General Approach and Recent Updates in In Vivo and In Vitro Cancer Studies on Medicinal Plant Treatments

Abstract

In recent years, the increasing incidence of cancer has heightened interest in alternative treatment approaches, particularly focusing on the antitumor potential of secondary metabolites derived from medicinal and aromatic plants, especially flavonoids. In this review, current in vitro and in vivo experimental studies published between 2020 and 2025 were examined to evaluate the effects of medicinal plants on various types of cancer. The primary focus was on breast, colon, gastric, pancreatic, liver, lung, and prostate cancers, as well as head and neck malignancies. The anticancer effects of flavonoids on tumor cells were explained through multifaceted biological mechanisms such as induction of apoptosis, inhibition of cell proliferation, cell cycle arrest, suppression of angiogenesis and metastasis, and modulation of the tumor microenvironment. Additionally, it was emphasized that flavonoid-loaded nanoparticle systems improve drug delivery efficiency, enhance chemosensitivity, and reduce systemic toxicity. Throughout the review, reliable databases such as PubMed, Web of Science, NCBI, and Turkish Cancer Statistics were utilized. The findings indicated that medicinal and aromatic plants are a valuable natural source for the development of anticancer agents and may hold significant potential for future clinical applications.

Keywords

• Seconder Metabolites
• Phytochemicals
• Tumor
• Chemosensitizer

Tıbbi Bitkilerle Tedaviye Yönelik İn Vivo ve İn Vitro Kanser Çalışmalarında Genel Yaklaşım ve Son Güncellemeler

Abstract

Son yıllarda artan kanser vakaları, alternatif tedavi yaklaşımlarına olan ilgiyi artırmış ve bu kapsamda tıbbi ve aromatik bitkilerden elde edilen sekonder metabolitlerin (özellikle flavonoidlerin) antitümör potansiyeli birçok araştırmaya konu olmuştur. Bu derleme çalışmasında, 2020–2025 yılları arasında yayımlanmış güncel in vitro ve in vivo deneysel araştırmalar temel alınarak, çeşitli kanser türlerinde tıbbi bitkilerin etkileri değerlendirilmiştir. Başlıca odak noktaları; meme, kolon, mide, pankreas, karaciğer, akciğer ve prostat kanserleri ile baş ve boyun maligniteleri olmuştur. Flavonoidlerin kanser hücreleri üzerindeki etkileri; apoptoz indüksiyonu, hücre proliferasyonunun baskılanması, hücre döngüsünün durdurulması, anjiyogenezin inhibisyonu, metastazın engellenmesi ve tümör mikro çevresinin modülasyonu gibi çok yönlü biyolojik mekanizmalar üzerinden açıklanmıştır. Ayrıca, flavonoid yüklü nanoparçacık sistemlerinin ilaç taşıma etkinliğini artırarak kemoterapiye duyarlılığı yükselttiği ve sistemik toksisiteyi azalttığı vurgulanmıştır. Derlemede, PubMed, Web of Science, NCBI ve Türkiye Kanser İstatistikleri gibi güvenilir veri tabanlarından yararlanılmıştır. Elde edilen bulgular, tıbbi ve aromatik bitkilerin antikanser ajanlar geliştirilmesinde önemli bir doğal kaynak olduğunu ve gelecekteki klinik uygulamalarda değerlendirilebileceğini göstermektedir.

