Abstract
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.
Highlights
Acute myeloid leukemia (AML) remains a hematological malignity characterized by extremely low curability and survival rate
We aim to provide information as to whether abemaciclib, palbociclib, and ribociclib interact with ATP-binding cassette (ABC) efflux transporters and/or carbonyl reducing enzymes (CRE), as well as whether such interactions could affect therapeutic outcomes of conventional cytotoxic drugs in peripheral blood mononuclear cells (PBMC) isolated directly from patients with de novo diagnosed acute myeloid leukemia (AML)
The other two drugs were found more effective in ABCB1 inhibition, with the respective inhibitory IC50 values of 0.354 μM for abemaciclib and 6.65 μM for Cancers 2020, 12, x palbociclib calculated by considering the effect of model inhibitor as 100% inhibition
Summary
Acute myeloid leukemia (AML) remains a hematological malignity characterized by extremely low curability and survival rate. Despite the overall progress in therapeutic strategies during the past decade [1,2,3], only 28.3% of patients with AML diagnosis currently achieve five-year survival [4]. Clinicians’ decisions regarding optimal treatment strategy are influenced by factors such as age at diagnosis, comorbidities, and risk stratification of AML. Patients eligible for intensive therapy generally undergo induction chemotherapy to reach first remission. That treatment is followed either by courses of consolidation therapy or by bone marrow transplantation to maintain remission status.
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