The role of transporters in the toxicity of nucleoside and nucleotide analogs

Abstract

Introduction Two families of nucleoside analogs have been developed to treat viral infections and cancer, but these compounds can cause tissue and cell-specific toxicity related to their uptake and subcellular activity which are dictated by host enzymes and transporters. Cellular uptake of these compounds requires nucleoside transporters that share functional similarities but differ in substrate specificity. Tissue-specific cellular expression of these transporters enables nucleoside analogs to produce their tissue specific toxic effects, a limiting factor in the treatment of retroviruses and cancer. Areas Covered This review discusses the families of nucleoside transporters and how they mediate cellular uptake of nucleoside analogs. Specific focus is placed on examples of known cases of transporter-mediated cellular toxicity and classification of the toxicities resulting. Efflux transporters are also explored as a contributor to analog toxicity and cell-specific effects. Expert Opinion Efforts to modulate transporter uptake/clearance remain long-term goals of oncologists and virologists. Accordingly, subcellular approaches that either increase or decrease intracellular nucleoside analog concentrations are eagerly sought and include transporter inhibitors and targeting transporter expression. However, additional understanding of nucleoside transporter kinetics, tissue expression, and genetic polymorphisms are required to design better molecules and better therapies.

Expression, purification and functional characterization of human equilibrative nucleoside transporter subtype-1 (hENT1) protein from Sf9 insect cells

“…In mammalian cells, two major families of nucleoside transporters exist; the SLC28 family of concentrative sodium dependent transporters (CNTs) and the SLC29 family of equilibrative sodium independent transporters (ENTs) [1]. Members of both families transport natural nucleosides as well as nucleoside analogs used to treat various types of cancers, HIV and many other viral diseases [4,5].…”

Transgenic mouse model with deficient mitochondrial polymerase exhibits reduced state IV respiration and enhanced cardiac fibrosis

“…Although NRTIs effectively inhibit HIV replication, limiting side effects relate to mitochondrial polymerase, pol γ (6–8). By inhibiting pol γ, NRTIs decrease mtDNA abundance, reduce mitochondrial energy production, and promote cellular dysfunction and disease (2).…”

Cyclic AMP efflux inhibitors as potential therapeutic agents for leukemia

“…We anticipate that identification of drugs that inhibit this transport could allow for selective targeting of cancers that capitalize on cAMP pathway modulation for survival, and this merits further investigation into the effects of ICE on multiple ABC transporters. The fact that the machinery responsible for apoptotic evasion by cAMP efflux can also potentially support the removal of structurally related chemotherapy drugs (e.g., ara-C), and thus may contribute to multidrug resistance [38-40], makes this work unusually promising.…”