Keywords

• Sekonder Metabolitler
• Fitokimyasallar
• Tümör
• Kemosensitizör

References

1. Abd El-Hafeez A A, Khalifa H O, Mahdy E A M, Sharma V, Hosoi T, Ghosh P, Ozawa K, Montano M M, Fujimura T, Ibrahim A R N, Abdelhamid M A A, Pack S P, Shouman S A, Kawamoto S (2019). Anticancer effect of nor-wogonin (5,7,8-trihydroxyflavone) on human triple-negative breast cancer cells via downregulation of TAK1, NF-κB, and STAT3. Pharmacological Reports 71(2): 289–298
2. Adhami V M, Ahmad N, Mukhtar H (2003). Molecular targets for green tea in prostate cancer prevention. Journal of Nutrition 133(7 Suppl): 2417S–2424S. doi: 10.1093/jn/133.7.2417S
3. Adjakly M, Ngollo M, Boiteux J P, Bignon Y J, Guy L, Bernard-Gallon D (2013). Genistein and daidzein: different molecular effects on prostate cancer. Anticancer Research 33(1): 39–44. PMID: 23267126
4. Ahmadi A, Shadboorestan A, Nabavi S F, Setzer W N, Nabavi S M (2015). The role of hesperidin in cell signal transduction pathway for the prevention or treatment of cancer. Current Medicinal Chemistry 22(30): 3462–3471
5. Aktas H G, Akgun T (2018). Naringenin inhibits prostate cancer metastasis by blocking voltage-gated sodium channels. Biomedicine and Pharmacotherapy 106: 770–775
6. Amin A R M R, Wang D, Nannapaneni S, Lamichhane R, Chen Z G, Shin D M (2021). Combination of resveratrol and green tea epigallocatechin gallate induces synergistic apoptosis and inhibits tumor growth in vivo in head and neck cancer models. Oncology Reports 45(5): 87. doi: 10.3892/or.2021.8038
7. Anderson G, Ebadi M, Vo K, Novak J, Govindarajan A, Amini A (2021). An updated review on head and neck cancer treatment with radiation therapy. Cancers (Basel) 13(19): 4912. doi: 10.3390/cancers13194912
8. Asgharian P, Tazehkand A P, Soofiyani S R, Hosseini K, Martorell M, Tarhriz V, Ahangari H, Cruz-Martins N, Sharifi-Rad J, Almarhoon Z M, Ydyrys A, Nurzhanyat A, Yessenbekova A, Cho W C (2021). Quercetin impact in pancreatic cancer: an overview on its therapeutic effects. Oxidative Medicine and Cellular Longevity 2021: 4393266. doi: 10.1155/2021/4393266

9. Atiq A, Parhar I (2020). Anti-neoplastic potential of flavonoids and polysaccharide phytochemicals in glioblastoma. Molecules 25(21): 4895. doi: 10.3390/molecules25214895
10. Banerjee A, Chabria Y, Kanna N R R, Gopi J, Rowlo P, Sun X F, Pathak S (2019). Role of tumor specific niche in colon cancer progression and emerging therapies by targeting tumor microenvironment. Advances in Experimental Medicine and Biology, Springer: New York, NY, pp. 1–16
11. Banerjee S (2006). Inhibition of mackerel (Scomber scombrus) muscle lipoxygenase by green tea polyphenols. Food Research International 39: 486–491
12. Banik K, Khatoon E, Harsha C, Rana V, Parama D, Thakur K K, Bishayee A, Kunnumakkara A B (2022). Wogonin and its analogs for the prevention and treatment of cancer: a systematic review. Phytotherapy Research 36(5): 1854–1883. doi: 10.1002/ptr.7386
13. Bettuzzi S, Brausi M, Rizzi F, Castagnetti G, Peracchia G, Corti A (2006). Chemoprevention of human prostate cancer by oral administration of green tea catechins in volunteers with high-grade prostate intraepithelial neoplasia: a preliminary report from a one-year proof-of-principle study. Cancer Research 66(2): 1234–1240. doi: 10.1158/0008-5472.CAN-05-1145
14. Bhattacharya S, Mondal L, Mukherjee B, Dutta L, Ehsan I, Debnath M C, Gaonkar R H, Pal M M, Majumdar S (2018). Apigenin loaded nanoparticle delayed development of hepatocellular carcinoma in rats. Nanomedicine 14: 1905–1917. doi: 10.1016/j.nano.2018.05.011
15. Bonham M, Posakony J, Coleman I, Montgomery B, Simon J, Nelson P S (2005). Characterization of chemical constituents in Scutellaria baicalensis with antiandrogenic and growth-inhibitory activities toward prostate carcinoma. Clinical Cancer Research 11(10): 3905–3914.
