Anticancer Mechanisms of Chalcone Derivatives

Öz

Cancer; It is a process in which cells undergo metabolic changes that cause them to proliferate uncontrollably, escape the surveillance of the immune system, and spread by invading distant tissues. One out of every five people will develop cancer at some point in their life. Despite all the treatment methods that have been developed, deaths caused by cancer still rank second in developed societies. A wide variety of drugs are used in chemotherapy treatments that affect different metabolic pathways of cancer cells. Many herbal anti-cancer drugs such as paclitaxel and docetaxel, which are known for their anti-neoplastic properties, are used in the clinic. Treatment possibilities of herbal chemotherapeutic agents against various types of cancer continue to be investigated. In recent studies, flavonoid-based compounds that can target different molecular pathways in cancer treatment have been synthesized. It has been determined that chalcones, which belong to the flavonoid family, have anti-cancer activity as well as different biological effects. Scientific research continues to reveal the mechanism of action of chalcone compounds. In this review, the anti-cancer roles of chalcone derivatives through mechanisms such as anti-proliferation, apoptosis induction, microtubule polymerization, anti-angiogenesis and cell cycle arrest are discussed.

Anahtar Kelimeler

• Flavonoid
• Chalcones
• Anti-Cancer
• Cytotoxicity

Kalkon Türevlerinin Antikanser Mekanizmaları

Öz

Kanser; hücrelerin kontrolsüz çoğalmalarına, immün sistemin gözetiminden kaçmalarına ve uzaktaki dokuları istila ederek yayılmalarına yol açan, metabolik değişiklikler geçirdikleri bir süreçtir. Hayatı boyunca her beş kişiden biri, yaşamının bir döneminde kansere yakalanmaktadır. Geliştirilmiş olan tüm tedavi yöntemlerine rağmen, hala kanserin neden olduğu ölümler gelişmiş toplumlarda ikinci sırada yer almaktadır. Kemoterapik tedavilerde kanser hücresinin farklı metabolik yolaklarına etki eden çok çeşitli ilaçlar kullanılmaktadır. Anti-neoplastik özelliği ile bilinen paklitaksel ve dosetaksel gibi birçok bitkisel kökenli anti-kanser ilaç klinikte kullanılmaktadır. Bitkisel kökenli kemoterapötik ajanların çeşitli kanser türlerine karşı tedavi olanakları araştırılmaya devam edilmektedir. Son dönemlerde yapılan çalışmalarda, kanser tedavisinde farklı moleküler yolakları hedefleyebilen flavonoid bazlı bileşikler sentezlenmiştir. Flavonoid ailesine ait olan kalkonlarında farklı biyolojik etkilerinin yanı sıra anti-kanser aktiviteye sahip oldukları belirlenmiştir. Kalkon bileşiklerinin etki mekanizmasını ortaya çıkarmak için bilimsel araştırmalar devam etmektedir. Bu derlemede, kalkon türevlerinin anti-proliferasyon, apoptoz indüksiyonu, mikrotübül polimerizasyonu, anti-anjiyogenezis ve hücre döngüsünün durdurulması gibi mekanizmalar yoluyla anti-kanser rollerinden bahsedilmektedir.

