THE EFFECTS OF FLAVONOIDS AGAINST LUNG CANCER

Öz

Objective: Cancer is a type of chronic and non-contagious disease that is common in our country and in the world. Chemotherapy, immunotherapy, radiotherapy, phytotherapy, palliative treatments and surgical methods are used in cancer treatment. This review aims to evaluate the results of in vitro, in vivo and clinical studies examining the effects of flavonoids on the prevention and treatment of lung cancer. In addition, the mechanisms by which flavonoids are used to prevent and treat lung cancer were investigated. Result and Discussion: There are many studies on the efficacy of flavonoids in lung, breast, ovarian, esophageal and colorectal cancers. In vitro, in vivo and clinical study findings are also available to evaluate their efficacy especially in lung cancer. In the light of these findings, flavonoids show anticancer activity with many effects including antioxidant, anti-inflammatory, antiproliferative activities, inhibition of bioactivating enzymes and induction of detoxifying enzymes. In addition, flavonoids selectively induce apoptosis of lung cancer cells, thereby providing anticancer effects and do not harm normal healthy cells. In conclusion, flavonoids inhibit lung carcinogenesis in preclinical studies and have the capacity to target the signaling pathways involved in lung carcinogenesis, but much more clinical studies are needed.

Anahtar Kelimeler

• Clinical trials
• in vitro
• in vivo
• flavonoid
• lung cancer

Etik Beyan

Yazarlar bu çalışma için etik kurul onayının zorunlu olmadığını beyan etmektedir.

FLAVONOİTLERİN AKCİĞER KANSERİNE KARŞI ETKİLERİ

Öz

Amaç: Kanser, ülkemizde ve dünyada yaygın olarak görülen, kronikleşebilen ve bulaşıcı olmayan bir hastalık türüdür. Kanser tedavisinde kemoterapi, immünoterapi, radyoterapi, fitoterapi, palyatif tedaviler ve cerrahi yöntemler kullanılmaktadır. Bu derleme flavonoitlerin akciğer kanserini önleme ve tedavi etme üzerindeki etkilerini inceleyen in vitro, in vivo ve klinik çalışma sonuçlarını değerlendirmeyi amaçlamaktadır. Ayrıca flavonoitlerin hangi mekanizmalar ile akciğer kanserini önlemede ve tedavi etmede kullanıldığı araştırılmıştır. Sonuç ve Tartışma: Flavonoitlerin akciğer, meme, yumurtalık, özofagus ve kolorektal kanserlerdeki etkinlikleri ile ilgili pek çok çalışma bulunmaktadır. Özellikle akciğer kanserindeki etkinliklerini değerlendirmek için in vitro, in vivo ve klinik çalışma bulguları da mevcuttur. Bu bulgular ışığında flavonoitler antioksidan, antienflamatuvar, antiproliferatif aktiviteler, biyoaktifleştirici enzimlerin inhibisyonu ve detoksifiye edici enzimlerin indüksiyonu dahil olmak üzere birçok etki ile antikanser aktivite göstemektedir. Bunun yanı sıra flavonoitler seçici olarak akciğer kanseri hücrelerini apoptoza teşvik ederek antikanser etki sağlamaktadırlar ve normal sağlıklı hücrelere zarar vermemektedirler. Sonuç olarak flavonoitlerin preklinik çalışmalarda akciğer karsinogenezini inhibe ettiği ve burada görevli olan sinyal yolaklarını hedefleme kapasitesine sahip olduğu anlaşılmakla beraber, çok daha fazla klinik çalışmanın yapılmasının gerekliliği ortaya çıkmıştır.

