The Dihydroorotate Dehydrogenase Inhibitor Brequinar Is Synergistic with ENT1/2 Inhibitors

Overview

Journal ACS Pharmacol Transl Sci

Publisher American Chemical Society

Specialty Biochemistry

Date 2020 Dec 21

PMID 33344900

Citations 13

Authors

Christine R Cuthbertson

Hui Guo

Armita Kyani

Joseph T Madak

Zahra Arabzada

Nouri Neamati

Affiliations

Soon will be listed here.

Abstract

The dihydroorotate dehydrogenase (DHODH) inhibitor brequinar failed all clinical trials for solid tumors. To investigate mechanisms to increase brequinar's efficacy, we employed a combination strategy to simultaneously inhibit the nucleotide salvage pathways. Brequinar is synergistic with the equilibrative nucleoside transporter (ENT) inhibitor dipyridamole, but not the concentrative nucleoside transporter inhibitor phlorizin. This synergy carries over to ENT1/2 inhibition, but not ENT4. Our previously described brequinar analogue was also synergistic with dipyridamole as were the FDA-approved DHODH inhibitors leflunomide and teriflunomide but the latter required much higher concentrations than brequinar. Therefore, a combination of brequinar and ENT inhibitors presents a potential anti-cancer strategy in select tumors.

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References

Bajzikova M, Kovarova J, Coelho A, Boukalova S, Oh S, Rohlenova K . Reactivation of Dihydroorotate Dehydrogenase-Driven Pyrimidine Biosynthesis Restores Tumor Growth of Respiration-Deficient Cancer Cells. Cell Metab. 2018; 29(2):399-416.e10. PMC: 7484595. DOI: 10.1016/j.cmet.2018.10.014. View

Dexter D, Hesson D, Ardecky R, Rao G, TIPPETT D, Dusak B . Activity of a novel 4-quinolinecarboxylic acid, NSC 368390 [6-fluoro-2-(2'-fluoro-1,1'-biphenyl-4-yl)-3-methyl-4-quinolinecarb oxylic acid sodium salt], against experimental tumors. Cancer Res. 1985; 45(11 Pt 1):5563-8. View

Murata Y, Hamada T, Kishiwada M, Ohsawa I, Mizuno S, Usui M . Human equilibrative nucleoside transporter 1 expression is a strong independent prognostic factor in UICC T3-T4 pancreatic cancer patients treated with preoperative gemcitabine-based chemoradiotherapy. J Hepatobiliary Pancreat Sci. 2011; 19(4):413-25. DOI: 10.1007/s00534-011-0440-3. View

Lomize A, Hage J, Schnitzer K, Golobokov K, LaFaive M, Forsyth A . PerMM: A Web Tool and Database for Analysis of Passive Membrane Permeability and Translocation Pathways of Bioactive Molecules. J Chem Inf Model. 2019; 59(7):3094-3099. PMC: 6781619. DOI: 10.1021/acs.jcim.9b00225. View

Andres A, Roses M, Rafols C, Bosch E, Espinosa S, Segarra V . Setup and validation of shake-flask procedures for the determination of partition coefficients (logD) from low drug amounts. Eur J Pharm Sci. 2015; 76:181-91. DOI: 10.1016/j.ejps.2015.05.008. View

Giovannetti E, Del Tacca M, Mey V, Funel N, Nannizzi S, Ricci S . Transcription analysis of human equilibrative nucleoside transporter-1 predicts survival in pancreas cancer patients treated with gemcitabine. Cancer Res. 2006; 66(7):3928-35. DOI: 10.1158/0008-5472.CAN-05-4203. View

Liu Z, Han Y, Zhang X, Chu L, Fang J, Zhao H . Prognostic value of human equilibrative nucleoside transporter1 in pancreatic cancer receiving gemcitabin-based chemotherapy: a meta-analysis. PLoS One. 2014; 9(1):e87103. PMC: 3903621. DOI: 10.1371/journal.pone.0087103. View

Kunicka T, Prochazka P, Krus I, Bendova P, Protivova M, Susova S . Molecular profile of 5-fluorouracil pathway genes in colorectal carcinoma. BMC Cancer. 2016; 16(1):795. PMC: 5062913. DOI: 10.1186/s12885-016-2826-8. View

Snezhkina A, Krasnov G, Zaretsky A, Zhavoronkov A, Nyushko K, Moskalev A . Differential expression of alternatively spliced transcripts related to energy metabolism in colorectal cancer. BMC Genomics. 2017; 17(Suppl 14):1011. PMC: 5249009. DOI: 10.1186/s12864-016-3351-5. View

10.