16. Borah N, Gunawardana S, Torres H, McDonnell S, Van Slambrouck S (2017). 5,6,7,3′,4′,5′-Hexamethoxyflavone inhibits growth of triple-negative breast cancer cells via suppression of MAPK and Akt signaling pathways and arresting cell cycle. International Journal of Oncology 51(6): 1685–1693.
17. Butt S S, Khan K, Badshah Y, Rafiq M, Shabbir M (2021). Evaluation of pro-apoptotic potential of taxifolin against liver cancer. PeerJ 9: e11276. doi: 10.7717/peerj.11276
18. Cai X, Lu W, Yang Y, Yang J, Ye J, Gu Z, Hu C, Wang X, Cao P (2013). Digitoflavone inhibits IκBα kinase and enhances apoptosis induced by TNFα through downregulation of expression of nuclear factor κB-regulated gene products in human pancreatic cancer cells. PLoS ONE 8(10): e77126.
19. Chan D S, Vieira A R, Aune D, Bandera E V, Greenwood D C, McTiernan A, Navarro Rosenblatt D, Thune I, Vieira R, Norat T (2014). Body mass index and survival in women with breast cancer: systematic literature review and meta-analysis of 82 follow-up studies. Annals of Oncology 25(10): 1901–1914
20. Chang H, Lei L, Zhou Y, Ye F, Zhao G (2018). Dietary flavonoids and the risk of colorectal cancer: an updated meta-analysis of epidemiological studies. Nutrients 10(7): 950.
21. Chen F, Qin X, Xu G, Gou S, Jin X (2017). Reversal of cisplatin resistance in human gastric cancer cells by a wogonin-conjugated Pt(IV) prodrug via attenuating casein kinase 2-mediated nuclear factor-kappaB pathways. Biochemical Pharmacology 135: 50–68.
22. Chen H J, Chung Y L, Li C Y, Chang Y T, Wang C C N, Lee H Y, Lin H Y, Hung C C (2018). Taxifolin resensitizes multidrug resistance cancer cells via uncompetitive inhibition of P-glycoprotein function. Molecules 23(12): 3055. doi: 10.3390/molecules23123055
23. Chen J, Wang X, Xia T, Bi Y, Liu B, Fu J, Zhu R (2021). Molecular mechanisms and therapeutic implications of dihydromyricetin in liver disease. Biomedicine and Pharmacotherapy 142: 111927. doi: 10.1016/j.biopha.2021.111927
24. Chen S S, Corteling R, Stevanato L, Sinden J (2012). Polyphenols inhibit indoleamine 3,5-dioxygenase-1 enzymatic activity—a role of immunomodulation in chemoprevention. Discovery Medicine 14(78): 327–333
25. Chen X, Wei L, Yang L, Guo W, Guo Q, Zhou Y (2020). Glycolysis inhibition and apoptosis induction in human prostate cancer cells by FV-429-mediated regulation of AR-AKT-HK2 signaling network. Food and Chemical Toxicology 143: 111517. https://doi.org/10.1016/j.fct.2020.111517
26. Cheong J H, Hong S Y, Zheng Y, Noh S H (2011). Eupatilin inhibits gastric cancer cell growth by blocking STAT3-mediated VEGF expression. Journal of Gastric Cancer 11(1): 16–22.
