L-type amino acid transporter 1 (LAT1)-utilizing efflux transporter inhibitors can improve the brain uptake and apoptosis-inducing effects of vinblastine in cancer cells.

Efflux transporter-mediated multidrug resistance (MDR) prevents chemotherapeutics to achieve therapeutically relevant concentrations within the cancer cells. Therefore, inhibitors of efflux transporters have been in demand. However, to be safe, these inhibitors are needed to be targeted into the cancer cells. For this purpose, L-type amino acid transporter 1 (LAT1), overexpressed in many different cancer cell types, can be utilized. In the present study, two LAT1-utilizing derivatives of probenecid (PRB) that can inhibit e.g., multiresistance proteins (MRPs) and organic anion transporters (OATs), were studied for their apoptosis-inducing effects in cancer cells alone and a combination with another chemotherapeutic, vinblastine (VBL). Also, their hemocompatibility and off-target toxicity were evaluated. Moreover, the brain uptake rate and extent of VBL together with the most promising LAT1-utilizing efflux inhibitor was studied after in situ rat brain perfusion and after intraperitoneal administration to mice. As a result, these targeted inhibitors increased significantly the apoptosis-inducing effects of VBL and more effectively than PRB itself. They also were hemocompatible and non-toxic in healthy cells with a concentration below 100 µM. Interestingly, the most promising compound doubled the penetration rate of VBL across the rat blood-brain barrier (BBB). This makes it a promising candidate for further studies to improve efflux transporter-related MDR of brain-targeted anti-cancer agents.