Natale R, Wheeler R, Moore M, Dallaire B, Lynch W, Carlson R . Multicenter phase II trial of brequinar sodium in patients with advanced melanoma. Ann Oncol. 1992; 3(8):659-60. DOI: 10.1093/oxfordjournals.annonc.a058298. View

11.

Farrell J, Elsaleh H, Garcia M, Lai R, Ammar A, Regine W . Human equilibrative nucleoside transporter 1 levels predict response to gemcitabine in patients with pancreatic cancer. Gastroenterology. 2008; 136(1):187-95. DOI: 10.1053/j.gastro.2008.09.067. View

12.

Aoyama T, Kazama K, Miyagi Y, Murakawa M, Yamaoku K, Atsumi Y . Predictive role of human equilibrative nucleoside transporter 1 in patients with pancreatic cancer treated by curative resection and gemcitabine-only adjuvant chemotherapy. Oncol Lett. 2017; 14(1):599-606. PMC: 5494679. DOI: 10.3892/ol.2017.6220. View

13.

Chan T, Howell S . Mechanism of synergy between N-phosphonacetyl-L-aspartate and dipyridamole in a human ovarian carcinoma cell line. Cancer Res. 1985; 45(8):3598-604. View

14.

Kim R, Tan A, Lai K, Jiang J, Wang Y, Rybicki L . Prognostic roles of human equilibrative transporter 1 (hENT-1) and ribonucleoside reductase subunit M1 (RRM1) in resected pancreatic cancer. Cancer. 2011; 117(14):3126-34. DOI: 10.1002/cncr.25883. View

15.

WILLSON J, FISCHER P, Tutsch K, Alberti D, Simon K, HAMILTON R . Phase I clinical trial of a combination of dipyridamole and acivicin based upon inhibition of nucleoside salvage. Cancer Res. 1988; 48(19):5585-90. View

16.

Madak J, Bankhead 3rd A, Cuthbertson C, Showalter H, Neamati N . Revisiting the role of dihydroorotate dehydrogenase as a therapeutic target for cancer. Pharmacol Ther. 2018; 195:111-131. DOI: 10.1016/j.pharmthera.2018.10.012. View

17.

Hagmann W, Jesnowski R, Matthias Lohr J . Interdependence of gemcitabine treatment, transporter expression, and resistance in human pancreatic carcinoma cells. Neoplasia. 2010; 12(9):740-7. PMC: 2933694. DOI: 10.1593/neo.10576. View

18.

Chen S, Papp L, Ardecky R, Rao G, Hesson D, Forbes M . Structure-activity relationship of quinoline carboxylic acids. A new class of inhibitors of dihydroorotate dehydrogenase. Biochem Pharmacol. 1990; 40(4):709-14. DOI: 10.1016/0006-2952(90)90305-5. View

19.

Chan T, Markman M, Cleary S, Howell S . Plasma uridine changes in cancer patients treated with the combination of dipyridamole and N-phosphonacetyl-L-aspartate. Cancer Res. 1986; 46(6):3168-72. View

20.

Marechal R, Mackey J, Lai R, Demetter P, Peeters M, Polus M . Human equilibrative nucleoside transporter 1 and human concentrative nucleoside transporter 3 predict survival after adjuvant gemcitabine therapy in resected pancreatic adenocarcinoma. Clin Cancer Res. 2009; 15(8):2913-9. DOI: 10.1158/1078-0432.CCR-08-2080. View