Abstract
Increased amounts of amino acids are essential for cancer cells to support their sustained growth and survival. Therefore, inhibitors of amino acid transporters, such as l-type amino acid transporter 1 (LAT1) have been developed. In this study, a previously reported LAT1-inhibitor (KMH-233) was studied for its hemocompatibility and toxicity towards human umbilical vein endothelial cells (HUVEC) and human aortic smooth muscle cells (AoSMCs). Furthermore, the cytotoxic effects against human breast adenocarcinoma cells (MCF-7) and its ability to affect mammalian (or mechanistic) target of rapamycin (mTOR) and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) signaling were evaluated. Moreover, the effects of this inhibitor to modulate LAT1 function on the cell surface and the brain amino acid homeostasis were evaluated after intraperitoneal (i.p.) administration of LAT1-inhibitor (23 µmol/kg) in mice. The results showed that LAT1-inhibitor (KMH-233) is hemocompatible at concentrations below 25 µM and it does not affect coagulation in plasma. However, it can reduce the total protein amount of mTOR and NF-κB, resulting in increased apoptosis in LAT1-expressing cancer cells. Most importantly, the inhibitor did not affect mouse brain levels of l-Leu, l-Tyr or l-Trp or modulate the function of LAT1 on the MCF-7 cell surface. Therefore, this inhibitor can be considered as a safe but effective anti-cancer agent. However, due to the compensative mechanism of cancer cells for their increased amino acid demand, this compound is most effective inducing apoptosis when used in combinations with other chemotherapeutics, such as protease inhibitor, bestatin, as demonstrated in this study.
Highlights
Cancer cells require enormous amounts of nutrients to support their uncontrolled and rapid division [1, 2]
These results showed that the exposure to compound 1 did not significantly affect the value of prothrombin time (PT), or international normalized ratio (INR) (Fig. 2a, b)
The results of partially activated thromboplastin time (APTT) measurements revealed that the compound did not influence the intrinsic coagulation pathway either (Fig. 2c)
Summary
Cancer cells require enormous amounts of nutrients to support their uncontrolled and rapid division [1, 2]. L-Type amino acid transporter 1 (LAT1, SLC7A5) is a pH and sodium independent transporter carrying large, neutral, aromatic or branched essential l-amino acids (EAAs), such as l-Leu, l-Phe, l-Tyr, l-Trp, l-His, l-Met, l-Ile, and l-Val into the cells [4, 5]. Amino acids are essential nutrients for protein synthesis and metabolism and cancer cells must have increased uptake of amino acid across the plasma membrane [3]. It functions as an antiporter and exchanges an intracellular EAAs or glutamine, for the external ones with 1:1 stoichiometry [6]. High LAT1 expression has been associated with a significantly shorter survival of patients and poorer prognosis in the case of breast, and prostate cancers [12, 13]
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