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

ABSTRACT: 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) ?. Although in primary EOC specimens, FR? 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 FR? and similar amounts (within ?2-fold) of PCFT. Novel 6-substituted pyrrolo[2,3-d]pyrimidine thienoyl antifolates AGF94 and AGF154 exhibited potent antiproliferative activities toward all of the EOC cell lines, reflecting selective cellular uptake by FR? and/or PCFT over RFC. When IGROV1 cells were pretreated with AGF94 at pH 6.8, clonogenicity was potently inhibited, confirming cell killing. FR? was knocked down in IGROV1 cells with lentiviral shRNAs. Two FR? knockdown clones (KD-4 and KD-10) showed markedly reduced binding and uptake of [3H]folic acid and [3H]AGF154 by FR?, but maintained high levels of [3H]AGF154 uptake by PCFT compared to nontargeted control cells. In proliferation assays, KD-4 and KD-10 cells preserved in vitro inhibition by AGF94 and AGF154, compared to a nontargeted control, attributable to residual FR?- and substantial PCFT-mediated uptake. KD-10 tumor xenografts in severe-compromised immune-deficient mice were likewise sensitive to AGF94 Collectively, our results demonstrate the substantial therapeutic potential of novel 6-substituted pyrrolo[2,3-d]pyrimidine antifolates with dual targeting of PCFT and FR? toward EOCs that express a range of FR?, along with PCFT, as well as cisplatin resistance. Mol Cancer Ther; 16(5); 819-30. ©2017 AACR.

SUBMITTER: Hou Z 

PROVIDER: S-EPMC5443351 | biostudies-literature | 2017 May

REPOSITORIES: biostudies-literature

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

Hou Zhanjun Z   Gattoc Leda L   O'Connor Carrie C   Yang Si S   Wallace-Povirk Adrianne A   George Christina C   Orr Steve S   Polin Lisa L   White Kathryn K   Kushner Juiwanna J   Morris Robert T RT   Gangjee Aleem A   Matherly Larry H LH  

Molecular cancer therapeutics 20170130 5

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  ...[more]

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