Anahtar Kelimeler

• Akciğer kanseri
• flavonoit
• in vitro
• in vivo
• klinik çalışmalar

Kaynakça

1. 1. Debela, D.T., Muzazu, S.G., Heraro, K.D., Ndalama, M.T., Mesele, B.W., Haile, D.C., Kitui, S.H., Manyazewal, T. (2021). New approaches and procedures for cancer treatment: Current perspectives. SAGE Open Medicine, 9, 20503121211034366. [CrossRef]
2. 2. Bray, F., Laversanne, M., Sung, H., Ferlay, J., Siegel, R.L., Soerjomataram, I., Jemal, A. (2024). Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA: A Cancer Journal for Clinicians, 74(3), 229-263. [CrossRef]
3. 3. Sung, H., Ferlay, J., Siegel, R.L., Laversanne, M., Soerjomataram, I., Jemal, A., Bray, F. (2021). Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA: A Cancer Journal for Clinicians, 71(3), 209-249. [CrossRef]
4. 4. Yalçın, G.T. (2013). Yüksek Lisans Tezi. Flavonoidlerin Kanser Hücrelerine Etkisi. Enstitüsü Tıbbi Biyokimya Anabilim Dalı, Selçuk Üniversitesi Sağlık Bilimleri Enstitüsü, Konya, Türkiye.
5. 5. Li, G., Ding, K., Qiao, Y., Zhang, L., Zheng, L., Pan, T., Zhang, L. (2020). Flavonoids regulate inflammation and oxidative stress in cancer. Molecules, 25(23), 5628. [CrossRef]
6. 6. Simeone, J.C., Nordstrom, B.L., Patel, K., Klein, A.B. (2019). Treatment patterns and overall survival in metastatic non-small-cell lung cancer in a real-world, US setting. Future Oncology, 15(30), 3491-3502. [CrossRef]
7. 7. Yao, H., Xu, W., Shi, X., Zhang, Z. (2011). Dietary flavonoids as cancer prevention agents. Journal of Environmental Science and Health, Part C, 29(1), 1-31. [CrossRef]
8. 8. Vazhappilly, C.G., Amararathna, M., Cyril, A.C., Linger, R., Matar, R., Merheb, M., Ramadan, W.S., Radhakrishnan, R., Rupasinghe, H.V. (2021). Current methodologies to refine bioavailability, delivery, and therapeutic efficacy of plant flavonoids in cancer treatment. The Journal of Nutritional Biochemistry, 94, 108623. [CrossRef]

