Cancer Chemotherapy and Pharmacology

, Volume 81, Issue 1, pp 1–15 | Cite as

The promise and challenges of exploiting the proton-coupled folate transporter for selective therapeutic targeting of cancer

  • Larry H. MatherlyEmail author
  • Zhanjun Hou
  • Aleem Gangjee
Review Article
Part of the following topical collections:
  1. Cytotoxic Reviews


This review considers the “promise” of exploiting the proton-coupled folate transporter (PCFT) for selective therapeutic targeting of cancer. PCFT was discovered in 2006 and was identified as the principal folate transporter involved in the intestinal absorption of dietary folates. The recognition that PCFT was highly expressed in many tumors stimulated substantial interest in using PCFT for cytotoxic drug targeting, taking advantage of its high level transport activity under the acidic pH conditions that characterize many tumors. For pemetrexed, among the best PCFT substrates, transport by PCFT establishes its importance as a clinically important transporter in malignant pleural mesothelioma and non-small cell lung cancer. In recent years, the notion of PCFT-targeting has been extended to a new generation of tumor-targeted 6-substituted pyrrolo[2,3-d]pyrimidine compounds that are structurally and functionally distinct from pemetrexed, and that exhibit near exclusive transport by PCFT and potent inhibition of de novo purine nucleotide biosynthesis. Based on compelling preclinical evidence in a wide range of human tumor models, it is now time to advance the most optimized PCFT-targeted agents with the best balance of PCFT transport specificity and potent antitumor efficacy to the clinic to validate this novel paradigm of highly selective tumor targeting.


Antifolate Folate Glycinamide ribonucleotide formyltransferase Hypoxia Proton-coupled folate transporter Purine Reduced folate carrier Targeted therapy 


Compliance with ethical standards


This study was supported by grants from the National Cancer Institute, National Institutes of Health [R01 CA53535 (LHM, ZH), R01 CA152316 (LHM, AG), R01 CA166711 (AG, LHM)], the Eunice and Milton Ring Endowed Chair for Cancer Research (LHM), and the Duquesne University Adrian Van Kaam Chair in Scholarly Excellence (AG).

Conflict of interest

Larry H. Matherly declares that he has no conflict of interest. Zhanjun Hou declares that he has no conflict of interest. Aleem Gangjee declares that he has no conflict of interest.

Ethical approval

All applicable international, national, and/or institutional guidelines for the care and use of animals were followed. This article does not contain any studies with human participants performed by any of the authors.


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Copyright information

© Springer-Verlag GmbH Germany 2017

Authors and Affiliations

  • Larry H. Matherly
    • 1
    • 2
    • 3
    Email author
  • Zhanjun Hou
    • 1
    • 2
  • Aleem Gangjee
    • 4
  1. 1.Molecular Therapeutics ProgramBarbara Ann Karmanos Cancer InstituteDetroitUSA
  2. 2.Department of OncologyWayne State University School of MedicineDetroitUSA
  3. 3.Department of PharmacologyWayne State University School of MedicineDetroitUSA
  4. 4.Division of Medicinal Chemistry, Graduate School of Pharmaceutical SciencesDuquesne UniversityPittsburghUSA

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