ABSTRACT
Resistance to cytarabine remains a major challenge in the treatment of acute myeloid leukemia (AML). Based on previous studies implicating ABCC4/MRP4 in the transport of nucleosides, we hypothesized that cytarabine is sensitive to ABCC4-mediated efflux, thereby decreasing its cytotoxic response against AML blasts. The uptake of cytarabine and its monophosphate metabolite was found to be facilitated in ABCC4-expressing vesicles and intracellular retention was significantly impaired by overexpression of human ABCC4 or mouse Abcc4 (P < 0.05). ABCC4 was expressed highly in AML primary blasts and cell lines, and cytotoxicity of cytarabine in cells was increased in the presence of the ABCC4 inhibitors MK571 or sorafenib, as well as after ABCC4 siRNA. In Abcc4-null mice, cytarabine-induced hematological toxicity was enhanced and ex vivo colony-forming assays showed that Abcc4-deficiency sensitized myeloid progenitors to cytarabine. Collectively, these studies demonstrate that ABCC4 plays a protective role against cytarabine-mediated insults in leukemic and host myeloid cells.
Subject(s)
Cytarabine/pharmacology , Multidrug Resistance-Associated Proteins/metabolism , Myeloid Progenitor Cells/pathology , Animals , Biological Transport/drug effects , Cell Death/drug effects , Cell Line, Tumor , Child, Preschool , Gene Knockdown Techniques , Gene Silencing/drug effects , Humans , Leukemia, Myeloid, Acute/pathology , Mice, Inbred C57BL , Myeloid Progenitor Cells/drug effects , Myeloid Progenitor Cells/metabolismABSTRACT
Using broad interrogation of clinically relevant drug absorption, distribution, metabolism, and excretion (ADME) genes on the DMET platform, we identified a genetic variant in SLCO1B1 (rs2291075; c.597C>T), encoding the transporter OATP1B1, associated with event-free (P = 0.006, hazard ratio = 1.74) and overall survival (P = 0.012, hazard ratio = 1.85) in children with de novo acute myeloid leukemia (AML). Lack of SLCO1B1 expression in leukemic blasts suggested the association might be due to an inherited rather than a somatic effect. rs2291075 was in strong linkage with known functional variants rs2306283 (c.388A>G) and rs4149056 (c.521T>C). Functional studies in vitro determined that four AML-directed chemotherapeutics (cytarabine, daunorubicin, etoposide, and mitoxantrone) are substrates for OATP1B1 and the mouse ortholog Oatp1b2. In vivo pharmacokinetic studies using Oatp1b2-deficient mice further confirmed our results. Collectively, these findings demonstrate an important role for OATP1B1 in the systemic pharmacokinetics of multiple drugs used in the treatment of AML and suggest that inherited variability in host transporter function influences the effectiveness of therapy.
Subject(s)
Leukemia, Myeloid, Acute/drug therapy , Leukemia, Myeloid, Acute/genetics , Liver-Specific Organic Anion Transporter 1/genetics , Animals , Antineoplastic Agents/metabolism , Antineoplastic Combined Chemotherapy Protocols/metabolism , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Child , Cohort Studies , Cytarabine/pharmacokinetics , DNA/genetics , DNA/isolation & purification , Female , Genetic Linkage , Genetic Variation , Humans , Male , Mice , Mice, Knockout , Polymorphism, Single Nucleotide , Survival Analysis , Treatment OutcomeABSTRACT
Tyrosine kinases have emerged as important tumor targets for the design of potent and selective inhibitors. Eighteen of these tyrosine kinase inhibitors (TKIs) have already been approved for the treatment of diseases that were previously essentially resistant to standard chemotherapy. Major efforts are ongoing that focus on the development of companion diagnostics for investigational and approved TKIs, as well as on integrating clinical pharmacology principles in clinical practice to decrease toxicity and improve efficacy.
