ZERUMBONE’UN ANTİANJİYOJENİK AKTİVİTESİ VE ROS ARACILI AKCİĞER KANSERİ HÜCRE HATTI HASARI

Öz

Amaç: Zerumbone (ZER), kanser önleyici etkisi olduğu bildirilen, iyi bilinen bir doğal bileşiktir. Bu nedenle, bu çalışma, ZER'in Timidin Fosforilaz'ı (TP) inhibe etme potansiyelini ve küçük hücreli dışı akciğer kanser, NCI-H460, hücre hattında Reaktif oksijen türleri (ROS) aracılı sitotoksisiteyi tetikleme yeteneğini araştırmıştır. Gereç ve Yöntem: ZER’in antianjiyogenik aktivitesi, timidin fosforilaz inhibitör testi kullanılarak değerlendirilmiiştir. Akış sitometrisi kullanılarak DCFDA boyası ile reaktif oksijen türleri (ROS) üretimi belirlenmiştir. Sonuç ve Tartışma: ZER'in 50.3±0.31 μg/ml veya 230±1.42 µM IC50 değeri ile güçlü bir TP inhibitörü olduğu bulunmuştur. ZER ile işleme tabi tutulduktan sonra NCI-H460 hücrelerinin, %55.7 gibi yüksek bir oranda ROS ürettiği bulunmuştur. Sonuç olarak, ZER’in, anti-anjiyojenik özellikler sergilediği ve akciğer kanseri hücrelerinde ROS üretimini modüle ederek kanser tedavisinde daha iyi terapötik indeks sunduğu tespit edilmiştir.

Anahtar Kelimeler

• Akış sitometrisi
• NCI-H460
• timidin fosforilaz

ANTIANGIOGENIC ACTIVITY AND ROS-MEDIATED LUNG CANCER CELL LINE INJURY OF ZERUMBONE

Öz

Objective: Zerumbone (ZER) is a well-known natural compound that has been reported to have anti-cancer effect. Thus, this study investigated the ZER potential to inhibit Thymidine Phosphorylase (TP) and the ability to trigger Reactive oxygen species (ROS)-mediated cytotoxicity in non-small cell lung cancer, NCI-H460, cell line. Material and Method: The antiangiogenic activity for ZER was evaluated by using the thymidine phosphorylase inhibitory test. Reactive oxygen species (ROS) production was determined via DCFDA dye by using flow cytometry. Result and Discussion: ZER was found to be potent TP inhibitory with the IC50 value of 50.3± 0.31 μg/ml or 230±1.42 µM. NCI-H460 cells upon treatment with ZER produced significant ROS by 55.7%. Consequently, ZER exerts anti-angiogenic properties and modulates ROS production in lung cancer cells, serving as leads for better therapeutic index in cancer drug.

Anahtar Kelimeler

• Flow cytometry
• NCI-H460
• thymidine phosphorylase

Kaynakça

1. 1. Bashir, M.F., Qadir, M.I. (2017). Effect of ginger extract on angiogenesis using CAM assay. Bangladesh Journal of Pharmacology, 12(3), 348-353. [CrossRef]
2. 2. Elamin, Y.Y., Rafee, S., Osman, N., Kenneth, J.O., Gately, K. (2016). Thymidine phosphorylase in cancer; enemy or friend? Cancer Microenvironment, 9(1), 33-43. [CrossRef]
3. 3. Ahir, B.K., Engelhard, H.H., Lakka, S.S. (2020). Tumor development and angiogenesis in adult brain tumor: Glioblastoma. Molecular Neurobiology, 57(5), 2461-2478. [CrossRef]
4. 4. Cho, W.C., Jour, G., Aung, P.P. (2019). Role of angiogenesis in melanoma progression: Update on key angiogenic mechanisms and other associated components. Seminars in Cancer Biology, 59, 175-186. [CrossRef]
5. 5. Zaman, K., Rahim, F., Taha, M., Wadood, A., Shah, S.A.A., Ahmed, Q.U., Zakaria, Z.A. (2019). Synthesis of new isoquinoline-base-oxadiazole derivatives as potent inhibitors of thymidine phosphorylase and molecular docking study. Scientific Reports, 9(1), 1-11. [CrossRef]
6. 6. Albaayit, S.F.A., Maharjan, R., Abdullah, R., Noor, M.H.M. (2021). Anti-Enterococcus faecalis, cytotoxicity, phytotoxicity, and anticancer studies on Clausena excavata burum. f. (Rutaceae) leaves. BioMed Research International, 2021, 3123476. [CrossRef]
7. 7. Abou Khouzam, R., Brodaczewska, K., Filipiak, A., Zeinelabdin, N.A., Buart, S., Szczylik, C., Chouaib, S. (2020). Tumor hypoxia regulates immune escape/invasion: Influence on angiogenesis and potential impact of hypoxic biomarkers on cancer therapies. Frontiers in Immunology, 11, 3479. [CrossRef]
8. 8. Albaayit, S.F.A., Rasedee, A., Abdullah, N., Abba, Y. (2020). Methanolic extract of Clausena excavata promotes wound healing via antiinflammatory and anti-apoptotic activities. Asian Pacific Journal of Tropical Biomedicine, 10(5), 232-238. [CrossRef]

