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.

Alectinib is a tyrosine kinase inhibitor currently used as a first-line treatment of ALK-positive metastatic non-small cell lung cancer (NSCLC). In the present work, we investigated possible interactions of this novel drug with ABC drug efflux transporters and cytochrome P450 (CYP) biotransformation enzymes that play significant roles in the phenomenon of multidrug resistance (MDR) of cancer cells as well as in pharmacokinetic drug-drug interactions. Using accumulation studies in MDCKII cells, alectinib was identified as an inhibitor of ABCB1 and ABCG2 but not of ABCC1. In subsequent drug combination studies, we demonstrated the ability for alectinib to effectively overcome MDR in ABCB1- and ABCG2-overexpressing MDCKII and A431 cells. To describe the pharmacokinetic interaction profile of alectinib in a complete fashion, its possible inhibitory properties toward clinically relevant CYP enzymes (i.e., CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP3A4 or CYP3A5) were evaluated using human CYP-expressing insect microsomes, revealing alectinib as a poor interactor. Advantageously for its use in pharmacotherapy, alectinib further exhibited negligible potential to cause any changes in expression of ABCB1, ABCG2, ABCC1 and CYP1A2, CYP3A4, CYP2B6 in intestine, liver and NSCLC models. Our in vitro observations might serve as a valuable foundation for future in vivo studies that could support the rational for our conclusions and possibly enable providing more efficient and safer therapy to many oncological patients. SIGNIFICANCE STATEMENT N/A

Background: In the last decade, the concept of uncharged reactivators potentially able to penetrate the CNS has been introduced as an alternative to the classic charged oxime reactivators. However, this concept brings with it several associated drawbacks such as higher lipophilicity, difficulty in administration, lower affinity to cholinesterases, and higher toxicity risk. Objective: In this study we compare data obtained for a set of five classic charged reactivators and a set of three recently published uncharged oximes supplemented by two novel ones. Methods: This time, we used only in silico prediction and in vitro approaches. Results: Our data showed that uncharged oximes have low affinity for cholinesterases, do not possess high reactivation potency, and certainly represent a greater toxicity risk due to higher lipophilicity. We assume that balanced physicochemical properties will be required for the successful treatment of OP poisoning. Nevertheless, the compound meeting such criteria and pinpointed in silico (K1280) failed in this particular case. Conclusion: From the presented data, it is clear that the concept of uncharged reactivators will have to be modified, at least to improve the bioavailability and to satisfy requirements for in vivo administration.

Maraviroc is a chemokine receptor 5 (CCR5) inhibitor used in the treatment of 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 ABC efflux transporters that have a recognized role in the protection of a developing fetus, i.e. ABCB1, ABCG2 and 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 Abcb1 expressed in MDCKII cells. Perfusion of rat term placenta showed accelerated transport of maraviroc in the feto-maternal direction, which suggests that ABCB1/Abcb1 facilitate in situ maraviroc transport. This transplacental transport was saturable and significantly diminished following 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 potential and therefore it is a good candidate for prevention of mother-to-child transmission of HIV when failure of recommended therapy occurs. Although previous studies suggested interactions of maraviroc with ABCB1 transporter and its limited transfer across the placenta, this interaction has never been tested functionally in placental tissue. Using in vitro cell-based experiments and in situ method of dually perfused rat term placenta, here we examined maraviroc interactions with the three most important placental ABC drug transporters, ABCB1, ABCG2 and ABCC2. We demonstrate for the first time that placental ABCB1 significantly decreases mother-to-fetus transport of maraviroc. We conclude that ABCB1 may be responsible for the low cord blood/maternal blood ratio observed in humans.