Anahtar Kelimeler

• Flavanoid
• Kalkonlar
• Anti-Kanser
• Sitotoksisite

Destekleyen Kurum

Bursa Uludağ Üniversitesi

Kaynakça

1. Abrahim-Vieira, B. A., de Mello, M. V. P., Domingos, T. F. S., de Jesus, J. B., de Sousa, A. C. C., Rodrigues, C. R., Souza, A. M. T. (2018). A comprehensive review of chalcone derivatives as anti-leishmanial agents. European Journal of Medicinal Chemistry, 150, 920-929.
2. Abdel-Aziz, M., Abuo-Rahma, G. E. D. A., Eisa, M. A., Fathy, M., Nazmy, M. H. (2021). Anti-proliferative and pro-apoptotic activities of synthesized 3, 4, 5 tri-methoxy ciprofloxacin chalcone hybrid, through p53 up-regulation in hepg2 and mcf7 cell lines. Asian Pacific Journal of Cancer Prevention, 22(10), 3393-3404.
3. Abuo-Rahma, G. E. D. A., Alaaeldin, R., Fathy, M., Zhao, Q. L. (2021). Modulation of apoptosis and epithelial-Mesenchymal transition E-cadherin/TGF-β/Snail/TWIST pathways by a new ciprofloxacin chalcone in breast cancer cells. Anti-cancer Research, 41(5), 2383-2395.
4. Ahn, J. H., Bhattarai, K. R., Chae, H. J., Chaudhary, M., Kim, H. K., Lee, H. Y., Riaz, T. A. (2021). Chalcone suppresses tumor growth through NOX4-IRE1α sulfonation-RIDD-miR-23b axis. Redoxbiology, 40, 101853.
5. Aiello, P., Ardekan, A. P., Bishayee, A., Daraei, N., Heidari, M., Jouybari, L., Kooti, W., Mansourkhani, S. M., Mohamadian, S., Peiro, K., Rezaei, M., Sharghi, M. (2019a.) Medicinal plants in the prevention and treatment of colon cancer. Oxidative Medicine and Cellular Longevity.
6. Aiello, A., Casertano, M., Della Sala, G., Imperatore, C., Laurenzana, I., Luciano, P., Menna, M., Piccoli, C. (2019b). In vitro anti-proliferative evaluation of synthetic meroterpenes ınspired by marine natural products. Marine Drugs, 17(12), 684.
7. Alam, M. J., Alam, O., Perwez, A., Rizvi, M. A., Naim, M. J., Naidu, V. G., ... & Shakeel, F. (2022). Design, synthesis, molecular docking, and biological evaluation of pyrazole hybrid chalcone conjugates as potential anticancer agents and tubulin polymerization inhibitors. Pharmaceuticals, 15(3), 280.
8. Alesse, E., Balsano, C., Belloni, L., Costanzo, A., Cimino, L., Gallo, R., Gulino, A., Ianari, A., Levrero, M., Pediconi, N., Porcellini, A., Screpanti, I. (2003). Differential regulation of E2F1 apoptotic target genes in response to DNA damage. Nature Cell Biology, 5(6), 552-558.