9. 9. Al-Bahrani, R.M., Radif, H.M., Albaayit, S.F.A. (2020). Evaluation of potent silver nanoparticles production from Agaricus bisporus against Helicobacter pylori. Pakistan Journal of Agricultural Sciences, 57(4), 1197-1201. [CrossRef]
10. 10. Albaayit, S.F.A., Al-Khafaji, A.S.K., Alnaimy, H.S. (2019). In vitro macrophage nitric oxide and interleukin-1 beta suppression by Moringa peregrina seed. Turkish Journal of Pharmaceutical sciences. 16(3), 362-365. [CrossRef]
11. 11. Al-Ani, L.K.T., Yonus, M.I., Mahdii, B.A., Omer, M.A., Taher, J.K., Albaayit, S.F.A., Al-Khoja, S.B. (2018). First record of use Fusarium proliferatum fungi in direct treatment to control the adult of wheat flour Tribolium confusum, as well as, use the entomopathogenic fungi Beauveria bassiana. Ecology, Environment and Conservation, 24(3), 29-34.
12. 12. Cragg, G.M., Pezzuto, J.M. (2016). Natural products as a vital source for the discovery of cancer chemotherapeutic and chemopreventive agents. Medical Principles and Practice, 25(Suppl. 2), 41-59. [CrossRef]
13. 13. Huang, M., Lu, J.J., Ding, J. (2021). Natural products in cancer therapy: Past, present and future. Natural Products and Bioprospecting, 11(1), 5-13. [CrossRef]
14. 14. Greenwell, M., Rahman, P.K.S.M. (2015). Medicinal plants: Their use in anticancer treatment. International Journal of Pharmaceutical Sciences, 6(10), 4103-4112. [CrossRef]
15. 15. Albaayit, S.F.A., Maharjan, R. (2018). Immunomodulation of zerumbone via decreasing the production of reactive oxygen species from immune cells. Pakistan Journal of Biological Sciences, 21(9), 475-479. [CrossRef]
16. 16. Albaayit, S.F.A., Rasedee, A., Abdullah, N. (2020). Zerumbone-loaded nanostructured lipid carrier gel facilitates wound healing in rats. Revista Brasileira de Farmacognosia, 30(2), 272-278. [CrossRef]
17. 17. Albaayit, S.F.A., Maharjan, R, Abdullah, R., Mohd Noor, M.H. (2022). Evaluation of anti-methicillin-resistant Staphylococcus aureus property of zerumbone. Journal of Applied Biomedicine, 20(1), 15-21. [CrossRef]
18. 18. Albaayit, S.F.A., Maharjan, R., Khan, M. (2021). Evaluation of hemolysis activity of Zerumbone on RBCs and brine shrimp toxicity. Baghdad Science Journal, 18(1), 65-69. [CrossRef]
19. 19. Albaayit, S.F.A., Mariam, K.H.A.N., Abdullah, R. (2021). Zerumbone induces growth inhibition of Burkitt’s lymphoma cell line via apoptosis. Natural Volatiles and Essential Oils, 8(3), 56-63. [CrossRef]
20. 20. Albaayit, S.F.A., Khan, M., Rasedee, A., Noor, M.H.M. (2022). Zerumbone-loaded nanostructured lipid carrier gel enhances wound healing in diabetic rats. BioMed Research International, 2022(9), 1-11. [CrossRef]
21. 21. Hu, Z., Zeng, Q., Zhang, B., Liu, H., Wang, W. (2014). Promotion of p53 expression and reactive oxidative stress production is involved in zerumbone-induced cisplatin sensitization of non-small cell lung cancer cells. Biochimie, 107, 257-262. [CrossRef]
22. 22. Iftikhar, F., Yaqoob, F., Tabassum, N., Jan, M.S., Sadiq, A., Tahir, S., (2018). Design, synthesis, in-vitro thymidine phosphorylase inhibition, in-vivo antiangiogenic and in-silico studies of C-6 substituted dihydropyrimidines. Bioorganic Chemistry, 80, 99-111. [CrossRef]
23. 23. Albaayit, S.F.A., Khan, M., Rasedee, A., Noor, M.H.M. (2021). Ethyl acetate extract of Clausena excavata induces growth inhibition of non-small-lung cancer, NCI-H460, cell line via apoptosis. Journal of Applied Biomedicine, 19(1), 40-47. [CrossRef]
