The human proton-coupled folate transporter: Biology and therapeutic applications to cancer

Our plain-English summary of The human proton-coupled folate transporter: Biology and therapeutic applications to cancer, by S.K. Desmoulin, Z. Hou, A. Gangjee, et al (Cancer Biology & Therapy, 2012).

The study

• Authors: S.K. Desmoulin, Z. Hou, A. Gangjee, L.H. Matherly
• Journal: Cancer Biology & Therapy
• Published: 2012;13(14):1355-73
• Type of article: Review
• Cited by: 124 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

This review summarizes the biology of the proton-coupled folate transporter (PCFT). PCFT was identified in 2006 as the primary transporter for intestinal absorption of dietary folates, as mutations in PCFT are causal in hereditary folate malabsorption (HFM) syndrome. Since 2006, there have been major advances in understanding the mechanistic roles of critical amino acids and/or domains in the PCFT protein, many of which were identified as mutated in HFM patients, and in characterizing transcriptional control of the human PCFT gene. With the recognition that PCFT is abundantly expressed in human tumors and is active at pHs characterizing the tumor microenvironment, attention turned to exploiting PCFT for delivering novel cytotoxic antifolates for solid tumors. The finding that pemetrexed is an excellent PCFT substrate explains its demonstrated clinical efficacy for mesothelioma and non-small cell lung cancer, and prompted development of more PCFT-selective tumor-targeted 6-substituted pyrrolo[2,3-d]pyrimidine antifolates that derive their cytotoxic effects by targeting de novo purine nucleotide biosynthesis.

In plain English

This article was a review, not a new study, of research on the proton-coupled folate transporter (PCFT), a protein that carries folates and some drugs into cells. It reported no data on asbestos exposure. Its link to asbestos-related disease is pemetrexed, a mesothelioma drug. The authors described work showing that PCFT's main role is intestinal absorption of dietary folate, that its loss causes hereditary folate malabsorption, and that it works best in acidic conditions. They reviewed findings of substantial PCFT levels in most solid tumor cell lines but very low to undetectable levels in leukemia lines. They stated that pemetrexed being an excellent PCFT substrate validated its established clinical efficacy for malignant mesothelioma and non-small cell lung cancer. They also reviewed experimental drugs, compounds 16 and 17, which entered cells through PCFT with almost no reduced folate carrier transport but were also active against cells with folate receptors. These drugs were tested in laboratory cells and in mice with human tumor grafts. The authors said questions remain, including how PCFT is regulated and how drug resistance might develop.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: narrative review of published laboratory and clinical research on the proton-coupled folate transporter (PCFT)
• Who was studied: Not applicable: no study population. The review covers published laboratory, animal and clinical research on PCFT and antifolate drugs.
• Exposure: Not applicable: no asbestos or other occupational exposure was studied. The review concerns folate transport and antifolate cancer drugs, including pemetrexed.
• Main results:
  • Reviewed work indicated that PCFT's primary role is intestinal absorption of dietary folates.
  • Reviewed work indicated that loss of PCFT function impairs intestinal folate absorption, as in hereditary folate malabsorption.
  • PCFT transport falls sharply as pH rises above 5.5 and is scarcely detectable above pH 7.
  • A reviewed study examined 80 cell lines (53 from human solid tumors, 27 from leukemias). It found substantial PCFT transcript levels in most tumor cell lines and very low to undetectable levels in leukemias.
  • The authors stated that pemetrexed being an excellent PCFT substrate validated its established clinical efficacy for malignant mesothelioma and non-small cell lung cancer.
  • Experimental compounds 16 and 17 inhibited PCFT-expressing R2/hPCFT4 Chinese hamster ovary (CHO) cells, with IC50s of 3.34 nM and 43 nM respectively.
  • The 6-substituted pyrrolo[2,3-d]pyrimidine antifolates, which include compounds 16 and 17, were nearly exclusively selective for PCFT over the reduced folate carrier.
  • Compounds 16 and 17 were also active toward cell lines expressing folate receptors. The authors noted that no compound yet identified is selective for PCFT transport without substantial folate receptor uptake as well.
  • In protection experiments, the enzyme GARFTase was identified as the main cellular target of these experimental compounds.
  • Studies in SCID mice bearing human tumor grafts (HepG2, HeLa) were described as proof-of-concept that compounds 16 and 17 can target tumors through PCFT.
• The authors' conclusion: The authors concluded that the selectivity of the new PCFT-targeted drugs is enhanced because the acidic pH of solid tumors favors transport by PCFT over the reduced folate carrier (RFC).
• Limitations the authors state:
  • The detailed three-dimensional (tertiary) structure of human PCFT had not been determined.
  • Further understanding of how PCFT is regulated is needed.
  • Resistance to the new PCFT-selective drugs still needs to be studied.

Topics

Medical terms in this study, explained in our Lexicon: Tumor Microenvironment, Antifolate, Pemetrexed (Alimta), Mesothelioma, Non-Small Cell Lung Cancer, De Novo.

Related studies

• Therapeutic targeting malignant mesothelioma with a novel 6-substituted pyrrolo[2,3-d]pyrimidine thienoyl antifolate via its selective uptake by the proton-coupled folate transporter — C. Cherian, S. Kugel Desmoulin, et al. (2013)
• The promise and challenges of exploiting the proton-coupled folate transporter for selective therapeutic targeting of cancer — L.H. Matherly, Z. Hou, et al. (2018)
• Impact of hypoxia on chemoresistance of mesothelioma mediated by the proton-coupled folate transporter, and preclinical activity of new anti-LDH-A compounds — G. Li Petri, B. El Hassouni, et al. (2020)
• The impact of folate status on the efficacy of colorectal cancer treatment — L. Porcelli, Y.G. Assaraf, et al. (2011)
• Pemetrexed disodium: a novel antifolate clinically active against multiple solid tumors — A.R. Hanauske, V. Chen, et al. (2001)
• Clinical and pharmacokinetic phase I study of multitargeted antifolate (LY231514) in combination with cisplatin — R. Thödtmann, H. Depenbrock, et al. (1999)

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