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Article

The mechanism underlying resistance to 5‑fluorouracil and its reversal by the inhibition of thymidine phosphorylase in breast cancer cells

  • Authors:
    • Ryutaro Mori
    • Junko Ukai
    • Yoshihisa Tokumaru
    • Yoshimi Niwa
    • Manabu Futamura
  • View Affiliations / Copyright

    Affiliations: Department of Breast Surgery, Gifu University Graduate School of Medicine, Gifu 501‑1194, Japan
  • Article Number: 311
    |
    Published online on: July 15, 2022
       https://doi.org/10.3892/ol.2022.13431
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Abstract

Fluoro‑deoxyuridine monophosphate (FdUMP) is an active metabolite of 5‑fluorouracil (5‑FU) synthesized through two hypothesized pathways: The orotate phosphoribosyl transferase‑ribonucleotide reductase (OPRT‑RR) pathway and the thymidine phosphorylase‑thymidine kinase (TP‑TK) pathway. In the present study, the mechanism underlying 5‑FU resistance was investigated, focusing on changes in 5‑FU metabolism using MCF‑7, 5‑FU‑resistant MCF‑7/5‑FUR, MDA‑MB‑231 and 5‑FU‑resistant MDA‑MB‑231/5‑FUR breast cancer cells. The amount of FdUMP present following treatment with 5‑FU was determined by the density of the upper band of thymidylate synthase detected by western blotting, and its changes were investigated. MCF‑7/5‑FUR cells exhibited 5‑FU resistance (36.6‑fold), and showed decreased OPRT (‑69.3%) and TK (‑42.6%) levels. MDA‑MB‑231/5‑FUR cells also exhibited 5‑FU resistance (15.8‑fold), and showed decreased TP (‑79.0%) and increased TK (+184%) levels. MCF‑7/5‑FUR and MDA‑MB‑231/5‑FUR cells both showed decreased synthesis of FdUMP by 91 and 86%, respectively. In MCF‑7 and MCF‑7/5‑FUR cells, the synthesis of FdUMP was decreased when 5‑FU was combined with an RR inhibitor, indicating that FdUMP was synthesized through the OPRT‑RR pathway. The synthesis of FdUMP was decreased when 5‑FU was combined with a TP inhibitor in MDA‑MB‑231 cells and combined with an RR inhibitor in MDA‑MB‑231/5‑FUR cells, indicating that the synthesis pathway of FdUMP was changed from the TP‑TK pathway to the OPRT‑RR pathway on acquiring resistance to 5‑FU. Notably, the synthesis of FdUMP was increased and the resistance to 5‑FU was reversed in MCF‑7/5‑FUR cells (half maximal inhibitory concentration (IC50): 219.9 to 0.093 µM) and MDA‑MB‑231/5‑FUR cells (IC50: 157.3 to 31.0 µM) when 5‑FU was combined with a TP inhibitor. In conclusion, the metabolism of 5‑FU and the mechanism underlying the resistance to 5‑FU differed among cell lines, and inhibition of TP reversed resistance to 5‑FU, thus suggesting that the combination of 5‑FU and a TP inhibitor may be considered a promising cancer therapy.
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1 

Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A and Bray F: Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 71:209–249. 2021. View Article : Google Scholar : PubMed/NCBI

2 

Longley DB, Harkin DP and Johnston PG: 5-fluorouracil: Mechanisms of action and clinical strategies. Nat Rev Cancer. 3:330–338. 2003. View Article : Google Scholar : PubMed/NCBI

3 

Toi M, Imoto S, Ishida T, Ito Y, Iwata H, Masuda N, Mukai H, Saji S, Shimizu A, Ikeda T, et al: Adjuvant S-1 plus endocrine therapy for oestrogen receptor-positive, HER2-negative, primary breast cancer: A multicentre, open-label, randomised, controlled, phase 3 trial. Lancet Oncol. 22:74–84. 2021. View Article : Google Scholar

4 

Masuda N, Lee SJ, Ohtani S, Im YH, Lee ES, Yokota I, Kuroi K, Im SA, Park BW, Kim SB, et al: Adjuvant capecitabine for breast cancer after preoperative chemotherapy. N Engl J Med. 376:2147–2159. 2017. View Article : Google Scholar : PubMed/NCBI

