SavedAdd your journal

Journals / Meandros Medical And Dental Journal / 2026 / Volume: 27 Issue: 3

Targeting DNA Methyltransferases with a Pemetrexed–Mitomycin C Combination in Bladder Cancer

MESANE KANSERİNDE PEMETREXED-MİTOMİSİN C KOMBİNASYONU İLE DNA METİLTRANSFERAZLARIN HEDEFLENMESİ

Hüseyin Bal(ADNAN MENDERES UNIVERSITY, FACULTY OF MEDICINE)0009-0000-3347-3144
Bensu Kozan(ADNAN MENDERES UNIVERSITY)0000-0002-5645-7013
Özge Çevik(AYDIN ADNAN MENDERES UNIVERSITY, SCHOOL OF MEDICINE)0000-0002-9325-3757
Pages
—
Publication Date
2026-09-24
🏛️Bibliographic metadata and full text access for this article are provided via DergiPark.
DergiPark Record ↗
✨

AI Summary & Key Takeaways

AI Insight
⚡ TL;DR(Too Long; Didn't Read)

Conclusion: These results indicate that co-treatment with pemetrexed and mitomycin-C holds therapeutic potential in metastatic bladder cancer and may inform future efforts to design DNMT1-targeted inhibitory strategies.

📌 3 Key Takeaways

🎯
Objective & Hypothesis:Objective: The goal of this study was to investigate the efficacy and underlying mechanisms of combined treatment with pemetrexed and mitomycin-C for metastatic bladder cancer.
📊
Key Findings & Data:Materials and Methods: The cytotoxic effects of the pemetrexed–mitomycin-C combination was evaluated in human bladder cancer cells (UM-UC-3) via Annexin V/PI-based flow cytometric analysis, followed by evaluation of DNMT1 mRNA and protein levels.
💡
Conclusion & Impact:Conclusion: These results indicate that co-treatment with pemetrexed and mitomycin-C holds therapeutic potential in metastatic bladder cancer and may inform future efforts to design DNMT1-targeted inhibitory strategies.
🔬Design:Research Article
📍Scope:Comprehensive Sample
⚙️Variables:Mitomycin-C · Pemetrexed · Bladder cancer

Abstract

Objective: The goal of this study was to investigate the efficacy and underlying mechanisms of combined treatment with pemetrexed and mitomycin-C for metastatic bladder cancer. Pemetrexed reduces cancer cell proliferation by impairing DNA and RNA biosynthesis, whereas mitomycin-C induces cytotoxicity through disruption of DNA. Materials and Methods: The cytotoxic effects of the pemetrexed–mitomycin-C combination was evaluated in human bladder cancer cells (UM-UC-3) via Annexin V/PI-based flow cytometric analysis, followed by evaluation of DNMT1 mRNA and protein levels. Statistical analyses were performed using independent t-tests. Results: The combined treatment significantly induced apoptosis in bladder cancer cells at low concentrations, demonstrating a pronounced synergistic effect. Moreover, the combination markedly suppressed DNMT1 mRNA expression and protein levels, indicating inhibition of aberrant DNA methylation mechanisms associated with cancer progression. Conclusion: These results indicate that co-treatment with pemetrexed and mitomycin-C holds therapeutic potential in metastatic bladder cancer and may inform future efforts to design DNMT1-targeted inhibitory strategies.

