Current platinum (Pt) chemotherapy drugs rely mainly on passive diffusion for cellular uptake, leading to severe off target side effects including peripheral neuropathy, often the dose limiting side effect1. The amino acid glutamine plays important roles in cellular metabolism and has been extensively studied for its increased demand in cancer cells2. The Alanine Serine Cysteine Transporter (ASCT) 2, a major glutamine transporter, has shown to be upregulated in a variety of cancers. ASCT2 belongs to the SLC1A family of membrane transporters and is an obligatory exchanger of neutral amino acids, with each influx of one neutral amino acid and 3 sodium ions corresponding to efflux of the same. While this process is electroneutral, an uncoupled chloride conductance is activated during the transport cycle, allowing function to be measured via electrophysiology. To improve selectivity of these Pt-drugs, amino acid targeted drug delivery systems, Pt-aspartate and Pt-succinate, were developed. This project aimed to determine if these compounds enter cells via ASCT2
Membrane transporters were expressed in a Xenopus laevis oocyte epression model and their transport activity assessed via two-electrode voltage clamp electrophysiology. When the Pt-compounds were applied alone, they did not generate transporter currents, suggesting that they are unable to be transported by ASCT2. Instead, inhibition of the “leak current” was observed, suggesting they bind to and block substrate binding. When applied in the presense of substrate, both Pt compounds reduced transport currents and inhibit radiolabelled substrate uptake, with Pt-aspartate more potent than Pt-succinate. Future research will expand selectivity testing to assess alternative protein-mediated routes and transport mechanisms such as endocytosis. If these compounds are found to selectively enter cancer cells via one of the suggested mechanisms, it could lead to the start of a new and safer class of Pt-chemotherapy drugs.
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