib (Figure ) reversed MRP1‐mediated MDR in MDCK II MRP1 cells . Cihalova et al.…”

Section: Pharmacological and Experimental Drugs And Synthetic Analogsmentioning

confidence: 95%

Small‐molecule inhibitors of multidrug resistance‐associated protein 1 and related processes: A historic approach and recent advances

Stefan

Wiese

2018

Medicinal Research Reviews

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Multidrug resistance-associated protein 1 (MRP1, ABCC1) is an ATP-binding cassette (ABC) transport protein. This efflux pump uses the energy of ATP hydrolysis to export structurally diverse antineoplastic agents in human cancers. The upregulation of MRP1 (either inherent or acquired) is one major reason for the occurrence of the phenomenon called multidrug resistance (MDR). MDR is characterized by a reduced outcome of chemotherapy due to the active intracellular clearance of cytostatic drugs below the necessary effect concentration. Much effort has been made to overcome MDR, which implied high-throughput screenings of already known pharmacological and natural compounds, modification of intrinsic substrates, as well as design and synthesis of new inhibitors. This review is meant not only to summarize the most recent results over the past 10 years, but also to highlight major achievements regarding reversal of MRP1-mediated MDR, from the time of its discovery until today. The focus lies on small-molecule compounds that feature either direct MRP1 inhibition/transport blockage, toxicity against MRP1-overexpressing cells, inhibition/modification of intracellular processes necessary for MRP1 function, or modification of MRP1-related metabolic and genomic mechanisms. Considering all aspects, this review might be useful to (re)consider possible strategies to overcome MRP1-mediated MDR. Furthermore, it may be the basis for developing new, even better, highly potent, less toxic, and selective (as well as broad-spectrum) MRP1 inhibitors that will enter clinical evaluations in different malignancies and finally conduce to overcome MDR in general.

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Dinaciclib, a cyclin-dependent kinase inhibitor, is a substrate of human ABCB1 and ABCG2 and an inhibitor of human ABCC1 in vitro

Cited by 27 publications

References 40 publications

Interactions between Maraviroc and the ABCB1, ABCG2, and ABCC2 Transporters: An Important Role in Transplacental Pharmacokinetics

Interactions between Maraviroc and the ABCB1, ABCG2, and ABCC2 Transporters: An Important Role in Transplacental Pharmacokinetics

Ensartinib (X-396) Effectively Modulates Pharmacokinetic Resistance Mediated by ABCB1 and ABCG2 Drug Efflux Transporters and CYP3A4 Biotransformation Enzyme

Small‐molecule inhibitors of multidrug resistance‐associated protein 1 and related processes: A historic approach and recent advances

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