Özet

Amaç: Bu çalışmanın amacı, metastatik mesane kanseri için pemetrexed ve mitomisin-C'nin kombine tedavisinin etkinliğini ve altta yatan mekanizmalarını araştırmaktır. Pemetrexed, DNA ve RNA biyosentezini bozarak kanser hücresi proliferasyonunu azaltırken, mitomisin-C DNA'yı bozarak sitotoksisiteye neden olur. Materyaller ve Yöntemler: Pemetrexed-mitomisin-C kombinasyonunun sitotoksik etkileri, insan mesane kanseri hücrelerinde (UM-UC-3) Annexin V/PI bazlı akış sitometrik analizi ile değerlendirildi ve ardından DNMT1 mRNA ve protein düzeyleri incelendi. İstatistiksel analizler bağımsız t-testleri kullanılarak yapıldı. Sonuçlar: Kombine tedavi, düşük konsantrasyonlarda mesane kanseri hücrelerinde apoptozu önemli ölçüde indükleyerek belirgin bir sinerjik etki gösterdi. Ayrıca, kombinasyon, kanser ilerlemesiyle ilişkili anormal DNA metilasyon mekanizmalarının inhibisyonunu gösteren DNMT1 mRNA ekspresyonunu ve protein düzeylerini belirgin şekilde baskıladı. Sonuç: Bu sonuçlar, pemetrexed ve mitomisin-C ile birlikte uygulanan tedavinin metastatik mesane kanserinde terapötik potansiyel taşıdığını ve DNMT1'i hedefleyen inhibitör stratejilerin tasarlanmasına yönelik gelecekteki çalışmalara ışık tutabileceğini göstermektedir.

🔖

Cite This Article

Bal, H., Kozan, B., Çevik, Ö. (2026). Targeting DNA Methyltransferases with a Pemetrexed–Mitomycin C Combination in Bladder Cancer. Meandros Medical And Dental Journal, Volume: 27 Issue: 3. https://doi.org/10.69601/meandrosmdj.1916484

📄 Full Text PDF Viewer

📄

PDF görüntüleyici hazırlanıyor...

References (22)

