Determination of synergic antioxidant interactions of Ellagic acid and chemotherapy drug (Docetaxel and Mitoxantron) combinations

Year 2024, , 735 - 750, 15.09.2024

Cuma Zehiroğlu , S. Beyza Ö. Sarıkaya

https://doi.org/10.17714/gumusfenbil.1430653

Abstract

Chemotherapy drugs are commonly used in cancer treatment, despite their numerous negative side effects. Today, there are studies to reduce the side effects of these drugs and to increase their benefits by combining them with natural substances. Our study investigated the antioxidant and antiradical activities of Ellagic acid (EA), a natural substance, DOC and MIX, commonly used chemotherapeutics, as well as their combinations (EA+DOC, EA+MIX). For this purpose, the methods of DPPH• and ABTS•+ scavenging activity, Fe3+-Fe2+ and Cu2+-Cu1+ reduction capacity were used. After the study, the interactions were analysed with the combination index using Compusyn software. Concentrations with maximum synergy in combinations have been identified. For this purpose, firstly, the combination concentrations used in the antioxidant activity methods and the absorbance values were entered into the Compusyn programme. When DPPH• and ABTS•+ scavenging activity results were entered into the programme, more effective synergistic effect was observed for EA+DOC at lower concentrations (7:7µg/mL), (0.125:1µg/mL) respectively. For EA+MIX, no synergistic effect was observed with the application of DPPH scavenging activity results to the programme, while for ABTS•+ scavenging activity, more effective synergistic effect was observed at higher concentrations within the applied doses (0.750:6µg/ml). When Fe3+-Fe2+ and Cu2+-Cu1+ reduction results were applied to the programme; synergistic effect was observed at higher concentrations (17:17µg/mL) for both EA+DOC and EA+MIX and even strong synergistic effect was observed in many of them. The obtained results provide guidance for the use of these combinations in further studies, such as anticancer and enzyme studies.

Keywords

Antioxidant, Chemotherapy, Compusyn, Drug, Synergistic

Elajik asit ve kemoterapi ilaç (Dosetaksel ve Mitoksantron) kombinasyonlarının sinerjik antioksidan etkileşimlerinin belirlenmesi

Abstract

Kemoterapi ilaçları kanser tedavisinde yaygın olarak kullanılan ancak birçok negatif yan etkisi bulunan ilaçlardır. Günümüzde bu ilaçların yan etkilerini azaltmak ve doğal maddelerle birleştirerek faydalarını artırmak için çalışmalar bulunmaktadır. Çalışmamızda doğal bir madde olan Elajik asit (EA), yaygın olarak kullanılan kemoterapötikler olan DOC ve MIX ile bunların kombinasyonlarının (EA+DOC, EA+MIX) antioksidan ve antiradikal aktiviteleri araştırılmıştır. Bu amaçla DPPH• ve ABTS•+ giderme aktivitesi, Fe3+-Fe2+ ve Cu2+-Cu1+ indirgeme kapasitesi yöntemleri kullanılmıştır. Çalışma sonrasında etkileşimler CompuSyn yazılımı uygulanarak kombinasyon indeksi ile analiz edilmiştir. Kombinasyonlarda maksimum sinerjik gösteren konsantrasyonlar belirlenmiştir. Bu amaçla öncelikle antioksidan aktivite metotlarında kullanılan kombinasyon konsantrasyonları ve bulunan absorbans değerleri Compusyn programına girilmiştir. DPPH• ve ABTS•+ giderme aktivitesi sonuçları programa girildiğinde EA+DOC için sırasıyla daha düşük konsantrasyonlarda (7:7µg/mL), (0,125+1 µg/mL) daha etkin sinerjik etki gözlemlenmiştir. EA+MIX için ise DPPH giderme aktivitesi sonuçlarının programa uygulanmasıyla sinerjik etki gözlemlenmemiş, ABTS•+ giderme aktivitesi için ise uygulanan dozlar içinde daha yüksek konsantrasyonlarda daha etkin sinerjik etki gözlemlenmiştir (0.750:6 µg/ml). Fe3+-Fe2+ ve Cu2+-Cu1+ indirgeme sonuçları programa uygulandığında; hem EA+DOC hemde EA+MIX için daha yüksek konsantrasyonlarda (17:17µg/mL) sinerjik etki gözlenmiş olup hatta birçoğunda güçlü sinerjik etki gözlemlenmiştir. Elde edilen sonuçlar, bu kombinasyonların antikanser ve enzim çalışmaları gibi daha ileri çalışmalarda kullanılması için yol gösterici olmuştur.