9. 9. Purut, H.P., Köse, B.G., Akbal, Y., Özdemir, V.A., Çol, B.K. (2022). Kemoterapi Alan Kanser Hastalarinda Görülen Semptomlar ve Tamamlayici Terapi Uygulamalari Kullanımları. Sağlık Akademisyenleri Dergisi, 9(3), 211-219. [CrossRef]
10. 10. Knight, S.R., Shaw, C.A., Pius, R., Drake, T.M., Norman, L., Ademuyiwa, A.O., Fermani, C.G. (2021). Global variation in postoperative mortality and complications after cancer surgery: A multicentre, prospective cohort study in 82 countries. The Lancet, 397(10272), 387-397. [CrossRef]
11. 11. Atawodi, S.E., Atawodi, J.C., Idakwo, P., Pfundstein, B., Haubner, R., Wurtele, G., Spiegelhalder, B., Bartsch, H., Owen, R.W. (2009). Evaluation of the polyphenol composition and antioxidant activity of African variety of Dacryodes edulis (G. Don) HJ Lam fruit. Journal of Medicinal Food, 12(6), 1321-1325. [CrossRef]
12. 12. Ponte, L.G.S., Pavan, I.C.B., Mancini, M.C.S., da Silva, L.G.S., Morelli, A.P., Severino, M.B., Bezerra, R.M.N., Simabuco, F.M. (2021). The hallmarks of flavonoids in cancer. Molecules, 26(7), 2029. [CrossRef]
13. 13. Forni, C., Rossi, M., Borromeo, I., Feriotto, G., Platamone, G., Tabolacci, C., Mischiati, H., Beninati, S. (2021). Flavonoids: A myth or a reality for cancer therapy? Molecules, 26(12), 3583. [CrossRef]
14. 14. Slika, H., Mansour, H., Wehbe, N., Nasser, S.A., Iratni, R., Nasrallah, G., Shaito, A., Ghaddar, T., Kobeissy, F., Eid, A.H. (2022). Therapeutic potential of flavonoids in cancer: ROS-mediated mechanisms. Biomedicine and Pharmacotherapy, 146, 112442. [CrossRef]
15. 15. Le Marchand, L., Murphy, S.P., Hankin, J.H., Wilkens, L.R., Kolonel, L.N. (2000). Intake of flavonoids and lung cancer. Journal of the National Cancer Institute, 92(2), 154-160.
16. 16. Pang, X., Zhang, X., Jiang, Y., Su, Q., Li, Q., Li, Z. (2021). Autophagy: Mechanisms and therapeutic potential of flavonoids in cancer. Biomolecules, 11(2), 135. [CrossRef]
17. 17. Liskova, A., Koklesova, L., Samec, M., Smejkal, K., Samuel, S.M., Varghese, E., Abotalep, M., Biringer, K., Kudela, E., Danko, J., Şakibei, M., Kwon, T.K., Büsselberg, B., Kubatka, P. (2020). Flavonoids in cancer metastasis. Cancers, 12(6), 1498. [CrossRef]
18. 18. Chang, H.L., Chang, Y.M., Lai, S.C., Chen, K.M., Wang, K.C., Chiu, T.T., Chang, F.H., Hsu, L.S. (2017). Naringenin inhibits migration of lung cancer cells via the inhibition of matrix metalloproteinases-2 and-9. Experimental and Therapeutic Medicine, 13(2), 739-744. [CrossRef]
19. 19. Xia, R., Sheng, X., Xu, X., Yu, C., Lu, H. (2018). Hesperidin induces apoptosis and G0/G1 arrest in human non-small cell lung cancer A549 cells. International Journal of Molecular Medicine, 41(1), 464-472. [CrossRef]
20. 20. Govindaraju, S., Roshini, A., Lee, M.H., Yun, K. (2019). Kaempferol conjugated gold nanoclusters enabled efficient for anticancer therapeutics to A549 lung cancer cells. International Journal of Nanomedicine, 14, 5147-5157. [CrossRef]
21. 21. Kang, H.R., Moon, J.Y., Ediriweera, M.K., Song, Y.W., Cho, M., Kasiviswanathan, D., Cho, S.K. (2020). Dietary flavonoid myricetin inhibits invasion and migration of radioresistant lung cancer cells (A549‐IR) by suppressing MMP‐2 and MMP‐9 expressions through inhibition of the FAK‐ERK signaling pathway. Food Science and Nutrition, 8(4), 2059-2067. [CrossRef]
22. 22. Yan, W., Wu, T.H., Leung, S.S., To, K.K. (2020). Flavonoids potentiated anticancer activity of cisplatin in non-small cell lung cancer cells in vitro by inhibiting histone deacetylases. Life Sciences, 258(1), 118211. [CrossRef]
23. 23. Kang, L., Song, Y. G., Fang, X. Y., Zhang, J., Zhang, Y. N., Miao, J. X. (2021). Total flavonoids of Taraxacum mongolicum inhibit non-small cell lung cancer by regulating immune function. Journal of Ethnopharmacology, 281, 114514. [CrossRef]
24. 24. Jia, X.B., Zhang, Q., Xu, L., Yao, W.J., Wei, L. (2021). Lotus leaf flavonoids induce apoptosis of human lung cancer A549 cells through the ROS/p38 MAPK pathway. Biological Research, 54(1), 7. [CrossRef]
25. 25. Oo, A.M., Mohd Adnan, L.H., Nor, N.M., Simbak, N., Ahmad, N.Z., Lwin, O.M. (2021). Immunomodulatory effects of flavonoids: An experimental study on natural-killer-cell-mediated cytotoxicity against lung cancer and cytotoxic granule secretion profile. Proceedings of Singapore Healthcare, 30(4), 279-285. [CrossRef]
26. 26. Rajendran, P., Maheshwari, U., Muthukrishnan, A., Muthuswamy, R., Anand, K., Ravindran, B., Dhanaraj, P., Balamuralikrishnan, B., Chang, W., Chung, W.J. (2021). Myricetin: Versatile plant based flavonoid for cancer treatment by inducing cell cycle arrest and ROS-reliant mitochondria-facilitated apoptosis in A549 lung cancer cells and in silico prediction. Molecular and Cellular Biochemistry, 476(1), 57-68. [CrossRef]