9. Al-Farsi, H. F., Elkhalifa, D., Gupta, I., Khalil, A., Kheraldine, H., Moustafa, A. E. A., Rizeq, B. (2021). Novel nitrogen-based chalcone analogs provoke substantial apoptosis in HER2-positive human breast cancer cells via JNK and ERK1/ERK2 signaling pathways. International Journal Of Molecular Sciences, 22(17), 9621.
10. Anand, A., Kumar, V., Singh, P. (2014). Recent developments in biological activities of chalcones: A mini review. European Journal of Medicinal Chemistry, 85, 758-777.
11. Andreu, J. M., Briand, C., Leynadie, D., Nieto, J. M., Peyrot, V., Rodriquez, A., Sarrazin, M. (1989). Interaction of tubulin and cellular microtubules with the new anti-tumor drug MDL 27048: a powerful and reversible microtubule inhibitor. Journal of Biological Chemistry, 264(35), 21296-21301.
12. Andreu, J. M., Briand, C., Laynez, J., Leynadier, D., Menendez, M., Peyrot, V., Sarrazin, M. (1992). Mechanism of binding of the new anti-mitotic drug MDL 27048 to the colchicine site of tubulin: equilibrium studies. Biochemistry, 31(45), 11125-11132.
13. Andrade, C. H., Cravo, P. V. L., Gomes, M. N., Muratov, E. N., Neves, B. J., Pereira, M., Peixoto, J. C., Rosseto, L. P. (2017). Chalcone derivatives: Promising starting points for drug design. Molecules, 22(8), 1210.
14. Ari, F., Coskun, D., Coskun, M. F., Erkisa, M., Ulukaya, E. (2017). Novel 1-(7-ethoxy-1-benzofuran-2-yl) substituted chalcone derivatives: synthesis, characterization and anti-cancer activity. European Journal of Medicinal Chemistry, 136, 212-222.
15. Arfuso, F., Banik, K., Bordoloi, D., Harsha, C., Kumar, A. P., Kunnumakkara, A. B., Monisha, J., Padmavathi, G., Roy, N. K., Wang, H. (2019). An ınvestigation on the therapeutic potential of butein, a tretra hydroxy chalcone against human oral squamous cell carcinoma. Asian Pacific Journal of Cancer Prevention: APJCP, 20(11), 3437-3446.
16. Asati, V., Bharti, S. K., Mahapatra, D. K. (2017). Chalcone derivatives: Anti-inflammatory potential and molecular targets perspectives. Current Topics İn Medicinal Chemistry, 17(28), 3146-3169.
17. Babu, G., Perumal, P. T. (1997). Convenıent Synthesis of α, α'-bis(substituted furfuryldine) cycloalkanones and chalcones under microwave irradiation. Synthetic Communications, 27, 3677-3682.
18. Bargsten, K., Bueno, O., Canela, M. D., Liekens, S., Noppen, S., Prota, A. E., Sáez-Calvo, G. (2017). Antivascular and anti-tumor properties of the tubulin-binding chalcone TUB091. Oncotarget, 8(9), 14325.
19. Bashir, N., Hussain, S., Khan, A., Kumar, R., Mehrotra, R., Nazir, S. U., Singh, A., Tanwar, P., Tulsyan, S. (2019). Cance rdrug resistance:A fleetto conquer. Journal of Cellular Biochemistry, 120(9), 14213-14225.
20. Baykara, O. (2016). Kanser tedavisinde güncel yaklaşımlar. Balıkesir Sağlık Bilimleri Dergisi, 5(3), 154-165.
21. Benink, H. A., Duellman, S., Minor, L., Moravec, R. A., Niles, A. L., Riss, T. L., Worzella, T. J. (2016). Cell viability assays. Assay Guidance Manual [Internet].
22. Binoy, A., Mishra, N., Nair, B. G., Nedungadi, D., Pandurangan, N. (2021). Proteasomal dysfunction and ER stress triggers 2′-hydroxy-retrochalcone induced paraptosis in cancer cells. Cell Biology International, 45(1), 164-176.
23. Bird, S. J., Collins, M., Cassella, J. P., Gowland, P., Henry, E. J. (2020). Ferrocenyl chalcone derivatives as possible anti-microbial agents. The Journal Of Antibiotics, 73(5), 299-308. Blackwell, T. K., Fernández-Cárdenas, L. P., Hourihan, J. M., Mazzeo, L. E. M. (2016). Cysteine sulfenylation directs IRE-1 to activate the SKN-1/Nrf2 anti-oxidant response. Molecular Cell, 63(4), 553-566.