24. 24. Rasul, A., Di, J., Millimouno, F.M., Malhi, M., Tsuji, I., Ali, M., Li, X. (2013). Reactive oxygen species mediate isoalantolactone-induced apoptosis in human prostate cancer cells. Molecules, 18(8), 9382-9396. [CrossRef]
25. 25. Zhang, Q., Qin, Y., Zhao, J., Tang, Y., Hu, X., Zhong, W., Yang, C. (2019). Thymidine phosphorylase promotes malignant progression in hepatocellular carcinoma through pentose Warburg effect. Cell death and disease, 10(2), 1-17. [CrossRef]
26. 26. Hoseinkhani, Z., Norooznezhad, F., Rastegari-Pouyani, M., Mansouri, K. (2020). Medicinal plants extracts with antiangiogenic activity: Where is the link? Advanced Pharmaceutical Bulletin, 10(3), 370-378. [CrossRef]
27. 27. Albaayit, S.F.A. (2020). In vitro evaluation of anticancer activity of Moringa peregrina seeds on breast cancer cells. The Eurasia Proceedings of Science Technology Engineering and Mathematics, 11, 163-166.
28. 28. Albaayit, S.F.A., Abba, Y., Abdullah, R., Abdullah, N. (2016). Prophylactic effects of Clausena excavata burum. f. leaf extract in ethanol-induced gastric ulcers. Drug Design, Development and Therapy, 10, 1973-1986. [CrossRef]
29. 29. Albaayit, S.F.A., Maharjan, R. (2022). Immunomodulatory potential of clausena excavata leaves fractions via decreasing the production of reactive oxygen species from immune cells. Journal of Faculty of Pharmacy of Ankara University, 46(3), 703-711. [CrossRef]
30. 30. Albaayit, S.F.A. (2021). Evaluation of anti-methicillin resistant Staphylococcus aureus property of Clausena excavata leaves by using atomic force microscopy and flowcytometry techniques. Pakistan Journal of Agricultural Sciences, 58(1), 315-320.
31. 31. Javaid, S., Shaikh, M., Fatima, N., Choudhary, M.I. (2019). Natural compounds as angiogenic enzyme thymidine phosphorylase inhibitors: In vitro biochemical inhibition, mechanistic, and in silico modeling studies. PloS one, 14(11), e0225056. [CrossRef]
32. 32. Shamoto, T., Matsuo, Y., Shibata, T., Tsuboi, K., Nagasaki, T., Takahashi, H., Takeyama, H. (2014). Zerumbone inhibits angiogenesis by blocking NF-κB activity in pancreatic cancer. Pancreas, 43(3), 396-404. [CrossRef]
33. 33. Albaayit SFA (2021). Enzyme inhibitory properties of zerumbone. Pakistan Journal of Agricultural Sciences, 58(3), 1207-1209. [CrossRef]
34. 34. Kapitan, O.B., Ambarsari, L., Falah, S. (2016). Inhibition docking simulation of zerumbone, gingerglycolipid b, and curzerenone compound Zingiber zerumbet from timor island against mura enzyme. Journal of Applied Science, 3, 279-288. [CrossRef]
35. 35. Jyothilakshmi, M., Jyothis, M., Narayanan, G.N.H., Latha, M.S. (2017). Antidermatophytic and protease-inhibiting activities of zerumbone: A natural sesquiterpene from the rhizome of Zingiber zerumbet (L.) Roscoe ex JE; Smith. Pharmacognosy Magazine, 13(49), 2. [CrossRef]
36. 36. Singh, S.P., Nongalleima, K., Singh, N.I., Doley, P., Singh, C.B., Singh, T.R., Sahoo, D. (2018). Zerumbone reduces proliferation of HCT116 colon cancer cells by inhibition of TNF-alpha. Scientific Reports, 8(1), 1-11. [CrossRef]
37. 37. Wang, J., Luo, B., Li, X., Lu, W., Yang, J., Hu, Y., Huang, P., Wen, S. (2017). Inhibition of cancer growth in vitro and in vivo by a novel ROS-modulating agent with ability to eliminate stem-like cancer cells. Cell Death Disease, 8, e2887. [CrossRef]