27. 27. Wufuer, Y., Yang, X., Guo, L., Aximujiang, K., Zhong, L., Yunusi, K., Wu, G. (2022). The antitumor effect and mechanism of total flavonoids from Coreopsis tinctoria Nutt (snow chrysanthemum) on lung cancer using network pharmacology and molecular docking. Frontiers in Pharmacology, 13, 761785. [CrossRef]
28. 28. Jakimiuk, K., Szoka, Ł., Surażyński, A., Tomczyk, M. (2024). Using flavonoid substitution status to predict anticancer effects in human melanoma cancers: An in vitro study. Cancers, 16(3), 487. [CrossRef]
29. 29. Shin, S.C., Choi, J.S., Li, X. (2006). Enhanced bioavailability of tamoxifen after oral administration of tamoxifen with quercetin in rats. International Journal of Pharmaceutics, 313(1-2), 144-149. [CrossRef]
30. 30. Tan, B.J., Liu, Y., Chang, K.L., Lim, B.K., Chiu, G.N. (2012). Perorally active nanomicellar formulation of quercetin in the treatment of lung cancer. International Journal of Nanomedicine, 7, 651-661. [CrossRef]
31. 31. Majumdar, D., Jung, K.H., Zhang, H., Nannapaneni, S., Wang, X., Amin, A.R., Çen, Z., Çen, Z.G., Shin, D.M. (2014). Luteolin nanoparticle in chemoprevention: In vitro and in vivo anticancer activity. Cancer Prevention Research, 7(1), 65-73. [CrossRef]
32. 32. Hsu, Y.C., Chiang, J.H., Yu, C.S., Hsia, T.C., Wu, R.S.C., Lien, J.C., Lai, K.C., Yu, F.S., Chung, J.G. (2017). Antitumor effects of deguelin on H 460 human lung cancer cells in vitro and in vivo: Roles of apoptotic cell death and H 460 tumor xenografts model. Environmental Toxicology, 32(1), 84-98. [CrossRef]
33. 33. Ji, B.C., Yu, C.C., Yang, S.T., Hsia, T.C., Yang, J.S., Lai, K.C., Ko, Y.C., Lin, J.Y., Lai, K.Y., Chung, J. G. (2012). Induction of DNA damage by deguelin is mediated through reducing DNA repair genes in human non-small cell lung cancer NCI-H460 cells. Oncology Reports, 27(4), 959-964. [CrossRef]
34. 34. Lee, H.Y., Oh, S.H., Woo, J.K., Kim, W.Y., Van Pelt, C.S., Price, R.E., Ccody, D., Tran, H., Pezutto, J.M., Moriarty, R.M., Hong, W.K. (2005). Chemopreventive effects of deguelin, a novel Akt inhibitor, on tobacco-induced lung tumorigenesis. Journal of the National Cancer Institute, 97(22), 1695-1699. [CrossRef]
35. 35. Liu, X., Jiang, Q., Liu, H., Luo, S. (2019). Vitexin induces apoptosis through mitochondrial pathway and PI3K/Akt/mTOR signaling in human non-small cell lung cancer A549 cells. Biological Research, 52(1), 1-7. [CrossRef]
36. 36. Huo, M., Wang, H., Zhang, Y., Cai, H., Zhang, P., Li, L., Zhou, J., Yin, T. (2020). Co-delivery of silybin and paclitaxel by dextran-based nanoparticles for effective anti-tumor treatment through chemotherapy sensitization and microenvironment modulation. Journal of Controlled Release, 321, 198-210. [CrossRef]
37. 37. Wright, M.E., Mayne, S.T., Stolzenberg-Solomon, R.Z., Li, Z., Pietinen, P., Taylor, P.R., Wirtamo, J., Albanes, D. (2004). Development of a comprehensive dietary antioxidant index and application to lung cancer risk in a cohort of male smokers. American Journal of Epidemiology, 160(1), 68-76. [CrossRef]
38. 38. Cui, Y., Morgenstern, H., Greenland, S., Tashkin, D.P., Mao, J.T., Cai, L., DO, W.D., Mack, T.M., Lu, Q.Y., Zhang, Z.F. (2008). Dietary flavonoid intake and lung cancer-A population‐based case‐control study. Cancer, 112(10), 2241-2248. [CrossRef]
39. 39. Lagiou, P., Rossi, M., Lagiou, A., Tzonou, A., La Vecchia, C., Trichopoulos, D. (2008). Flavonoid intake and liver cancer: A case-control study in Greece. Cancer Causes and Control, 19(8), 813-818. [CrossRef]
40. 40. Christensen, K.Y., Naidu, A., Parent, M.É., Pintos, J., Abrahamowicz, M., Siemiatycki, J., Koushik, A. (2012). The risk of lung cancer related to dietary intake of flavonoids. Nutrition and Cancer, 64(7), 964-974. [CrossRef]
41. 41. Zanoaga, O., Braicu, C., Jurj, A., Rusu, A., Buiga, R., Berindan-Neagoe, I. (2019). Progress in research on the role of flavonoids in lung cancer. International Journal of Molecular Sciences, 20(17), 4291. [CrossRef]
42. 42. Li, G., Ding, K., Qiao, Y., Zhang, L., Zheng, L., Pan, T., Zhang, L. (2020). Flavonoids regulate inflammation and oxidative stress in cancer. Molecules, 25(23), 5628. [CrossRef]
43. 43. Bhardwaj, V., Mandal, A.K.A. (2019). Next-generation sequencing reveals the role of epigallocatechin-3-gallate in regulating putative novel and known microRNAs which target the MAPK pathway in non-small-cell lung cancer A549 cells. Molecules, 24(2), 368. [CrossRef]
44. 44. Wang, H., Bian, S., Yang, C.S. (2011). Green tea polyphenol egcg suppresses lung cancer cell growth through upregulating mir-210 expression caused by stabilizing hif-1alpha. Carcinogenesis, 32(12), 1881-1889. [CrossRef]