Details

Autor(en) / Beteiligte

• 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

Titel

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

Ist Teil von

• Molecular cancer therapeutics, 2017-05, Vol.16 (5), p.819-830

Ort / Verlag

United States: American Association for Cancer Research Inc

Erscheinungsjahr

2017

Quelle

MEDLINE

Beschreibungen/Notizen

• 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. .