Dual Targeting of Epithelial Ovarian Cancer Via Folate Receptor α and the Proton-Coupled Folate Transporter with 6-Substituted Pyrrolo[2,3- d ]pyrimidine Antifolates

Folate uptake in epithelial ovarian cancer (EOC) involves the reduced folate carrier (RFC) and the proton-coupled folate transporter (PCFT), both facilitative transporters and folate receptor (FR) α. Although in primary EOC specimens, FRα is widely expressed and increases with tumor stage, PCFT was...

Full description

Saved in:
Bibliographic Details
Published in:Molecular cancer therapeutics 2017-05, Vol.16 (5), p.819-830
Main Authors: Hou, Zhanjun, Gattoc, Leda, O'Connor, Carrie, Yang, Si, Wallace-Povirk, Adrianne, George, Christina, Orr, Steve, Polin, Lisa, White, Kathryn, Kushner, Juiwanna, Morris, Robert T, Gangjee, Aleem, Matherly, Larry H
Format: Article
Language:English
Subjects:
Animal models
Animals
Cancer
Carcinoma, Ovarian Epithelial
Cell culture
Cell Line, Tumor
Cell proliferation
Cell Proliferation - drug effects
Cisplatin
Cisplatin - administration & dosage
Drug Resistance, Neoplasm - drug effects
Folate Receptor 1 - antagonists & inhibitors
Folate Receptor 1 - genetics
Folic acid
Folic Acid - genetics
Folic Acid Antagonists - administration & dosage
Folic Acid Antagonists - chemical synthesis
Humans
Mice
Neoplasms, Glandular and Epithelial - drug therapy
Neoplasms, Glandular and Epithelial - genetics
Neoplasms, Glandular and Epithelial - pathology
Ovarian cancer
Ovarian Neoplasms - drug therapy
Ovarian Neoplasms - genetics
Ovarian Neoplasms - pathology
pH effects
Polymerase chain reaction
Proton-Coupled Folate Transporter - genetics
Substitutes
Vitamin B
Xenograft Model Antitumor Assays
Xenografts
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:Folate uptake in epithelial ovarian cancer (EOC) involves the reduced folate carrier (RFC) and the proton-coupled folate transporter (PCFT), both facilitative transporters and folate receptor (FR) α. Although in primary EOC specimens, FRα is widely expressed and increases with tumor stage, PCFT was expressed independent of tumor stage (by real-time RT-PCR and IHC). EOC cell line models, including cisplatin sensitive (IGROV1 and A2780) and resistant (SKOV3 and TOV112D) cells, expressed a 17-fold range of FRα and similar amounts (within ∼2-fold) of PCFT. Novel 6-substituted pyrrolo[2,3- ]pyrimidine thienoyl antifolates and exhibited potent antiproliferative activities toward all of the EOC cell lines, reflecting selective cellular uptake by FRα and/or PCFT over RFC. When IGROV1 cells were pretreated with at pH 6.8, clonogenicity was potently inhibited, confirming cell killing. FRα was knocked down in IGROV1 cells with lentiviral shRNAs. Two FRα knockdown clones (KD-4 and KD-10) showed markedly reduced binding and uptake of [ H]folic acid and [ H] by FRα, but maintained high levels of [ H] uptake by PCFT compared to nontargeted control cells. In proliferation assays, KD-4 and KD-10 cells preserved inhibition by and , compared to a nontargeted control, attributable to residual FRα- and substantial PCFT-mediated uptake. KD-10 tumor xenografts in severe-compromised immune-deficient mice were likewise sensitive to Collectively, our results demonstrate the substantial therapeutic potential of novel 6-substituted pyrrolo[2,3- ]pyrimidine antifolates with dual targeting of PCFT and FRα toward EOCs that express a range of FRα, along with PCFT, as well as cisplatin resistance. .
ISSN:1535-7163
1538-8514
DOI:10.1158/1535-7163.MCT-16-0444