HCT116 KOLON KANSERİ HÜCRELERİNDE KARMOFUR VE C VİTAMİNİ KOMBİNASYONUNUN SİTOTOKSİK VE APOPTOTİK ETKİLERİ

Yıl 2022, , 6 - 11, 18.03.2022

Ferdane Danışman Kalındemirtaş

https://doi.org/10.26650/experimed.2021.1038579

Öz

Amaç: Kanser tedavisinde birçok yaklaşım bulunmasına rağmen, daha etkili tedavilerin geliştirilmesine ihtiyaç duyulmaktadır. Son yıllarda özellikle ilaçların yan etkisini azaltacak kombine tedavi seçenekleri ilgi çekmektedir. Seramidaz inhibitörü olan karmofur, kanser tedavisinde araştırılan yeni güçlü bir adaydır. Bu çalışmada, özellikle C vitamini gibi doğal bileşiklerin karmofurla birlikte kullanılmasının kanser hücrelerinde sitotoksite ve apoptotik aktiviteyi nasıl etkilediğinin araştırılması amaçlanmıştır.
Gereç ve Yöntem: Bu çalışmada, HCT116 kolon kanseri üzerinde, karmofur 7,8-250 µM aralığında, C Vitamini 7.8µM-2mM aralığında ve Karmofur+C Vitamini ise, farklı konsantrasyonlarda MTT testi ile, değerlendirildi. Ayrıca hücre ölümü yolu apoptoz-nekroz tayini ile belirlendi.
Bulgular: Karmofurun kolon kanseri hücrelerinde IC50 değerinin 8 µM olduğu, C vitaminin düşük dozlarda etkili olmadığı, IC50 değerinin ise 2.2 mM olduğu tespit edildi. HCT116 hücrelerine karmofur ve C Vitamini birlikte uygulandığında, 4 µM karmofur ile 125 µM C vitamini birlikte hücrelerin yarısını inhibe ederken (IC50), 4 µM karmofur ile 2 mM C vitaminin de benzer şekilde hücrelerin yarısını inhibe ettiği görüldü.
Sonuç: C vitamini antikanser ilaçlarla birlikte antikanser ilacın etkisini 2 katına çıkardı. Sonuç olarak antikanser ilaç uygulamasında, C vitamini desteğinin hücre ölümünü anlamlı bir şekilde arttırdığı görüldü. Ayrıca, C vitamini ilavesinin apoptotik aktiviteyi de önemli bir şekilde arttırdığı tespit edildi.

Anahtar Kelimeler

Karmofur, C Vitamini, Kombine tedavi, Kolon kanseri, HCT116

Teşekkür

Yazar, büyük desteği nedeniyle Prof Dr Serap KURUCA'ya ve flow sitometri analizlerindeki yardımlarından dolayı Esra SERT'e teşekkür eder.

Cytotoxic and Apoptotic Effects of Carmofur and Vitamin C Combination on HCT116 Colon Cancer Cells

Öz

Objective: In recent years, especially combined treatment options that will reduce the side effects of drugs have attracted attention. Carmofur is a potent new agent being investigated in the treatment of cancer. This study was aimed to investigate the cytotoxic and apoptotic effects of carmofur+vitamin C combination in cancer cells.
Materials and Methods: In this study, carmofur in the range of 7.8-250 µM, Vitamin C in 7.8µM-2mM and Carmofur+Vitamin C in different concentrations were evaluated on HCT116 cells by MTT test. In addition, the cell death pathway was determined by apoptosis-necrosis assay.
Results: The IC50 value of carmofur in HCT116 cells was 8 µM, vitamin C was not effective at low doses, and the IC50 value was 2.2 mM. When carmofur+Vitamin C were applied to HCT116 cells, 4 µM carmofur and 125 µM vitamin C together inhibited half of the cells (IC50), while 4 µM carmofur and 2 mM vitamin C inhibited half of the cells similarly.
Conclusion: Vitamin C doubled the anticancer effect of carmofur. As a result, it was observed that vitamin C supplementation significantly increased cell death in anticancer drug administration. In addition, it was determined that the addition of vitamin C significantly increased the apoptotic activity.