24. Blair, C. A., Jandial, D. D., Krill, L. S., Zi, X., Zhang, S., Zhang, Y. B. (2014). Molecular targeted approaches to cancer therapy and prevention using chalcones. Current Cancer Drug Targets, 14(2), 181-200.
25. Bortoleti, B. T. S., Concato, V. M., Conchon-Costa, I., Costa, I. N., Gonçalves, M. D., Mantovani, M. S., Miranda-Sapla, M. M., Panis, C., Pavanelli, W. R., Silva, T. F., Siqueira, E. S., Tomiotto-Pellissier, F., Verri Junior, W. A. (2021). Trans-chalcone in duces death by autophagy mediated by p53 up-regulation and β-catenin down-regulation on human hepatocellular carcinoma HuH7.5 cell line. Phytomedicine, 80, 1-9.
26. Bray, F., Ferlay, J., Jemal, A., Laversanne, M., Siegel, R. L., Soerjomataram, I., Sung, H. (2021b). Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality World widefor 36 cancers in 185 countries. CA: a cancer journal for clinicians, 71(3), 209-249.
27. Bray, F., Laversanne, M., Soerjomataram, I., Weiderpass, E. (2021a). The ever-increasing importance of cancer as a leading cause of prematüre death Worldwide. Cancer, 127(16), 3029-3030.
28. Bustos, L., Echiburú-Chau, C., Castro-Alvarez, A., Bradshaw, B., Simirgiotis, M. J., Mellado, M., Cuellar, M. (2022). Cytotoxic effects on breast cancer cell lines of chalcones derived from a natural precursor and their molecular docking analysis. Molecules, 27(14), 4387.
29. Champavier, Y., Gamond, A., Laurent, A., Martin, F., Pinon, A., Pouget, C., Rioux, B. (2021). Synthesis and biological evaluation of chalcone-polyamine conjugates as novel vectorized agents in colorectal and prostate cancer chemotherapy. European Journal of Medicinal Chemistry, 222, 113586.
30. Chao, C. C. K. (2015). Mechanisms of p53 degradation. Clinica Chimica Acta, 438, 139-147.
31. Chen, M., Chen, W., Hui, J., Hu, S., Ji, J., Liang, G., Wang, Y., Xu, S., Zhou, J. (2015). Chemopreventive effect of chalconederivative, L2H17, in colon cancer development. BMC Cancer, 15(1), 870.
32. Chen, C., Lin, Y., Lu, Q., Wu, J., Xie, J., Zhang, M. (2019a). A novel chalcone derivative exerts anti-inflammatory and anti-oxidant effects after a cute lungin jury. Aging (Albany NY), 11(18), 7805-7816.
33. Chen, Y., Chen, H., Fan, C., Li, Y., Liu, X., Liu, Y., Wang, C., Wang, Y., Wu, D., Yang, J. (2019b). Inhibition of COX-2, mPGES-1 and CYP4A by isoliquiritigenin blocks the angiogenic Akt signaling in glioma through ceRNA effect of miR-194-5p and lncRNA NEAT1. Journal of Experimental & Clinical Cancer Research, 38(1), 371.
34. Chen, X., Lv, X., Gao, L., Liu, J., Wang, W., Guo, L., Liu, X. (2023). Chalcone Derivative CX258 Suppresses Colorectal Cancer via Inhibiting the TOP2A/Wnt/β-Catenin Signaling. Cells, 12(7), 1066.
35. Cheng, P., Gong, M., Huang, X., Wang, X., Yang, L. (2020). Chalcone hybrids and their anti-malarial activity. Archiv der Pharmazie, 353(4), 1900350.
36. Chhikara, B. S., & Parang, K. (2023). Global Cancer Statistics 2022: the trends projection analysis. Chemical Biology Letters, 10(1), 451-451.
37. Cho, S. G., Choi, Y. K., Kim, A. J., Ko, S. G., Woo, S. M. (2016). p53 causes butein-mediated apoptosis of chronic myeloid leukemia cells. Molecular Medicine Reports, 13(2), 1091-1096.
38. Chew, E. H., Gan, F. F., Karuppasamy, M., Ng, H. L., Seah, W., Yeap, W. H., Zhang, R. (2018). Novel dual-targeting anti-proliferative dihydrotriazine-chalcone derivatives display suppression of cancer cell invasion and inflammation by inhibiting the NF-κB signaling pathway. Food and Chemical Toxicology, 116, 238-248.
39. Darwish, M. I., Moustafa, A. M., Youssef, A. M., Mansour, M., Yousef, A. I., El Omri, A., Oishi, H. (2023). Novel Tetrahydro-[1, 2, 4] triazolo [3, 4-a] isoquinoline Chalcones Suppress Breast Carcinoma through Cell Cycle Arrests and Apoptosis. Molecules, 28(8), 3338.