38. 38. Wang, Y., Qi, H., Liu, Y., Duan, C., Liu, X., Xia, T., Liu, H.X. (2021). The double-edged roles of ROS in cancer prevention and therapy. Theranostics, 11(10), 4839. [CrossRef]
39. 39. Reczek, C.R., Chandel, N.S. (2018). ROS promotes cancer cell survival through calcium signaling. Cancer Cell, 33(6), 949-951. [CrossRef]
40. 40. de Sá Junior, P.L., Câmara, D.A.D., Porcacchia, A.S., Fonseca, P.M.M., Jorge, S.D., Araldi, R.P., Ferreira, A.K. (2017). The Roles of ROS in Cancer Heterogeneity and Therapy. Oxidative Medicine and Cellular Longevity, 2017, 2467940. [CrossRef]
41. 41. Su, L.J., Zhang, J.H., Gomez, H., Murugan, R., Hong, X., Xu, D., Peng, Z.Y. (2019). Reactive oxygen species-induced lipid peroxidation in apoptosis, autophagy, and ferroptosis. Oxidative Medicine and Cellular Longevity, 2019, 5080843. [CrossRef]
42. 42. Villalpando-Rodriguez, G.E., Gibson, S.B. (2021). Reactive oxygen species (ROS) regulates different types of cell death by acting as a rheostat. Oxidative Medicine and Cellular Longevity, 2021, 9912436. [CrossRef]
43. 43. Wang, J., Yi, J. (2008). Cancer cell killing via ROS: To increase or decrease, that is the question. Cancer Biology and Therapy, 7(12), 1875-1884. [CrossRef]
44. 44. Albaayit, S.F.A., Abba, Y., Abdullah, R., Abdullah, N. (2014). Evaluation of antioxidant activity and acute toxicity of Clausena excavata leaves extract. Evidence-Based Complementary and Alternative Medicine, 2014, 1-10. [CrossRef]
45. 45. Albaayit, S.F.A. (2023). Ethyl acetate extract of Clausena execavata promotes growth inhibition of Burkett’s Lymphoma cell line via apoptotic activities. Boletín Latinoamericano y del Caribe de Plantas Medicinales y Aromáticas, 22(3), 350-359. [CrossRef]
46. 46. Perillo, B., Di Donato, M., Pezone, A., Di Zazzo, E., Giovannelli, P., Galasso, G., Migliaccio, A. (2020). ROS in cancer therapy: The bright side of the moon. Experimental Molecular Medicine, 52(2), 192-203. [CrossRef]
47. 47. Jalili-Nik, M., Sadeghi, M.M., Mohtashami, E., Mollazadeh, H., Afshari, A.R., Sahebkar, A. (2020). Zerumbone promotes cytotoxicity in human malignant glioblastoma cells through reactive oxygen species (ROS) generation. Oxidative Medicine and Cellular Longevity, 2020, 3237983. [CrossRef]
48. 48. Li, J., Wang, L., Sun, Y., Wang, Z., Qian, Y., Duraisamy, V., Antary, T.M.A. (2022). Zerumbone‐induced reactive oxygen species‐mediated oxidative stress re‐sensitizes breast cancer cells to paclitaxel. Biotechnology and Applied Biochemistry, 70, 28-37. [CrossRef]
49. 49. Deorukhkar, A., Ahuja, N., Mercado, A.L., Diagaradjane, P., Raju, U., Patel, N., Krishnan, S. (2015). Zerumbone increases oxidative stress in a thiol‐dependent ROS‐independent manner to increase DNA damage and sensitize colorectal cancer cells to radiation. Cancer Medicine, 4(2), 278-292. [CrossRef]
50. 50. Rajan, I., Jayasree, P.R., Kumar, P.R. (2015). Zerumbone induces mitochondria-mediated apoptosis via increased calcium, generation of reactive oxygen species and upregulation of soluble histone H2AX in K562 chronic myelogenous leukemia cells. Tumor Biology, 36(11), 8479-8489. [CrossRef]
51. 51. Ali, S.H., Hamadi, S.A., Al-Jaff, A.N. (2007). Effect of ergotamine and its combination with vitamin E or melatonin on total antioxidant status in migraine patients. Iraqi Journal of Pharmaceutical Sciences, 16(2), 27-33. [CrossRef]