ABC drug transporters and immunity: novel therapeutic targets in autoimmunity and cancer

Abstract

ABC transporters were identified originally for their contribution to clinical MDR as a result of their capacity to extrude various unrelated cytotoxic drugs. More recent reports have shown that ABC transporters can play important roles in the development, differentiation, and maturation of immune cells and are involved in migration of immune effector cells to sites of inflammation. Many of the currently identified, endogenous ABC transporter substrates have immunostimulating effects. Increasing the expression of ABC transporters on immune cells and thereby enhancing immune cell development or functionality may be beneficial to immunotherapy in the field of oncology. On the contrary, in the treatment of autoimmune diseases, blockade of these transporters may prove beneficial, as it could dampen disease activity by compromising immune effector cell functions. This review will focus on the expression, regulation, and substrate specificity of ABC transporters in relation to functional activities of immune effector cells and discusses implications for the treatment of cancer on the one hand and autoimmune diseases on the other.

In Vivo 31P-Nuclear Magnetic Resonance Studies of Glyphosate Uptake, Vacuolar Sequestration, and Tonoplast Pump Activity in Glyphosate-Resistant Horseweed

“…Furthermore, glyphosate entry into the cell can be markedly inhibited by vanadate pretreatment. These characteristics are similar to those of ATP-binding cassette transporters in plants (Hetherington et al, 1998;Rea, 2007;Verrier et al, 2008;Prosecka et al, 2009;Conte and Lloyd, 2011) and mammalian cells (van de Ven et al, 2009;Ernst et al, 2010).…”

Detergent-free purification of ABC (ATP-binding-cassette) transporters

“…The human transporters are involved in a wide range of functions within the body including protection from toxins, metabolism, controlling drug distribution in the body, mediating inflammatory responses and transporting lipids [2][3][4][5]. Several members are involved in causing drug resistance during cancer treatment [6], while others are responsible for genetic diseases such as cystic fibrosis and adrenoleukodystrophy [7,8].…”

The Human P-Glycoprotein Transporter Enhances the Type I Interferon Response to Listeria monocytogenes Infection

“…This is the first report linking P-gp to activation of innate immunity in response to bacterial infection. There is no evidence that P-gp is directly involved in sensing bacterial ligands; however, there is burgeoning evidence that the membrane transporter influences the development of immune responses, including cytokine production (15). We noted that P-gp is activated and mediates cytokine enhancement only when bacteria invade the cytosol of host cells.…”

“…Furthermore, certain cytokines were shown to induce MDR1 transcription during inflammation (25, 26). P-gp's function in immune cells appears to impact distinct immune processes, such as activation of inflammatory cells and maturation of antigenpresenting cells (13,15,23,27). Taken together, these findings indicate an important role for P-gp in the development and function of immune cells and in the progression of inflammatory responses (15).…”

“…P-gp, encoded by the MDR1 gene, is the most prominent and best-characterized member of the ABCtype superfamily, first isolated in clinical cancers (6,10). Aside from its well-documented multidrug resistance function in cancer cells, P-gp is naturally expressed in a variety of normal tissues and cells, including immune cells, such as macrophages, dendritic cells, T and B lymphocytes, and natural killer (NK) cells, and was shown to possess physiological functions beyond detoxification (11)(12)(13)(14)(15). Several studies have indicated roles for P-gp in lipid transport, intracellular trafficking of cholesterol, cell death, cell differentiation, and immune responses (16,17).…”