5 

Takashima T, Mukai H, Hara F, Matsubara N, Saito T, Takano T, Park Y, Toyama T, Hozumi Y, Tsurutani J, et al: Taxanes versus S-1 as the first-line chemotherapy for metastatic breast cancer (SELECT BC): An open-label, non-inferiority, randomised phase 3 trial. Lancet Oncol. 17:90–98. 2016. View Article : Google Scholar

6 

Kufe DW and Major PP: 5-Fluorouracil incorporation into human breast carcinoma RNA correlates with cytotoxicity. J Biol Chem. 256:9802–9805. 1981. View Article : Google Scholar : PubMed/NCBI

7 

Saito K, Nagashima H, Noguchi K, Yoshisue K, Yokogawa T, Matsushima E, Tahara T and Takagi S: First-in-human, phase I dose-escalation study of single and multiple doses of a first-in-class enhancer of fluoropyrimidines, a dUTPase inhibitor (TAS-114) in healthy male volunteers. Cancer Chemother Pharmacol. 73:577–83. 2014. View Article : Google Scholar

8 

Francini G, Petrioli R, Lorenzini L, Mancini S, Armenio S, Tanzini G, Marsili S, Aquino A, Marzocca G, Civitelli S, et al: Folinic acid and 5-fluorouracil as adjuvant chemotherapy in colon cancer. Gastroenterology. 106:899–906. 1994. View Article : Google Scholar : PubMed/NCBI

9 

Goodsell DS: The molecular perspective: methotrexate. Oncologist. 4:340–341. 1999. View Article : Google Scholar

10 

Rose MG, Farrell MP and Schmitz JC: Thymidylate synthase: A critical target for cancer chemotherapy. Clin Colorectal Cancer. 1:220–229. 2002. View Article : Google Scholar : PubMed/NCBI

11 

Wolmark N, Rockette H, Fisher B, Wickerham DL, Redmond C, Fisher ER, Jones J, Mamounas EP, Ore L, Petrelli NJ, et al: The benefit of leucovorin-modulated fluorouracil as postoperative adjuvant therapy for primary colon cancer: Results from national surgical adjuvant breast and bowel project protocol C-03. J Clin Oncol. 11:1879–1887. 1993. View Article : Google Scholar

12 

Hironaka S, Sugimoto N, Yamaguchi K, Moriwaki T, Komatsu Y, Nishina T, Tsuji A, Nakajima TE, Gotoh M, Machida N, et al: S-1 plus leucovorin versus S-1 plus leucovorin and oxaliplatin versus S-1 plus cisplatin in patients with advanced gastric cancer: A randomised, multicentre, open-label, phase 2 trial. Lancet Oncol. 17:99–108. 2016. View Article : Google Scholar

13 

Drake JC, Allegra CJ and Johnston PG: Immunological quantitation of thymidylate synthase-FdUMP-5,10-methylenetetrahydrofolate ternary complex with the monoclonal antibody TS 106. Anticancer Drugs. 4:431–435. 1993. View Article : Google Scholar : PubMed/NCBI

14 

MacFarlane AJ, Anderson DD, Flodby P, Perry CA, Allen RH, Stabler SP and Stover PJ: Nuclear localization of de novo thymidylate biosynthesis pathway is required to prevent uracil accumulation in DNA. J Biol Chem. 286:44015–44022. 2011. View Article : Google Scholar : PubMed/NCBI

15 

Kodera Y, Ito S, Fujiwara M, Mochizuki Y, Nakayama G, Ohashi N, Koike M, Yamamura Y and Nakao A: Gene expression of 5-fluorouracil metabolic enzymes in primary gastric cancer: Correlation with drug sensitivity against 5-fluorouracil. Cancer Lett. 252:307–313. 2007. View Article : Google Scholar

16 

Tsutani Y, Yoshida K, Sanada Y, Wada Y, Konishi K, Fukushima M and Okada M: Decreased orotate phosphoribosyltransferase activity produces 5-fluorouracil resistance in a human gastric cancer cell line. Oncol Rep. 20:1545–1551. 2008.PubMed/NCBI

17 

Isshi K, Sakuyama T, Gen T, Nakamura Y, Kuroda T, Katuyama T and Maekawa Y: Predicting 5-FU sensitivity using human colorectal cancer specimens: comparison of tumor dihydropyrimidine dehydrogenase and orotate phosphoribosyl transferase activities with in vitro chemosensitivity to 5-FU. Int J Clin Oncol. 7:335–342. 2002. View Article : Google Scholar