27. Chung L Y, Cheung T C, Kong S K, et al. (2001). Induction of apoptosis by green tea catechins in human prostate cancer DU145 cells. Life Sciences 68(10): 1207–1214. doi: 10.1016/S0024-3205(00)01080-5
28. Clark S B, Alsubait S (2022). Non-small cell lung cancer. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2023 Jan–. PMID: 32965978
29. Dafni U, Tsourti Z, Alatsathianos I (2019). Breast cancer statistics in the European Union: incidence and survival across European countries. Breast Care (Basel) 14(6): 344–353. doi: 10.1159/000503219
30. de Ruijter T C, Veeck J, de Hoon J P J, van Engeland M, Tjan-Heijnen V C (2011). Characteristics of triple-negative breast cancer. Journal of Cancer Research and Clinical Oncology 137: 183–192. doi: 10.1007/s00432-010-0957-x
31. Deng Y T, Lin J K (2011). EGCG inhibits the invasion of highly invasive CL1-5 lung cancer cells through suppressing MMP-2 expression via JNK signaling and induces G2/M arrest. Journal of Agricultural and Food Chemistry 59: 13318–13327
32. Dihal A A, Woutersen R A, Ommen B, van I M C M, Rietjens R H, Stierum R (2006). Modulatory effects of quercetin on proliferation and differentiation of the human colorectal cell line Caco-2. Cancer Letters 238(2): 248–259. https://doi.org/10.1016/j.canlet.2005.07.007
33. Ding J, Polier G, Kohler R, Giaisi M, Krammer P H, Li-Weber M (2012). Wogonin and related natural flavones overcome tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) protein resistance of tumors by down-regulation of c-FLIP protein and up-regulation of TRAIL receptor 2 expression. Journal of Biological Chemistry 287(1): 641–649.
34. Dong Z, Wang Y, Guo J, Tian C, Pan W, Wang H, Yan J (2022). Prostate cancer therapy using docetaxel and formononetin combination: hyaluronic acid and epidermal growth factor receptor targeted peptide dual ligands modified binary nanoparticles to facilitate the in vivo anti-tumor activity. Drug Design, Development and Therapy 16: 2683–2693. doi: 10.2147/DDDT.S366622
35. Fahad Ullah M (2019). Breast cancer: current perspectives on the disease status. Breast Cancer Metastasis and Drug Resistance 1152: 51–64
36. Ganai S A (2017). Plant-derived flavone apigenin: the small molecule with promising activity against therapeutically resistant prostate cancer. Biomedicine and Pharmacotherapy 85: 47–56.
37. Ghosh A, Ghosh D, Sarkar S, Mandal A K, Thakur Choudhury S, Das N (2012). Anticarcinogenic activity of nanoencapsulated quercetin in combating diethylnitrosamine-induced hepatocarcinoma in rats. European Journal of Cancer Prevention 21: 32–41. doi: 10.1097/CEJ.0b013e32834a7e2b
38. Gong W Y, Wu J F, Liu B J, Zhang H Y, Cao Y X, Sun J, Lv Y B, Wu X, Dong J C (2014). Flavonoid components in Scutellaria baicalensis inhibit nicotine-induced proliferation, metastasis and lung cancer-associated inflammation in vitro. International Journal of Oncology 44(5): 1561–1570.
39. Haque M W, Pattanayak S P (2018). Taxifolin inhibits 7,12-dimethylbenz(a)anthracene-induced breast carcinogenesis by regulating AhR/CYP1A1 signaling pathway. Pharmacognosy Magazine 13(Suppl 4): S749–S755. doi: 10.4103/pm.pm_315_17
40. Hatono M, Ikeda H, Suzuki Y, Kajiwara Y, Kawada K, Tsukioki T, Kochi M, Suzawa K, Iwamoto T, Yamamoto H, et al. (2021). Effect of isoflavones on breast cancer cell development and their impact on breast cancer treatments. Breast Cancer Research and Treatment 185: 307–316. doi: 10.1007/s10549-020-05957-z
41. He L, Wu Y, Lin L, Wang J, Wu Y, Chen Y, Yi Z, Liu M, Pang X (2011). Hispidulin, a small flavonoid molecule, suppresses the angiogenesis and growth of human pancreatic cancer by targeting vascular endothelial growth factor receptor 2-mediated PI3K/Akt/mTOR signaling pathway. Cancer Science 102(1): 219–225.