Keywords

Antioksidan, Kemoterapi, Compusyn, İlaç, Sinerjik

References

• Anantharaju, P. G., Gowda, P. C., Vimalambike, M. G. & Madhunapantula, S. V. (2016). An overview on the role of dietary phenolics for the treatment of cancers. Nutrition Journal, 15(99), 1–16. https://doi.org/10.1186/s12937-016-0217-2
• Apak, R., Güçlü, K., Özyürek, M., Karademir, S. E. & Erça, E. (2006). The cupric ion reducing antioxidant capacity and polyphenolic content of some herbal teas. International Journal of Food Sciences and Nutrition, 57(5-6), 292–304. https://doi.org/10.1080/09637480600798132
• Ayvat, İ. (2019). Ayaktan kemoterapi alan kanser hastalarının karşılanmamış destekleyici bakım gereksinimlerinin yaş bağlamında incelenmesi. [Yüksek Lisans Tezi, Hacettepe Üniversitesi, Sağlık Bilimleri Enstitüsü].
• Aziz, A., Sarwar, S., Akter, T., Uddin, S., Xun, S., Zhu, Y., Islam, M. S. & Hongjie, Z. (2021). Polyphenolic molecules targeting STAT3 pathway for the treatment of cancer. Life Sciences, 268, 118999. https://doi.org/10.1016/j.lfs.2020.118999
• Blois, M. S. (1958). Antioxidant determinations by the use of a stable free radical. Nature, 26, 1199-1200. https://doi.org/10.1038/1811199a0
• Buczkowski, A., Tokarz, P., Stepniak, A., Lewkowski, J., Rodacka, A. & Palecz, B. (2019). Spectroscopic and calorimetric studies of interactions between Mitoxantrone and cucurbituril Q7 in aqueous solutions. Journal of Molecular Liquids, 290, 111190. https://doi.org/10.1016/j.molliq.2019.111190
• Chai, H., Wu, J., Liu, J., Liu, T., Ren, Q. & Zheng, X. (2021). δ-tocopherol enhances Docetaxel-ınduced growth ınhibition and apoptosis in ovarian cancer SKOV3 cells. Natural Product Communications, 16(3), 1–8. https://dx.doi.org/10.1177/1934578X211002298
• Chou, T. C. (2006). Theoretical basis, experimental design, and computerized simulation of synergism and antagonism in drug combination studies. Pharmacological Reviews, 58(3), 621–681. https://doi.org/10.1124/pr.58.3.10
• Chou, T. C. (2010). Drug combination studies and their synergy quantification using the Chou-Talalay method. Cancer Research, 70(2), 440–446. https://doi.org/10.1158/0008-5472.CAN-09-1947
• Durante, S., Dunet, V., Gorostidi, F., Mitsakis, P., Schaefer, N., Delage, J. & Prior, J. O. (2020). Head and neck tumors angiogenesis imaging with 68Ga-NODAGA-RGD in comparison to 18F-FDG PET/CT: A pilot study. EJNMMI Research, 10(1), 1–11. 1 https://doi.org/0.1186/s13550-020-00638-w.
• Fox, E. J. (2006). Management of worsening multiple sclerosis with Mitoxantrone: A review. Clinical Therapeutics, 28(4), 461-74. https://dx.doi.org/10.1016/j.clinthera.2006.04.013
• García-Niño, W. R. & Zazueta, C. (2015). Ellagic acid: Pharmacological activities and molecular mechanisms involved in liver protection. Pharmacological Research, 97, 84-103. https://doi.org/10.1016/j.phrs.2015.04.008
• Granja, A., Lima-Sousa, R., Alves, C. G., de Melo-Diogo, D., Pinheiro, M., Sousa, C. T., Correia I. J. & Reis, S. (2021). Mitoxantrone-loaded lipid nanoparticles for breast cancer therapy – quality-by-design approach and efficacy assessment in 2D and 3D in vitro cancer models. International Journal of Pharmaceutics, 607, 121044. https://dx.doi.org/10.1016/j.ijpharm.2021.121044
