Pharmacotherapy of acute myeloid leukemia (AML) remains challenging, and the disease has one of the lowest curability rates among hematological malignancies. The therapy outcomes are often compromised by the existence of a resistant AML phenotype associated with overexpression of ABCB1 and ABCG2 transporters. Because AML induction therapy frequently consists of anthracycline-like drugs, their efficiency may also be diminished by drug biotransformation via carbonyl reducing enzymes (CRE). In this study, we investigated the modulatory potential of the CDK4/6 inhibitors abemaciclib, palbociclib, and ribociclib on AML resistance using peripheral blood mononuclear cells (PBMC) isolated from patients with de novo diagnosed AML. We first confirmed inhibitory effect of the tested drugs on ABCB1 and ABCG2 in ABC transporter-expressing resistant HL-60 cells while also showing the ability to sensitize the cells to cytotoxic drugs even as no effect on AML-relevant CRE isoforms was observed. All tested CDK4/6 inhibitors elevated mitoxantrone accumulations in CD34+ PBMC and enhanced accumulation of mitoxantrone was found with abemaciclib and ribociclib in PBMC of FLT3-ITD- patients. Importantly, the accumulation rate in the presence of CDK4/6 inhibitors positively correlated with ABCB1 expression in CD34+ patients and led to enhanced apoptosis of PBMC in contrast to CD34- samples. In summary, combination therapy involving CDK4/6 inhibitors could favorably target multidrug resistance, especially when personalized based on CD34- and ABCB1-related markers.

• Klíčová slova
• ABC transporters, CDK4/6 inhibitors, acute myeloid leukemia, drug resistance,
• Publikační typ
• časopisecké články MeSH

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.

• Klíčová slova
• ABC transporter, cancer, cytochrome P450, drug-drug interaction, ensartinib, multidrug resistance,
• Publikační typ
• časopisecké články MeSH

PURPOSE: S-(4-Nitrobenzyl)-6-thioinosine (NBMPR) is routinely used at concentrations of 0.10 μM and 0.10 mM to specifically inhibit transport of nucleosides mediated by equilibrative nucleoside transporters 1 (ENT1) and 2 (ENT2), respectively. We recently showed that NBMPR (0.10 mM) might also inhibit placental active efflux of [3H]zidovudine and [3H]tenofovir disoproxil fumarate. Here we test the hypothesis that NBMPR abolishes the activity of P-glycoprotein (ABCB1) and/or breast cancer resistance protein (ABCG2). METHODS: We performed accumulation assays with Hoechst 33342 (a model dual substrate of ABCB1 and ABCG2) and bi-directional transport studies with the ABCG2 substrate [3H]glyburide in transduced MDCKII cells, accumulation studies in choriocarcinoma-derived BeWo cells, and in situ dual perfusions of rat term placenta with glyburide. RESULTS: NBMPR inhibited Hoechst 33342 accumulation in MDCKII-ABCG2 cells (IC50 = 53 μM) but not in MDCKII-ABCB1 and MDCKII-parental cells. NBMPR (0.10 mM) also inhibited bi-directional [3H]glyburide transport across monolayers of MDCKII-ABCG2 cells and blocked ABCG2-mediated [3H]glyburide efflux by rat term placenta in situ. CONCLUSION: NBMPR at a concentration of 0.10 mM abolishes ABCG2 activity. Researchers using NBMPR to evaluate the effect of ENTs on pharmacokinetics must therefore interpret their results carefully if studying compounds that are substrates of both ENTs and ABCG2.

• Klíčová slova
• NBMPR, breast cancer resistance protein, equilibrative nucleoside transporters, inhibition, selectivity,
• MeSH
• ABC transportér z rodiny G, člen 2 antagonisté a inhibitory   metabolismus   MeSH
• antivirové látky metabolismus   farmakokinetika   MeSH
• biologický transport účinky léků   MeSH
• buněčné linie MeSH
• buňky MDCK MeSH
• krysa rodu Rattus MeSH
• lidé MeSH
• nádorové proteiny antagonisté a inhibitory   metabolismus   MeSH
• P-glykoproteiny antagonisté a inhibitory   metabolismus   MeSH
• placenta účinky léků   metabolismus   MeSH
• potkani Wistar MeSH
• psi MeSH
• těhotenství MeSH
• thioinosin analogy a deriváty   farmakologie   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• lidé MeSH
• psi MeSH
• těhotenství MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• 4-nitrobenzylthioinosine MeSH Prohlížeč
• ABC transportér z rodiny G, člen 2 MeSH
• ABCB1 protein, human MeSH Prohlížeč
• ABCG2 protein, human MeSH Prohlížeč
• antivirové látky MeSH
• nádorové proteiny MeSH
• P-glykoproteiny MeSH
• thioinosin MeSH