42. Hsieh P L, Liao Y W, Hsieh C W, Chen P N, Yu C C (2020). Soy isoflavone genistein impedes cancer stemness and mesenchymal transition in head and neck cancer through activating miR-34a/RTCB axis. Nutrients 12(7): 1924. doi: 10.3390/nu12071924
43. Hu Q, Zhang W, Wu Z, Tian X, Xiang J, Li L, Li Z, Peng X, Wei S, Ma X, Zhao Y (2021). Baicalin and the liver-gut system: pharmacological bases explaining its therapeutic effects. Pharmacological Research 165: 105444. doi: 10.1016/j.phrs.2021.105444
44. Idrissi Janati A, Karp I, Sabri H, Emami E (2019). Is a Fusobacterium nucleatum infection in the colon a risk factor for colorectal cancer? A systematic review and meta-analysis protocol. Systematic Reviews 8(1): 114.
45. Imran M, Rauf A, Abu-Izneid T, Nadeem M, Shariati M A, Khan I A, Imran A, Orhan I E, Rizwan M, Atif M, Gondal T A, Mubarak M S (2019). Luteolin, a flavonoid, as an anticancer agent: a review. Biomedicine and Pharmacotherapy 112: 108612. doi: 10.1016/j.biopha.2019.108612
46. Jia S, Xu X, Zhou S, Chen Y, Ding G, Cao L (2019). Fisetin induces autophagy in pancreatic cancer cells via endoplasmic reticulum stress- and mitochondrial stress-dependent pathways. Cell Death and Disease 10(2): 142. doi: 10.1038/s41419-019-1366-y
47. Jiang K, Wang W, Jin X, Wang Z, Ji Z, Meng G (2015). Silibinin, a natural flavonoid, induces autophagy via ROS-dependent mitochondrial dysfunction and loss of ATP involving BNIP3 in human MCF7 breast cancer cells. Oncology Reports 33: 2711–2718. doi: 10.3892/or.2015.3915
48. Khan M A, Hussain A, Sundaram M K, et al. (2013). Garlic component diallyl disulfide inhibits proliferation and induces apoptosis in prostate cancer cells. Oncology Reports 30(2): 635–642. doi: 10.3892/or.2013.2481
49. Kim C H, Kim J E, Song Y J (2020). Antiviral activities of quercetin and isoquercitrin against human herpesviruses. Molecules 25: 2379. doi: 10.3390/molecules25102379
50. Kim U, Kim C Y, Lee J M, Oh H, Ryu B, Kim J, Park J H (2020). Phloretin inhibits the human prostate cancer cells through the generation of reactive oxygen species. Pathology and Oncology Research 26(2): 977–984. doi: 10.1007/s12253-019-00643-y
51. Kumar S, Pandey A K (2013). Chemistry and biological activities of flavonoids: an overview. The Scientific World Journal 2013: 162750. doi: 10.1155/2013/162750
52. Lambert J D, Kennett M J, Sang S, Reuhl K R, Ju J, Yang C S (2010). Hepatotoxicity of high oral dose (−)-epigallocatechin-3-gallate in mice. Food and Chemical Toxicology 48: 409–416. doi: 10.1016/j.fct.2009.10.030
53. Lee D H, Kim C, Zhang L, Lee Y J (2008). Role of p53, PUMA, and Bax in wogonin-induced apoptosis in human cancer cells. Biochemical Pharmacology 75(10): 2020–2033. https://doi.org/10.1016/j.bcp.2008.02.023
54. Lee D H, Rhee J G, Lee Y J (2009). Reactive oxygen species upregulate p53 and Puma; a possible mechanism for apoptosis during combined treatment with TRAIL and wogonin. British Journal of Pharmacology 157(7): 1189–1202. https://doi.org/10.1111/j.1476-5381.2009.00245.x
55. Lewinska A, Adamczyk-Grochala J, Kwasniewicz E, Deregowska A, Wnuk M (2017). Diosmin-induced senescence, apoptosis and autophagy in breast cancer cells of different p53 status and ERK activity. Toxicology Letters 265: 117–130.