• Guleria, K., Sehgal, A., Bhat, I. A., Singh, S. K., Vamanu, E. & Singh, M.P. (2022). Impact of Altering the Ratio of Black Tea Granules and Ocimum gratissimum Leaves in a Binary Infusion on Radical Scavenging Potential Employing Cell Free Models and Ex Vivo Assays. Applied Sciences, 12(20), 10632. https:// doi.org/10.3390/app122010632
• Guzman, R., Tang, H. & Salley, S.(2009). Synergistic effects of antioxidants on the oxidative stability of soybean oil- and poultry fat-based biodiesel. Journal of Oil & Fat Industries, 86, 459- 467. https://doi.org/10.1007/s11746-009-1373-8
• Gülçin, İ. (2012). Antioxidant activity of food constituents: An overview. Archives of Toxicology, 86(3), 345-391. https://doi.org/10.1007/s00204-011-0774-2
• Gündoğdu, B. (2020). Farklı kurutma yöntemlerinin balkabağı posasından fenolik madde ekstraksiyonuna etkisinin belirlenmesi [Yüksek Lisans Tezi, Osmaniye Korkut Ata Üniversitesi Fen Bilimleri Enstitüleri Ortak Yüksek Lisans Programı].
• Hajimehdipoor, H., Shahrestani, R., & Shekarchi, M. (2014). Investigating the synergistic antioxidant effects of some flavonoid and phenolic compounds. Research Journal of Pharmacognosy, 1(3), 35-40.
• Hazafa, A., Iqbal, MO, Javaid, U. Tareen, M. B. K., Amna, D., Ramzan, A., Piracha, S. & Naeem, M. (2022). Inhibitory effect of polyphenols (phenolic acids, lignans, and stilbenes) on cancer by regulating signal transduction pathways: A review. Clinical and Translational Oncology, 24(3), 432–445. https://doi.org/10.1007/s12094-021-02709-3
• Kannan, M. M. & Quine, S. D. (2012). Ellagic acid protects mitochondria from β-adrenergic agonist induced myocardial damage in rats: Evidence from in vivo, in vitro and ultra structural study. Food Research International, 45(1), 1-8. https://doi.org/10.1016/j.foodres.2011.09.018
• Kaur, H., Ghosh, S., Kumar, P., Basu, B. & Nagpal, K. (2021). Ellagic acid-loaded, tween 80-coated, chitosan nanoparticles as a promising therapeutic approach against breast cancer: In-vitro and in-vivo study. Life Sciences, 284, 119927. https://doi.org/10.1016/j.lfs.2021.119927
• Khanduja, K. L., Avti, P. K., Kumar, S., Mittal, N., Sohi, K. K. & Pathak, C. M. (2006). Anti-apoptotic activity of caffeic acid, Ellagic acid and ferulic acid in normal human peripheral blood mononuclear cells: A Bcl-2 independent mechanism. Biochimica et Biophysica Acta, 1760(2), 283–289. https://doi.org/10.1016/j.bbagen.2005.12.017
• Kılıç, I., Yesiloǧlu, Y. & Bayrak, Y. (2014). Spectroscopic studies on the antioxidant activity of Ellagic acid. Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy, 130, 447–452. https://doi.org/10.1016/j.saa.2014.04.052
• Kumar, N. & Goel, N. (2019). Phenolic acids: Natural versatile molecules with promising therapeutic applications. Biotechnology Reports, 20(24), 00370. https://doi.org/10.1016/j.btre.2019.e00370
• Lennan, E. (2011). Chemotherapy as a treatment for breast cancer. V., Harmer (Ed.), Breast cancer nursing care and management (ss. 149-172). Blackwell Publishing.
• Lu, L., Zhang, M., Wang, X., Zhang, Y., Chai, Z., Ying, M., Guan J, Gongi W., Zhao, Z., Liu, L., Hu, Y., Lu, W. & Dong J. (2020). Baicalein enhances the antitumor efficacy of Docetaxel on nonsmall cell lung cancer in a β‐catenin‐dependent manner. Phytotherapy Research, 34(1), 104–117. https://dx.doi.org/10.1002/ptr.6501