40. Dobles, M., Hyman, A. A., Sorger, P. K., Tournebize, R. (1997). Coupling cell division and cell death to microtubule dynamics. Current Opinion İn Cell Biology, 9(6), 807-814.
41. Eisvand, F., Ghodsi, R., Hadizade, F., Jafari-Nik, M. R., Mirzaei, S., Mosaffa, F., Oskuee, S. R. (2021). Design, synthesis and biological evaluation of novel imidazole-chalcone derivatives as potential anti-cancer agents and tubulin polymerization inhibitors. Bioorganic Chemistry, 112, 1-30.
42. Fahmi, M. Z., Aung, Y. Y., Ahmad, M. A., Kristanti, A. N., Sakti, S. C. W., Arjasa, O. P., Lee, H. V. (2023). In vivo Study of Chalcone Loaded Carbon Dots for Enhancement of Anticancer and Bioimaging Potencies. Nanotheranostics, 7(3), 281-298.
43. Feng, Y. C., Li, J. Q., Luo, Y. H., Piao, X. J., Wang, S. N., Wang, J. R., Xu, W.T., Zhang, Y., Zhang, Y., Zhang, T. (2019). Mechanisms underlying isoliquiritigenin-induced apoptosis and cell cycle arrest via ROS-mediated MAPK/STAT3/NF-κB pathways in human hepatocellular carcinoma cells. Drug Development Research, 80(4), 461-470.
44. Fernandes, E., Freitas, M., Ribeiro, D., Rocha, S. (2020). A Systematic review on anti-diabetic properties of chalcones. Current Medicinal Chemistry, 27(14), 2257-2321.
45. Gao, F., Huang, G., Xiao, J. (2020). Chalcone hybrids as potential anti-cancer agents: Current development, mechanism of action, and structure-activity relationship. Medicinal Research Reviews, 40(5), 2049-2084.
46. Giles, F. J., Mooberry, S. L., Risinger, A. L. (2009). Microtubule dynamics as a target in oncology. Cancer Treatment Reviews, 35(3), 255-261.
47. Hanahan, D. (2022). Hallmarks of cancer: New dimensions. Cancer Discovery, 12(1), 31-46.
48. Haupt, Y., Kazaz, A., Maya, R., Oren, M. (1997). Mdm2 promotes the rapid degradation of p53. Nature, 387(6630), 296-299.
49. He, M., Li, Y., Liu, W., Peng, Z., Wang, G. (2022). A review on synthetic chalcone derivatives as tubulin polymerisation inhibitors. Journal of Enzyme Inhibition and Medicinal Chemistry, 37(1), 9-38.
50. Huang, T., Li, J., Wang, K., Zhou, N., Zhou, Y., Zhu, J. (2018). Buteinactivates p53 in hepatocellular carcinoma cells via blocking MDM2-mediated ubiquitination. OncoTargets and Therapy, 11, 2007-2015.
51. Huang, J., Luo, Y., Wang, C., Wu, W., Zha, D., Zhou, W., Zhang, C. (2021). Synthesis and biological evaluation of novel ligustrazine-chalcone derivatives as potential anti-triple negative breast cancer agents. Bioorganic & Medicinal Chemistry Letters, 47, 128230.
52. Jones, S. N., Kubbutat, M. H., Vousden, K. H. (1997). Regulation of p53 stability by Mdm2. Nature, 387(6630), 299-303.
53. Jordan, M. A., Wilson, L. (2004). Microtubules as a target for anti-cancer drugs. Nature Reviews Cancer, 4(4), 253-265.
54. Karthikeyan, C., Karunagaran, D., Manivannan, E., Moorthy, N. S. H. N., Ramasamy, S., Trivedi, P., Vanam, U. (2015). Advancesin chalcones-with-anti-cancer activities. Recent Patents on Anti-Cancer Drug Discovery, 10(1), 97-115.
55. Kopnin, B. P. (2000). Targets of onkogenes and tümör suppressors: key for understanding basic mechanisms of carcinogenesis. Biochemistry, 65(1), 2-27.
56. Lee, S. J., Park, M. T. (2003). Cell cycle and cancer. BMB Reports, 36(1), 60-65.
57. Levine, A. J., Oren, M. (2009). The first 30 years of p53: growing ever more complex. Nature Reviews Cancer, 9(10), 749-758.
58. Lin, J., Liao, Q., Oyang, L., Tan, S., Wang, H., Xia, L., Zhou, Y. (2018). Role of the NFκB-signaling pathway in cancer. OncoTargets and Therapy, 11, 2063.