56. Li H, Zhang H, Zhang H, Wang Y, Wang X, Hou H (2022). Survival of gastric cancer in China from 2000 to 2022: a nationwide systematic review of hospital-based studies. Journal of Global Health 12: 11014. doi: 10.7189/jogh.12.11014
57. Li J, Hu L, Zhou T, Gong X, Jiang R, Li H, Kuang G, Wan J, Li H (2019). Taxifolin inhibits breast cancer cells proliferation, migration and invasion by promoting mesenchymal to epithelial transition via β-catenin signaling. Life Sciences 232: 116617. doi: 10.1016/j.lfs.2019.116617
58. Li S J, Sun S J, Gao J, Sun F B (2016). Wogonin induces Beclin1/PI3K and reactive oxygen species-mediated autophagy in human pancreatic cancer cells. Oncology Letters 12(6): 5059–5067.
59. Li Y, Zhang T, Korkaya H, et al. (2010). Sulforaphane, a dietary component of broccoli/broccoli sprouts, inhibits breast cancer stem cells. Clinical Cancer Research 16(9): 2580–2590. doi: 10.1158/1078-0432.CCR-09-2937
60. Lim W, Park S, Bazer F W, Song G (2017). Naringenin-induced apoptotic cell death in prostate cancer cells is mediated via the PI3K/AKT and MAPK signaling pathways. Journal of Cellular Biochemistry 118(5): 1118–1131
61. Lin C H, Chang C Y, Lee K R, Lin H J, Chen T H, Wan L (2015). Flavones inhibit breast cancer proliferation through the Akt/FOXO3a signaling pathway. BMC Cancer 15: 958. doi: 10.1186/s12885-015-1965-7
62. Lin E J, Zhang X, Wang D Y, Hong S Z, Li L Y (2014). Naringenin modulates the metastasis of human prostate cancer cells by down regulating the matrix metalloproteinases-2/-9 via ROS/ERK1/2 pathways. Bangladesh Journal of Pharmacology 9(3): 419–427
63. Lin Y C, Hung C M, Tsai J C, Lee J C, Chen Y L, Wei C W, Kao J Y, Way T D (2010). Hispidulin potently inhibits human glioblastoma multiforme cells through activation of AMP-activated protein kinase (AMPK). Journal of Agricultural and Food Chemistry 58(17): 9511–9517.
64. Liu H, Xiao Y, Xiong C, Wei A, Ruan J (2011). Apoptosis induced by a new flavonoid in human hepatoma HepG2 cells involves reactive oxygen species-mediated mitochondrial dysfunction and MAPK activation. European Journal of Pharmacology 654(3): 209–216.
65. Liu W, Wang X, Zhu H, Duan Y (2019). Precision tumor medicine and drug targets. Current Topics in Medicinal Chemistry 19(17): 1488–1489.
66. Luo Y, Yu H, Yang Y, Tian W, Dong K, Shan J, Ma X (2016). A flavonoid compound from Chrysosplenium nudicaule inhibits growth and induces apoptosis of the human stomach cancer cell line SGC-7901. Pharmaceutical Biology 54(7): 1133–1139.
