Targeting Pharmacokinetic Drug Resistance in Acute Myeloid Leukemia Cells with CDK4/6 Inhibitors

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.

The Resistance of Cancer Cells to Palbociclib, a Cyclin-Dependent Kinase 4/6 Inhibitor, is Mediated by the ABCB1 Transporter

“…Numerous studies have shown that the overexpression of the ABC transporters, ABCB1 and ABCG2, in certain types of solid tumors and leukemia, produce acquired drug resistance and attenuate, as well as abrogate, the efficacy of anticancer drugs with different chemical structures and mechanisms of action ( Mohammad et al, 2018 ; Boyer et al, 2019 ; Wu et al, 2020c ; Yang et al, 2021 ). It has been reported that palbociclib, a CDK4/6 inhibitor, may be a substrate of the ABCB1 and ABCG2 transporters ( De Gooijer et al, 2015 ; Parrish et al, 2015 ) and an ABCB1 chemosensitizer ( Fojo et al, 1985 ; Gao et al, 2017 ; Sorf et al, 2020 ). However, the exact interaction palbociclib with the ABCB1 and ABCG2 transporters remained to be determined, as this depends on the concentration range of the drug, the methodology and the activity of the transporters in the various cell types ( Yang et al, 2021 ).…”

“…Similarly, the penetration of palbociclib across the blood-brain barrier of ABCB1 and ABCG2 gene knockout mice was significantly decreased by ABCB1 and ABCG2 transporters, suggesting that palbociclib was a substrate for ABCB1 and ABCG2 transporters (De Gooijer et al, 2015). In contrast, studies by Gao et al (2017) and Sorf et al (2020) suggested that palbociclib may be an inhibitor of the ABCB1 transporter. Therefore, it is crucial to determine if palbociclib is a substrate or an inhibitor because if it is a substrate of the ABCB1 transporter, cancer cells that overexpress ABCB1 transporter will have lower intracellular levels of palbociclib, which could decrease or abrogate its efficacy.…”

Cytotoxic Marine Alkaloid 3,10-Dibromofascaplysin Induces Apoptosis and Synergizes with Cytarabine Resulting in Leukemia Cell Death

“…To better understand the effect of DBF on cell cycle we used well-known CDK4/6 inhibitor palbociclib (PD-0332991) as a reference. Palbociclib was found to be a promising candidate to treat leukemia [ 19 , 50 , 51 ] and undergoes several clinical trials to treat different malignant disorders [ 22 , 52 ]. Earlier, brominated compounds were shown to affect cell growth, suggesting potential anti-cancer activity [ 53 ].…”

The Increase in the Drug Resistance of Acute Myeloid Leukemia THP-1 Cells in High-Density Cell Culture Is Associated with Inflammatory-like Activation and Anti-Apoptotic Bcl-2 Proteins

“…Acute myeloid leukemia (AML) remains a hematologic malignancy with extremely low cure and survival rates [ 1 ]. Only 29.5% of patients that are diagnosed with AML currently achieve 5-year survival, despite the overall progress in therapeutic strategies over the past decade [ 2 , 3 ].…”