18 

Yoshino T, Mizunuma N, Yamazaki K, Nishina T, Komatsu Y, Baba H, Tsuji A, Yamaguchi K, Muro K, Sugimoto N, et al: TAS-102 monotherapy for pretreated metastatic colorectal cancer: A double-blind, randomised, placebo-controlled phase 2 trial. Lancet Oncol. 13:993–1001. 2012. View Article : Google Scholar

19 

Shitara K, Doi T, Dvorkin M, Mansoor W, Arkenau HT, Prokharau A, Alsina M, Ghidini M, Faustino C, Gorbunova V, et al: Trifluridine/tipiracil versus placebo in patients with heavily pretreated metastatic gastric cancer (TAGS): A randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 19:1437–1448. 2018. View Article : Google Scholar

20 

Mori R, Futamura M, Tanahashi T, Tanaka Y, Matsuhashi N, Yamaguchi K and Yoshida K: 5FU resistance caused by reduced fluoro-deoxyuridine monophosphate and its reversal using deoxyuridine. Oncol Lett. 14:3162–3168. 2017. View Article : Google Scholar

21 

Mori R, Yoshida K, Futamura M, Suetsugu T, Shizu K, Tanahashi T, Tanaka Y, Matsuhashi N and Yamaguchi K: The inhibition of thymidine phosphorylase can reverse acquired 5FU-resistance in gastric cancer cells. Gastric Cancer. 22:497–505. 2019. View Article : Google Scholar : PubMed/NCBI

22 

Suetsugu T, Mori R, Futamura M, Fukada M, Tanaka H, Yasufuku I, Sato Y, Iwata Y, Imai T, Imai H, et al: Mechanism of acquired 5FU resistance and strategy for overcoming 5FU resistance focusing on 5FU metabolism in colon cancer cell lines. Oncol Rep. 45:272021. View Article : Google Scholar : PubMed/NCBI

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Copy and paste a formatted citation
Spandidos Publications style
Mori R, Ukai J, Tokumaru Y, Niwa Y and Futamura M: The mechanism underlying resistance to 5‑fluorouracil and its reversal by the inhibition of thymidine phosphorylase in breast cancer cells. Oncol Lett 24: 311, 2022.
APA
Mori, R., Ukai, J., Tokumaru, Y., Niwa, Y., & Futamura, M. (2022). The mechanism underlying resistance to 5‑fluorouracil and its reversal by the inhibition of thymidine phosphorylase in breast cancer cells. Oncology Letters, 24, 311. https://doi.org/10.3892/ol.2022.13431
MLA
Mori, R., Ukai, J., Tokumaru, Y., Niwa, Y., Futamura, M."The mechanism underlying resistance to 5‑fluorouracil and its reversal by the inhibition of thymidine phosphorylase in breast cancer cells". Oncology Letters 24.3 (2022): 311.
Chicago
Mori, R., Ukai, J., Tokumaru, Y., Niwa, Y., Futamura, M."The mechanism underlying resistance to 5‑fluorouracil and its reversal by the inhibition of thymidine phosphorylase in breast cancer cells". Oncology Letters 24, no. 3 (2022): 311. https://doi.org/10.3892/ol.2022.13431
Copy and paste a formatted citation
x
Spandidos Publications style
Mori R, Ukai J, Tokumaru Y, Niwa Y and Futamura M: The mechanism underlying resistance to 5‑fluorouracil and its reversal by the inhibition of thymidine phosphorylase in breast cancer cells. Oncol Lett 24: 311, 2022.
APA
Mori, R., Ukai, J., Tokumaru, Y., Niwa, Y., & Futamura, M. (2022). The mechanism underlying resistance to 5‑fluorouracil and its reversal by the inhibition of thymidine phosphorylase in breast cancer cells. Oncology Letters, 24, 311. https://doi.org/10.3892/ol.2022.13431
MLA
Mori, R., Ukai, J., Tokumaru, Y., Niwa, Y., Futamura, M."The mechanism underlying resistance to 5‑fluorouracil and its reversal by the inhibition of thymidine phosphorylase in breast cancer cells". Oncology Letters 24.3 (2022): 311.
Chicago
Mori, R., Ukai, J., Tokumaru, Y., Niwa, Y., Futamura, M."The mechanism underlying resistance to 5‑fluorouracil and its reversal by the inhibition of thymidine phosphorylase in breast cancer cells". Oncology Letters 24, no. 3 (2022): 311. https://doi.org/10.3892/ol.2022.13431
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