67. López M J, Carbajal J, Alfaro A L, Saravia L G, Zanabria D, Araujo J M, Quispe L, Zevallos A, Buleje J L, Cho C E, Sarmiento M, Pinto J A, Fajardo W (2023). Characteristics of gastric cancer around the world. Critical Reviews in Oncology/Hematology 181: 103841. doi: 10.1016/j.critrevonc.2022.103841
68. Maalej A, Bouallagui Z, Hadrich F, Isoda H, Sayadi S (2017). Assessment of Olea europaea L. fruit extracts: phytochemical characterization and anti-cancer pathway investigation. Biomedicine and Pharmacotherapy 90: 179–186. https://doi.org/10.1016/j.biopha.2017.03.034
69. Mafuvadze B, Benakanakere I, Hyder S M (2010). Apigenin blocks induction of vascular endothelial growth factor mRNA and protein in progestin-treated human breast cancer cells. Menopause 17(5): 1055–1063.
70. McKinney S M, Sieniek M, Godbole V, Godwin J, Antropova N, Ashrafian H, Back T, Chesus M, Corrado G S, Darzi A (2020). International evaluation of an AI system for breast cancer screening. Nature 577: 89–94. doi: 10.1038/s41586-019-1799-6
71. Motallebi M, Bhia M, Rajani H F, Bhia I, Tabarraei H, Mohammadkhani N, Pereira-Silva M, Kasaii M S, Nouri-Majd S, Mueller A L, Veiga F J B, Paiva-Santos A C, Shakibaei M (2022). Naringenin: a potential flavonoid phytochemical for cancer therapy. Life Sciences 305: 120752. doi: 10.1016/j.lfs.2022.120752
72. Mukhtar E, Adhami V M, Khan N, Mukhtar H (2012). Apoptosis and autophagy induction as mechanism of cancer prevention by naturally occurring dietary agents. Current Drug Targets 13(14): 1831–1841. doi: 10.2174/138945012804545489
73. Nardin S, Mora E, Varughese F M, D’Avanzo F, Vachanaram A R, Rossi V, Saggia C, Rubinelli S, Gennari A (2020). Breast cancer survivorship, quality of life, and late toxicities. Frontiers in Oncology 10: 864. doi: 10.3389/fonc.2020.00864
74. Niedzwiecki A, Roomi M W, Kalinovsky T, Rath M (2016). Anticancer efficacy of polyphenols and their combinations. Nutrients 8(9): 552. doi: 10.3390/nu8090552
75. Owor R O, Bedane K G, Openda Y I, Zühlke S, Derese S, Ong’amo G, Ndakala A, Spiteller M (2021). Synergistic anti-inflammatory activities of a new flavone and other flavonoids from Tephrosia hildebrandtii vatke. Natural Product Research 35: 4486–4493. doi: 10.1080/14786419.2020.1736065
76. Padmavathi G, Monisha J, Banik K, Thakur K K, Choudhary H, Bordoloi D, Kunnumakkara A B (2018). Different chemosensitization approaches to overcome chemoresistance in prostate cancer. In: Cancer Cell Chemoresistance and Chemosensitization (pp. 583–613). Singapore: World Scientific
77. Park M Y, Ha S E, Vetrivel P, Kim H H, Bhosale P B, Abusaliya A, Kim G S (2021). Differences of key proteins between apoptosis and necroptosis. BioMed Research International 2021: 3420168. doi: 10.1155/2021/3420168 Petrick J, Steck S, Bradshaw P, Trivers K, Abrahamson P, et al. (2015). Dietary intake of flavonoids and oesophageal and gastric cancer: incidence and survival in the United States of America (USA). British Journal of Cancer 112: 1291–1300
78. Petroni G, Buqué A, Zitvogel L, Kroemer G, Galluzzi L (2021). Immunomodulation by targeted anticancer agents. Cancer Cell 39: 310–345. doi: 10.1016/j.ccell.2020.11.009
79. Polier G, Ding J, Konkimalla B V, Eick D, Ribeiro N, Kohler R, Li-Weber M (2011). Wogonin and related natural flavones are inhibitors of CDK9 that induce apoptosis in cancer cells by transcriptional suppression of Mcl-1. Cell Death and Disease 2: e182. https://doi.org/10.1038/cddis.2011.66
80. Qiu P, Dong P, Guan H, Li S, Ho C T, Pan M H, McClements D J, Xiao H (2010). Inhibitory effects of 5-hydroxy polymethoxyflavones on colon cancer cells. Molecular Nutrition and Food Research 54(Suppl. 2): S244–S252.
