Aminopeptidases represent a class of (zinc) metalloenzymes that catalyze the cleavage of amino acids nearby the N-terminus of polypeptides, resulting in hydrolysis of peptide bonds. Aminopeptidases operate downstream of the ubiquitin-proteasome pathway and are implicated in the final step of intracellular protein degradation either by trimming proteasome-generated peptides for antigen presentation or full hydrolysis into free amino acids for recycling in renewed protein synthesis. This review focuses on the function and subcellular location of five key aminopeptidases (aminopeptidase N, leucine aminopeptidase, puromycin-sensitive aminopeptidase, leukotriene A4 hydrolase and endoplasmic reticulum aminopeptidase 1/2) and their association with different diseases, in particular cancer and their current position as target for therapeutic intervention by aminopeptidase inhibitors. Historically, bestatin was the first prototypical aminopeptidase inhibitor that entered the clinic 35 years ago and is still used for the treatment of lung cancer. More recently, new generation aminopeptidase inhibitors became available, including the aminopeptidase inhibitor prodrug tosedostat, which is currently tested in phase II clinical trials for acute myeloid leukemia. Beyond bestatin and tosedostat, medicinal chemistry has emerged with additional series of potential aminopeptidases inhibitors which are still in an early phase of (pre)clinical investigations. The expanded knowledge of the unique mechanism of action of aminopeptidases has revived interest in aminopeptidase inhibitors for drug combination regimens in anti-cancer treatment. In this context, this review will discuss relevant features and mechanisms of action of aminopeptidases and will also elaborate on factors contributing to aminopeptidase inhibitor efficacy and/or loss of efficacy due to drug resistance-related phenomena. Together, a growing body of data point to aminopeptidase inhibitors as attractive tools for combination chemotherapy, hence their implementation may be a step forward in a new era of personalized treatment of cancer patients.
The absorption, efflux and transport properties of two of the most commonly used tyrosine kinase inhibitors (TKIs), Erlotinib (E)
Transport of erlotinib, gefitinib, sorafenib, sunitinib, dasatinib
Tyrosine kinase inhibitors (TKI) are a family of small molecules which inhibit the ATP driven phosphorylation of signaling proteins that normally activate transduction cascades. Aberrations in signal cascades have been linked to the development of tumors and their survival pathways. TKIs tend to be alkali in nature with a correspondingly high pKa (5-8) while absorption properties have been linked to both ABC and Organic Cation Transporters (OCT). Because of their poor solubility, TKI are administered orally but available pharmacokinetic data indicate that in most cases bioavailability is relatively low (∼60% or lower). Despite a molecular weight in a similar range, doses vary significantly: Sunitinib (Sun) - 50 mg/d, Dasatinib (Das) - 150 mg/d, Erlotinib (Erl) - 150 mg/d, Gefitinib (Gef) - 250 mg/d, Crizotinib (Cri) - 250 mg BID and Sorafenib (Sor) - 400 mg BID. Steady state plasma levels vary from 0.13 (Sun), 0.21 (Das), 0.29 (Gef), 0.7 (Cri), 2.54 (Erl) to 12.1 µM (Sor). Variations in intestinal absorption may seriously affect plasma concentrations, tumour exposure and antitumor effect. To investigate the mechanisms behind these differences a well-established model for intestinal transport was used: the human colon cell line, CaCo2, when grown in special coated transwell plates forms a confluent differentiated polarised monolayer resembling gut epithelium. This model was used to determine the permeability of Gef, Erl, Sun, Cri, Sor, and Das, using LC-MS-MS to determine drug concentrations. Absorption from the gut given as the transfer rates from Apical to Basolateral (A/B) sides using 20 µM TKI at the apical side was determined over a 3 hour period. Transfer was linear in this period. Transfer rates varied from about 30 for Cri, 43 for Sun, 209 for Das, 180 for Gef, 223 for Sor, to 479 pmol/hr for Erl. In order to determine the role of ABC pumps, we depleted ATP with azide, which partially reduced transfer of Gef, Sun and Sor, but did not affect Erl. Ko143, a specific ABCG2 inhibitor decreased transfer of Gef and Sor but unexpectedly increased Sun. Remarkably, permeability transfer rates from the basolateral (blood) side to gut (B/A) were much higher (252 for Gef, 621 for Sor, 685 for Sun, 1623 for Erl and 4630 pmol/hr for Das) than A/B transfer. Verapamil, an inhibitor of P-glycoprotein and to some extend OCT1 increased A/B transfer of Sor and Das, but did not affect the transfer of the other compounds. Desipramine, a general OCT inhibitor, did not affect transfer of Erl, increased that of Gef and Cri about 2-fold and that of Sun 1.5-fold, but hardly affected that of Sor and Das. In conclusion, absorption of TKI from the apical side (gut epithelium) is relatively poor, while there was a relatively high negative flow (B/A); this is in line with the low bioavailability of most TKI. Some ABC transporters and OCTs play a role in the absorption, in line with their substrate specificity. Citation Information: Mol Cancer Ther 2013;12(11 Suppl):C82. Citation Format: Richard J. Honeywell, Christien Fatmawati, Marita Boeddha, Sarina Hitzerd, Ietje Kathmann, Elisa Giovannetti, Godefridus J. Peters. Role of influx and efflux transporters on gut absorption of selected tyrosine kinase inhibitors in a polarized gut epithelium model system. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr C82.
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