Reduced folate carrier (RFC) as a predictive marker for response to pemetrexed in advanced non-small cell lung cancer (NSCLC)

Álvarez-Fernández, Carlos; Perez-Arnillas, Quionia; Ruiz-Echeverria, L.; Rodriguez-Rubi, David; Sánchez-Lorenzo, Luisa; Li-Torres, Walter; Izquierdo-Manuel, Marta; Berros, Jose Pablo; Luque-Cabal, María; Jiménez‐Fonseca, Paula; Villanueva-Palicio, Noemi; Esteban, Emilio

doi:10.1007/s10637-013-9992-1

Cited by 5 publications

(2 citation statements)

References 18 publications

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“…The role of RFC transport in MTX antitumor activity has been extensively documented (14, 46–48). In non–small cell lung cancer and malignant pleural mesothelioma, expression of RFC was also associated with clinical responses to treatment with PMX (49, 50), although in another study of malignant pleural mesothelioma an important role for PCFT in PMX clinical efficacy was strongly implied (51). Transport of cytotoxic antifolates by RFC into normal tissues is causal to toxicity since RFC is expressed in normal tissues as well as tumors (14).…”

Section: Discussionmentioning

confidence: 99%

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

Hou

Gattoc

O’Connor

et al. 2017

Molecular Cancer Therapeutics

128

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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. Whereas 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 immunohistochemistry). 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-d]pyrimidine thienoyl antifolates AGF94 and AGF154 exhibited potent anti-proliferative 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 AGF94 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 [3H]folic acid and [3H]AGF154 by FRα, but maintained high levels of [3H]AGF154 uptake by PCFT compared to non-targeted control cells. In proliferation assays, KD-4 and KD-10 cells preserved in vitro inhibition by AGF94 and AGF154, compared to a non-targeted control, attributable to residual FRα- 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 FRα toward EOCs that express a range of FRα, along with PCFT, as well as cisplatin resistance.

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Section: Discussionmentioning

confidence: 99%

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

Hou

Gattoc

O’Connor

et al. 2017

Molecular Cancer Therapeutics

128

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“…RFC is a member of the solute carrier family and plays an important role in the uptake of FA [12]. RFC is the major transport system in cells for folate cofactors and antifolate therapeutics [34]. Studies have shown that inactivation of RFC leads to severe folate deficiency in the body [35].…”

Section: Discussionmentioning

confidence: 99%

High Dietary Folic Acid Supplementation Reduced the Composition of Fatty Acids and Amino Acids in Fortified Eggs

Yu,

Deng,

Long

et al. 2024

Foods

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Aims: The study aimed to evaluate the effects of dietary folic acid (FA) on the production performance of laying hens, egg quality, and the nutritional differences between eggs fortified with FA and ordinary eggs. Methods: A total of 288 26-week-old Hy-Line Brown laying hens (initial body weights 1.65 ± 0.10 kg) with a similar weight and genetic background were used. A completely randomized design divided the birds into a control group and three treatment groups. Each group consisted of six replicates, with twelve chickens per replicate. Initially, all birds were fed a basal diet for 1 week. Subsequently, they were fed a basal diet supplemented with 0, 5, 10, or 15 mg/kg FA in a premix for a duration of 6 weeks. Results: Supplementation of FA could significantly (p < 0.05) enhance the FA content in egg yolks, particularly when 10 mg/kg was used, as it had the most effective enrichment effect. Compared to the control group, the Glu content in the 10 and 15 mg/kg FA groups showed a significant (p < 0.05) decrease. Additionally, the contents of Asp, Ile, Tyr, Phe, Cys, and Met in the 15 mg/kg FA group were significantly (p < 0.05) lower compared to the other groups. Adding FA did not have significant effects on the levels of vitamin A and vitamin E in egg yolk, but the vitamin D content in the 5 and 10 mg/kg FA groups showed a significant (p < 0.05) increase. Furthermore, the addition of FA did not have a significant effect on the levels of Cu, Fe, Mn, Se, and Zn in egg yolk. The dietary FA did not have a significant effect on the total saturated fatty acids (SFA) and polyunsaturated fatty acid (PUFA) content in egg yolk. However, the total monounsaturated fatty acid (MUFA) content in the 5 and 10 mg/kg groups significantly (p < 0.05) increased. These changes in nutritional content might be attributed to the increased very low-density lipoprotein (VLDL) protein content. The significant decrease in solute carrier family 1 Member 1 (SLC1A1), solute carrier family 1 Member 2 (SLC1A2), and solute carrier family 1 Member 3 (SLC1A3) gene expression compared to the control group appeared to be the reason for the decrease in amino acid content in egg yolk within the dietary FA group. Conclusion: The findings suggest that the appropriate addition of FA can enhance the levels of MUFA and vitamin D in egg yolks, thereby improving their nutritional value. Excessive intake of FA can decrease the effectiveness of enriching FA in egg yolk and impact the enrichment of certain amino acids. The yolk of eggs produced by adding 10 mg/kg of FA to the feed contains the optimal amount of nutrients. This study informs consumers purchasing FA-fortified eggs.

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Drug Resistance in Lung Cancer

Colarusso

Terlizzi

Pinto

et al. 2022

Interdisciplinary Cancer Research

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Reduced folate carrier (RFC) as a predictive marker for response to pemetrexed in advanced non-small cell lung cancer (NSCLC)

Abstract: These results suggest the possible relation between RFC expression and response to treatment with antifolates (pemetrexed) independently of the tumor histology. Further studies are required to confirm these results.

Cited by 5 publications

References 18 publications

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

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

High Dietary Folic Acid Supplementation Reduced the Composition of Fatty Acids and Amino Acids in Fortified Eggs

Drug Resistance in Lung Cancer

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