• Martinelli, V., Radaelli, M., Straffi, L., Rodegher, M. & Comi, G. (2009). Mitoxantrone: Benefits and risks in multiple sclerosis patients. Neurological Sciences, 30, 167-70. https://dx.doi.org/10.1007/s10072-009-0142-7
• Mehta, V., Verma, P., Sharma, N., Sharma, A., Thakur, A. & Malairaman, U. (2017). Quercetin, ascorbic acid, caffeine and Ellagic acid are more efficient than rosiglitazone, metformin and glimepiride in interfering with pathways leading to the development of neurological complications associated with diabetes: A comparative in-vitro study. Bulletin of Faculty of Pharmacy, 55(1), 115-121. https://doi.org/10.1016/j.bfopcu.2016.12.002
• Oyaizu, M. (1986). Studies on product of browning reaction prepared from glucose amine. Japanese Journal of Nutrition, 44, 307-315. http://dx.doi.org/10.5264/eiyogakuzashi.44.307
• Özyürek, M., Bektaşoğlu, B., Güçlü, K. & Apak, R. (2009). Measurement of xanthine oxidase inhibition activity of phenolics and flavonoids with a modified cupric reducing antioxidant capacity (CUPRAC) method. Analytica Chimica Acta, 636(1), 42-50. https://doi.org/10.1016/j.aca.2009.01.037
• Papadakis, M. A., McPhee, S. J. & Rabow M. W. (2016). Current medical diagnosis and treatment 2016 (55). McGraw-Hill Education / Medical.
• Razak, S. A., Mohd Gazzali, A., Fisol, F. A., M. Abdulbaqi, I., Parumasivam, T., Mohtar, N., & A. Wahab, H. (2021). Advances in Nanocarriers for Effective Delivery of Docetaxel in the Treatment of Lung Cancer: An Overview. Cancers, 13(3), 400. https://doi.org/10.3390/cancers13030400
• Re, R., Pellegrini, N., Proteggente, A., Pannala, A., Yang, M. & Rice-Evans, C. (1999). Antioxidant activity applying an ımproved abts radical cation decolorization assay. Free Radical Biology and Medicine, 26(9-10), 1231-1237. https://doi.org/10.1016/S0891-5849(98)00315-3
• Sarıkaya, S. B., Gülçin, İ. & Supuran, C.T. (2010). Carbonic anhydrase ınhibitors: Inhibition of human erythrocyte ısozymes I and II with a series of phenolic acids. Chemical Biology & Drug Design, 75(5), 515-520. https://doi.org/10.1111/j.1747-0285.2010.00965.x
• Sumaya, F. & Amit, S. (2019). Synergistic antioxidant interactions between green tea and Ocimum gratissimum. Asian Pacific Journal of Tropical Biomedicine, 9, 333-338. https://doi.org/10.4103/2221-1691.262081
• Şimşek, H. (2022). Meme kanserli kadınlarda kemoterapi sırasında stres topu uygulamasının stres, anksiyete ve konfor üzerine etkisi [Yüksek Lisans Tezi, Mersin Üniversitesi Sağlık Bilimleri Enstitüsü].
• Xue, P., Zhang, G., Zhang, J. & Ren, L. (2022). Synergism of Ellagic acid in combination with radiotherapy and chemotherapy for cancer treatment. Phytomedicine, 99, 153998. https://doi.org/10.1016/j.phymed.2022.153998
• Yan, M., Fan, X., Si, H., Wang, X., Wang, Z., Wang, Z., Lv, X., Yin, H., Jia, Y., Jiang, L., Xia, Y. & Liu, Y. (2022). Association between gene polymorphism and adverse effects in cancer patients receiving Docetaxel treatment: a meta-analysis. Cancer Chemother Pharmacol, 89, 173–181. https://doi.org/10.1007/s00280-021-04374-3