Anahtar Kelimeler

Carmofur, Vitamin C, combined therapy, colon cancer, HCT116

Kaynakça

• 1. Razali FN, Sinniah SK, Hussin H, Abidin NZ, Shuib AS. Tumor sup-pression effect of Solanum nigrum polysaccharide fraction on Breast cancer via immunomodulation. Int J Biol Macromol 2016; 92: 185-93. [CrossRef] google scholar
• 2. Sharma PC, Bansal KK, Sharma A, Sharma D, Deep A. Thiazole-con-taining compounds as therapeutic targets for cancer therapy. Eur J Med Chem 2020; 188: 112016. [CrossRef] google scholar
• 3. Sharma PC, Sharma D, Sharma A, Bhagat M, Ola M, Thakur VK, et al. Recent advances in microbial toxin-related strategies to com-bat cancer. In Seminars in Cancer Biology. Academic Press 2021. [CrossRef] google scholar
• 4. Reang J, Sharma PC, Thakur VK, Majeed J. Understanding the ther-apeutic potential of ascorbic acid in the battle to overcome can-cer. Biomolecules 2021; 11(8): 1130. [CrossRef] google scholar
• 5. Miao Y, Xiao B, Jiang Z, Guo Y, Mao F, Zhao J. Growth inhibition and cell-cycle arrest of human gastric cancer cells by Lycium barba-rum polysaccharide. Med Oncol 2010; 27(3):785-90. [CrossRef] google scholar
• 6. Zhang P, Liu S. Solvent Effects on the UV Absorption Spectrum of Carmofur. Detection 2016; 4: 25-31. [CrossRef] google scholar
• 7. Ken M, Masae K. Postoperative adjuvant use of carmofur for early breast cancer. Osaka City Med J 2003; 49(2):77-83. google scholar
• 8. Nakamura T, Ohno M, Tabuchi Y, Kamigaki T, Fujii H, Yamagishi H, et al. Optimal duration of oral adjuvant chemotherapy with Carmofur in the colorectal cancer patients: the Kansai Carmofur Study Group trial III. Int J Oncol 2001; 19(2): 29198. [CrossRef] google scholar
• 9. Realini N, Solorzano C, Pagliuca C, Pizzirani D, Armirotti A, Luciani R, et al. Discovery of highly potent acid ceramidase inhibitors with in vitro tumor chemosensitizing activity. Sci Rep 2013; 3: 1035. [CrossRef] google scholar
• 10. Clifford RE, Govindarajah N, Bowden D, Sutton P, Glenn M, Dar-vish-Damavandi M, et al. Targeting Acid Ceramidase to Improve the Radiosensitivity of Rectal Cancer. Cells 2020; 9(12): 2693. [CrossRef] google scholar
• 11. Maehara Y, Kusumoto H, Anal H, Kusumoto T, Hiramoto Y, Sugima-chi K. 1-Hexylcarbamoyl-5-fluorouracil is more cytostatic than 5-fluorouracil against human tumors in vitro. Eur J Cancer Clin Oncol 1987; 23(10): 1511-5. [CrossRef] google scholar
• 12. Mikirova NA, Ichim TE, Riordan NH. Anti-angiogenic effect of high doses of ascorbic acid. J Transl Med 2008; 6(1): 1-10. [CrossRef] google scholar
• 13. Lee WJ. The prospects of vitamin C in cancer therapy. Immune Netw 2009; 9(5): 147-52. [CrossRef] google scholar
• 14. Mosmann T. Rapid colorimetric assay for cellular growth and sur-vival: application to proliferation and cytotoxicity assays. J Immu-nol Methods, 1983; 65(1-2): 55-63. [CrossRef] google scholar
• 15. Ghavami G, Sardari S. Synergistic Effect of Vitamin C with Cisplatin for Inhibiting Proliferation of Gastric Cancer Cells. Iran Biomed J. 2020; 24(2): 119-27. [CrossRef] google scholar
• 16. Lee SJ, Jeong JH, Lee IH, Lee J, Jung JH, Park HY, et al. Effect of high-dose vitamin C combined with anti-cancer treatment on breast cancer cells. Anticancer Res 2019; 39(2): 751-8. [CrossRef] google scholar
• 17. Carneiro BA, El-Deiry WS. Targeting apoptosis in cancer therapy. Nat Rev Clin Oncol 2020; 17(7): 395-417. [CrossRef] google scholar
• 18. Çömlekçi E, Kutlu HM, Sezer CV. Toward stimulating apoptosis in human lung adenocarcinoma cells by novel nano-carmofur com-pound treatment. Anti-cancer drugs 2021; 32(6): 657-63. [Cross-Ref] google scholar
• 19. Doan NB, Nguyen HS, Montoure A, Al-Gizawiy MM, Mueller WM, Kurpad S, et al. Acid ceramidase is a novel drug target for pediatric brain tumors. Oncotarget 2017; 8(15): 24753. [CrossRef] google scholar
• 20. Dementiev A, Joachimiak A, Nguyen H, Gorelik A, Illes K, Shabani S, et al. Molecular mechanism of inhibition of acid ceramidase by carmofur. J Med Chem 2018; 62(2): 987-92. [CrossRef] google scholar