59. Liu, Z., Ma, Z., Terada, L. S., Wu, R. F. (2010). Nox4-derived H2O2 mediates endoplasmic reticulum signaling through local Ras activation. Molecular And Cellular Biology, 30(14), 3553-3568.
60. Liu, Z., Wang, C., Wang, Y., Wang, L., Yan, G., Zhang, Y. (2021). 4’-O-Methylbroussochalcone B as a novel tubulin polymerization inhibitor suppressed the proliferation and migration of acute myeloid leukaemia cells. BMC Cancer, 21(1), 1-13.
61. Liu, Z., Wang, M., Huang, R., Hu, T., Jing, Y., Huang, X., Wang, H. (2023). Novel Indole–Chalcone Derivative-Ligated Platinum (IV) Prodrugs Attenuate Cisplatin Resistance in Lung Cancer through ROS/ER Stress and Mitochondrial Dysfunction. Journal of Medicinal Chemistry.
62. Manzo, E. (2021). Synthesis of marine natural products and molecules ınspired by marine substances. Marine Drugs, 19(4), 208.
63. Miao, Z., Sheng, C., Xing, C., Zhang, W., Zhang, W., Zhuang, C. (2017). Chalcone: A Privileged structure in medicinal chemistry. Chemical Reviews, 117(12), 7762-7810.
64. Mirossay, L., Mojzis, J., Varinska, L. (2017). Anti-angiogenic effect of flavonoids and chalcones: an up date. International Journal of Molecular Sciences, 19(1), 27.
65. Omron, A. R. (1972). The epidemiologic transition: a theory of the epidemiology of populations change. Millbank Memorial Fund Q, 49, 509-538.
66. Osmaniye, D., Sağlık, B. N., Khalilova, N., Levent, S., Bayazıt, G., Gul, U. D., Kaplancıklı, Z. A. (2023). Design, Synthesis, and Biological Evaluation Studies of Novel Naphthalene-Chalcone Hybrids As Antimicrobial, Anticandidal, Anticancer, and VEGFR-2 Inhibitors. ACS omega, 8(7), 6669-6678.
67. Papierska, K., Krajka-Kuźniak, V., Kleszcz, R., Stefański, T., Kurczab, R., & Kubicki, M. (2022). The synthesis of novel thioderivative chalcones and their influence on NF-κB, STAT3 and Nrf2 signaling pathways in colorectal cancer cells. Scientific Reports, 12(1), 14915.
68. Sebti, S., Solhy, A., Tahir, R., Boulaajaj, S., Mayoral, J. A., Fraile, J. M., Kossır, A., Oumımoun, H. (2001). Calcined Sodium Nitrate/Natural Phosphate: An Extremely Active Catalyst for the Easy Synthesis of Chalcones in Heterogeneous Media. Tetrahedron Letters, 42, 7953-7955.
69. Sezgin, C. (2010). Kanserde bitkilerle tedavide örnek uygulamalar. Bitkilerle Tedavi Sempozyumu, 5-6 Haziran 2010, Zeytinburnu, İstanbul. 172s.
70. Shi, X., Xu, W., Yao, H., ve Zhang, Z. (2011). Dietary flavonoids as cancer prevention agents. Journal of Environmental Scienceand Health, 29(1), 1-31.
71. 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.
72. Taşkın, M. (2016). Benzofuran sübstitüe kalkonların sentezi (Yüksek lisans tezi). Erişim adresi: http://dspace.adiyaman.edu.tr:8080/xmlui/handle/20.500.12414/2071.
73. WalyEldeen, A. A., El-Shorbagy, H. M., Hassaneen, H. M., Abdelhamid, I. A., Sabet, S., & Ibrahim, S. A. (2022). [1, 2, 4] Triazolo [3, 4-a] isoquinoline chalcone derivative exhibits anticancer activity via induction of oxidative stress, DNA damage, and apoptosis in Ehrlich solid carcinoma-bearing mice. Naunyn-Schmiedeberg's Archives of Pharmacology, 395(10), 1225-1238.
74. Weinberg, R. A. (1996). How cancer arises. Scientific American, 275(3), 62-70.
75. World Health Organization. (2020). World health statistics 2020. Erişim adresi: https://digitalcommons.fiu.edu/srhreports/health/health/28/.
76. Xu, H., Wang, J., Chen, Y., Du, Y., Chen, L., Wu, C., Chen, G. (2023). Design, synthesis and evaluation of the novel chalcone derivatives with 2, 2-dimethylbenzopyran as HIF-1 inhibitors that possess anti-angiogenic potential. European Journal of Medicinal Chemistry, 250, 115171.
77. Zhou, B. (2015). Diverse molecular targets for chalcones with varied bioactivities. Medicinal Chemistry, 5(8), 388-404.