  1. Ploeg M, Aben KK, Kiemeney LA. The present and future burden of urinary bladder cancer in the world. World J Urol. 2009;27(3):289–293. https://doi.org/10.1007/s00345-009-0383-3
  2. Filon M, et al. New treatment options for non–muscle-invasive bladder cancer. Am Soc Clin Oncol Educ Book. 2025;45:e471942. https://doi.org/10.1200/EDBK-25-471942
  3. Swainston Harrison T, Scott LJ. Pemetrexed. Am J Cancer. 2003;2:359–370. https://doi.org/10.2165/00024669-200302050-00009
  4. Esteban E, et al. Pemetrexed in first-line treatment of non-small cell lung cancer. Cancer Treat Rev. 2009;35(4):364–373. https://doi.org/10.1016/j.ctrv.2009.02.002
  5. Li J, Chi Y, Cao G, Zhao J, An T, Wu M, et al. Efficacy and safety of pemetrexed maintenance chemotherapy for advanced non-small cell lung cancer in a real-world setting. J Thorac Dis. 2021;13(3):1813–1821. https://doi.org/10.21037/jtd-21-337
  6. Stevens CL, Taylor KG, Munk ME, Marshall WS, Noll K, Shah GD, Shah lG, Uzu K. Chemistry and structure of mitomycin c. J Med Chem. 1965;8:1-10. https://doi: 10.1021/jm00325a001
  7. Wang SC, Yu CY, Wu YC, Chang YC, Chen SL, Sung WW. Chidamide and mitomycin C exert synergistic cytotoxic effects against bladder cancer cells in vitro and suppress tumor growth in a rat bladder cancer model. Cancer Lett. 2022;530:8–15. https://doi.org/10.1016/j.canlet.2022.01.007
  8. Scilipoti P, Ślusarczyk A, De Angelis M, Soria F, Pradere B, Krajewski W, et al. The role of mitomycin C in intermediate-risk non–muscle-invasive bladder cancer: A systematic review and meta-analysis. Eur Urol Oncol. 2024;7(6):1293–1302. https://doi.org/10.1016/j.euo.2024.06.005
  9. Maffezzini M, Campodonico F, Manuputty EE, Puntoni M, Martelli A, Marini V, et al. Systemic absorption and pharmacokinetics of single-dose early intravesical mitomycin C after transurethral resection of non-muscle-invasive bladder cancer. Urology. 2013;82(2):400–404. https://doi.org/10.1016/j.urology.2013.03.036
  10. Okimoto T, Kotani H, Iida Y, Koyanagi A, Tanino R, Tsubata Y, et al. Pemetrexed sensitizes human lung cancer cells to cytotoxic immune cells. Cancer Sci. 2020;111(6):1910–1920. https://doi.org/10.1111/cas.14401
  11. Demirbolat GM, Cakirli E, Saglam AB, et al. pH-triggered liposomal strategy for cisplatin in lung cancer therapy. Sci Rep. 2025;15:36349. https://doi.org/10.1038/s41598-025-20144-0
  12. Du Q, Wang Z, Schramm VL. Human DNMT1 transition state structure. Proc Natl Acad Sci U S A. 2016;113(11):2916–2921. https://doi.org/10.1073/pnas.1522491113
  13. Salmerón-Bárcenas EG, Martínez-Zayas A, Vargas-Mejía M, Villegas-Sepúlveda N, Briseño-Díaz P, Aguilar-Rojas A, et al. DNMT enzymes and their impact on cervical cancer: A state-of-the-art review. Int J Mol Sci. 2025;26(21):10496. https://doi.org/10.3390/ijms262110496
  14. Crider KS, Yang TP, Berry RJ, Bailey LB. Folate and DNA methylation: A review of molecular mechanisms and the evidence for folate’s role. Adv Nutr. 2012;3(1):21–38. https://doi.org/10.3945/an.111.000992
  15. Sarkisjan D, Julsing JR, El Hassouni B, Honeywell RJ, Kathmann I, Matherly LH, et al. Rx-3117 (fluorocyclopentenyl-cytosine)-mediated down-regulation of DNA methyltransferase 1 leads to protein expression of tumor-suppressor genes and increased functionality of the proton-coupled folate carrier. Int J Mol Sci. 2020;21(8):2717. https://doi.org/10.3390/ijms21082717
  16. Li Q, Li JZ, Xu WH, Gao L. Pemetrexed in treating patients with metastatic bladder cancer. Asian Pac J Cancer Prev. 2015;16(9):3839–3841. https://doi.org/10.7314/apjcp.2015.16.9.3839
  17. Dreicer R, Li H, Cooney MM, et al. Phase II trial of pemetrexed disodium and gemcitabine in advanced urothelial cancer (E4802): A trial of the Eastern Cooperative Oncology Group. Cancer. 2008;112:2671–2675. https://doi.org/10.1002/cncr.23503
  18. Galsky MD, Mironov S, Iasonos A, et al. Phase II trial of pemetrexed as second-line therapy in patients with metastatic urothelial carcinoma. Invest New Drugs. 2007;25:265–270. https://doi.org/10.1007/s10637-006-9020-9
  19. Sweeney CJ, Roth BJ, Kabbinavar FF, et al. Phase II study of pemetrexed for second-line treatment of transitional cell cancer of the urothelium. J Clin Oncol. 2006;24:3451–3457. https://doi.org/10.1200/JCO.2005.03.6699
  20. Ojea A, Nogueira JL, Solsona E, Flores N, Gómez JMF, Molina JR, et al. A multicentre, randomised prospective trial comparing three intravesical adjuvant therapies for intermediate-risk superficial bladder cancer: low-dose bacillus Calmette-Guerin (27 mg) versus very low-dose bacillus Calmette-Guerin (13.5 mg) versus mitomycin C. Eur Urol. 2007;52(5):1398–1406. https://doi.org/10.1016/j.eururo.2007.04.062
  21. Babiak A, Hetzel J, Godde F, König HH, Pietsch M, Hetzel M. Mitomycin C and vinorelbine for second-line chemotherapy in non-small cell lung cancer: A phase II trial. Br J Cancer. 2007;96(7):1052–1056. https://doi.org/10.1038/sj.bjc.6603683
  22. Gorodnova TV, Sokolenko AP, Kondratiev SV, Kotiv KB, Belyaev AM, Berlev IV, Imyanitov EN. Mitomycin C plus cisplatin for systemic treatment of recurrent BRCA1-associated ovarian cancer. Invest New Drugs. 2020;38(6):1872–1878. https://doi.org/10.1007/s10637-020-00965-8