Importance of Influx and Efflux Systems and Xenobiotic Metabolizing Enzymes in Intratumoral Disposition of Anticancer Agents

Abstract

In this review, intratumoral drug disposition will be integrated into the wide range of resistance mechanisms to anticancer agents with particular emphasis on targeted protein kinase inhibitors. Six rules will be established: 1. There is a high variability of extracellular/intracellular drug level ratios; 2. There are three main systems involved in intratumoral drug disposition that are composed of SLC, ABC and XME enzymes; 3. There is a synergistic interplay between these three systems; 4. In cancer subclones, there is a strong genomic instability that leads to a highly variable expression of SLC, ABC or XME enzymes; 5. Tumor-expressed metabolizing enzymes play a role in tumor-specific ADME and cell survival and 6. These three systems are involved in the appearance of resistance (transient event) or in the resistance itself. In addition, this article will investigate whether the overexpression of some ABC and XME systems in cancer cells is just a random consequence of DNA/chromosomal instability, hypo- or hypermethylation and microRNA deregulation, or a more organized modification induced by transposable elements. Experiments will also have to establish if these tumor-expressed enzymes participate in cell metabolism or in tumor-specific ADME or if they are only markers of clonal evolution and genomic deregulation. Eventually, the review will underline that the fate of anticancer agents in cancer cells should be more thoroughly investigated from drug discovery to clinical studies. Indeed, inhibition of tumor expressed metabolizing enzymes could strongly increase drug disposition, specifically in the target cells resulting in more efficient therapies.

The Blood-Testis Barrier and Its Implications for Male Contraception

“…Besides drugs (e.g., male contraceptives), cations, anions, electrolytes, steroids (e.g., corticosteroids), small biomolecules, and even xenobiotics, toxicants and certain sex hormones (e.g., estrogens, androgens) can enter or be eliminated from a cell (e.g., Sertoli cell) via drug transporters (Löscher and Potschka, 2005;Cérec et al, 2007;Koshiba et al, 2008;Setchell, 2008;Su et al, 2011a), illustrating their significance in conferring a unique microenvironment in the apical compartment behind the BTB for meiosis and postmeiotic spermatid development during spermiogenesis. Approximately 60% of the ϳ800 drug transporters known to exist to date in mammalian cells and tissues are integral membrane proteins (Rochat, 2009;Hosoya and Tachikawa, 2011;. Drug transporters can be categorized into 1) ATP-binding cassette (ABC) transporters (i.e., ATP-dependent drug transporters) and 2) solute carrier (SLC) transporters, the transport function of which does not require the consumption of ATP (Löscher and Potschka, 2005;Su et al, 2011a).…”

“…Slco6b1 (also known as testis-specific transporter-1 or gonad-specific transporter-1, implicated in Schwann cell development and involved in the transport of dehydroepiandrosterone sulfate, sex steroids and thyroid hormones), and 3. Slco6c1 (also known as testis-specific transporter-2 or gonad-specific transporter-2, involved in the transport of thyroxine, taurocholic acid, dehydroepiandrosterone, which is highly expressed by Sertoli cells in the testis (Collarini et al, 1992;Mizuno et al, 2003;Suzuki et al, 2003;Augustine et al, 2005;Ueno et al, 2010) all of which are known to be involved in drug transport in epithelia under normal and pathological conditions (Rochat, 2009;Kis et al, 2010;Klaassen and Aleksunes, 2010)] It was shown that when [ 3 H]adjudin was placed in the basal compartment of the bicameral unit, it was capable of traversing the Sertoli cell epithelium (an intact TJpermeability barrier was established in these cultures when barrier function was assessed by quantifying transepithelial electrical resistance across the epithelium) (see Fig. 6) and reaching the apical compartment .…”

The Molecular Basis for the Pharmacokinetics and Pharmacodynamics of Curcumin and Its Metabolites in Relation to Cancer

“…The curcumin that is taken up by cancer cells is subsequently subjected to similar metabolic processing (phase I-II and excretion) as described for enterocytes (sections III.C.2.a through III.C.2.f) because cancer cells contain many of the enzymes responsible for phase I and II metabolism (Burchell et al, 1990;Tsuchida and Sato, 1992;Doherty and Michael, 2003;Rochat, 2009) and the transporters to facilitate bidirectional trafficking of xenobiotics and their conjugates (Rochat, 2009;Brozik et al, 2011;Tiwari et al, 2011). Accordingly, reductive metabolism of curcumin to hexahydrocurcumin and octahydrocurcumin as well as export of the metabolites into the culture medium was found in human endometrial adenocarcinoma (Ishikawa) cells and HepG2 cells (Dempe et al, 2008).…”

Role of pharmacogenetics of drug-metabolizing enzymes in treating osteosarcoma

“…Clinical relevance of DMEs in human tumors 5.1 Introduction and current state of art DMEs are deeply involved in determining patients' predisposition to adverse events, and variations in their expression and activity play a critical role not only in susceptibility to collateral toxicity but also in drug effectiveness [81]. Several studies have demonstrated that cancer cells have a unique metabolism compared to normal cells [82] and provided evidence that drug metabolism also occurs within tumors [44,83].…”