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Targeted efflux transporter inhibitors - A solution to improve poor cellular accumulation of anti-cancer agents

Johanna Huttunen1, Mikko Gynther1, Kristiina M Huttunen1

  • 1School of Pharmacy, Faculty of Health Sciences, University of Eastern Finland, P.O. Box 1627, FI-70211 Kuopio, Finland.

International Journal of Pharmaceutics
|August 28, 2018
PubMed

Insights

Novel LAT1-utilizing prodrugs of probenecid target efflux pumps in cancer cells, enhancing chemotherapy efficacy. These prodrugs improve vinblastine accumulation and anti-proliferative effects, offering a strategy against multidrug resistance.

Area of Science:

  • Pharmacology
  • Cancer Biology
  • Drug Delivery

Background:

  • Efflux transporters hinder drug efficacy by removing xenobiotics from cells.
  • Current efflux pump inhibitors lack cancer cell selectivity.
  • l-Type amino acid transporter 1 (LAT1) is upregulated in many cancers and can be exploited for targeted drug delivery.

Purpose of the Study:

  • To design and synthesize LAT1-utilizing prodrugs of the efflux pump inhibitor probenecid (PRB).
  • To evaluate the ability of these prodrugs to target cancer cells via LAT1.
  • To assess the impact of these prodrugs on the cellular accumulation and efficacy of chemotherapeutic agents.

Main Methods:

  • Synthesis of 5 novel LAT1-utilizing prodrugs of probenecid.
  • Assessment of prodrug transport into human breast cancer cells (MCF-7) via LAT1.
  • Evaluation of interaction with efflux pumps: multidrug resistance proteins (MRPs), P-glycoprotein (P-gp), and breast cancer resistant protein (BCRP).
  • Measurement of cellular accumulation of vinblastine (VBL) and methotrexate (MTX) in combination treatments.
  • Assessment of anti-proliferative efficacy of combination treatments.

Main Results:

  • All synthesized prodrugs were efficiently transported into MCF-7 cells primarily through LAT1.
  • The prodrugs interacted with MRPs, P-gp, or BCRP, significantly increasing vinblastine (VBL) cellular accumulation (3-4 fold).
  • Combination treatment with VBL and prodrugs improved anti-proliferative efficacy, reducing cell growth from 100% to 48-75%.
  • No similar enhancement was observed with methotrexate (MTX), indicating drug-specific effects.

Conclusions:

  • LAT1-utilizing prodrugs of probenecid effectively target cancer cells and inhibit efflux pumps.
  • These prodrugs enhance the efficacy of certain chemotherapeutics like VBL against multidrug resistance (MDR).
  • Careful selection of chemotherapeutics based on their uptake mechanisms is crucial for successful combination therapy with LAT1-utilizing prodrugs.
Keywords:
Drug targetingInhibitor of efflux transporterMultidrug resistanceProdrugTransporter-mediated drug deliveryl-type amino acid transporter 1 (LAT1)

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