81. Rawla P (2019). Epidemiology of prostate cancer. World Journal of Oncology 10(2): 63–89. doi: 10.14740/wjon1191
82. Razak S, Afsar T, Ullah A, Almajwal A, Alkholief M, Alshamsan A, Jahan S (2018). Taxifolin, a natural flavonoid interacts with cell cycle regulators causes cell cycle arrest and causes tumor regression by activating Wnt/β-catenin signaling pathway. BMC Cancer 18(1): 1043. doi: 10.1186/s12885-018-4959-4
83. Romagnolo D F, Selmin O I (2012). Flavonoids and cancer prevention: a review of the evidence. Journal of Nutrition in Gerontology and Geriatrics 31(3): 206–238.
84. Sajkowska-Kozielewicz K, Zawada K, Olchowik-Grabarek E, et al. (2021). Harvest time affects antioxidant capacity, total polyphenol and flavonoid content of Polish St. John's worts (Hypericum perforatum L.) flowers. Scientific Reports 11(1): 1–12. doi: 10.1038/s41598-021-83409-4
85. Sağlık Bilimleri Üniversitesi (2021). Prostat kanseri: güncel tanı ve tedavi. Yayın No: 38. Ankara: Sağlık Bilimleri Üniversitesi Yayınları
86. Sfanos K S, De Marzo A M (2012). Prostate inflammation and prostate cancer: new insights into the role of chronic inflammation in the pathogenesis of prostate cancer. American Journal of Pathology 181(5): 1472–1483. doi: 10.1016/j.ajpath.2012.06.060
87. Shukla S, Kanwal R, Shankar E, Datt M, Chance M R, Fu P, MacLennan G T, Gupta S (2015). Apigenin blocks IKKα activation and suppresses prostate cancer progression. Oncotarget 6(31): 31216–31232.
88. Siegel R L, Miller K D, Jemal A (2018). Cancer statistics, 2018. CA: A Cancer Journal for Clinicians 68(1): 7–30.
89. Siegel R L, Miller K D, Jemal A (2019). Cancer statistics, 2019. CA: A Cancer Journal for Clinicians 69: 7–34
90. Singh D, Gupta M, Sarwat M, Siddique H R (2022). Apigenin in cancer prevention and therapy: a systematic review and meta-analysis of animal models. Critical Reviews in Oncology/Hematology 176: 103751. doi: 10.1016/j.critrevonc.2022.103751
91. Song L, Chen X, Mi L, Liu C, Zhu S, Yang T, Luo X, Zhang Q, Lu H, Liang X (2020). Icariin-induced inhibition of SIRT6/NF-kappaB triggers redox mediated apoptosis and enhances anti-tumor immunity in triple-negative breast cancer. Cancer Science 111: 4242–4256. doi: 10.1111/cas.14648
92. Starley B Q, Calcagno C J, Harrison S A (2010). Nonalcoholic fatty liver disease and hepatocellular carcinoma: a weighty connection. Hepatology 51: 1820–1832
93. Steck S E, Murphy E A (2020). Dietary patterns and cancer risk. Nature Reviews Cancer 20: 125–138. doi: 10.1038/s41568-019-0227-4
94. Strobel O, Neoptolemos J, Jäger D, Büchler M W (2019). Optimizing the outcomes of pancreatic cancer surgery. Nature Reviews Clinical Oncology 16: 11–26. doi: 10.1038/s41571-018-0112-1
95. Sugiura Y, Katsuzaki H, Imai K, Amano H (2021). The anti-allergic and anti-inflammatory effects of phlorotannins from the edible brown algae, Ecklonia sp. and Eisenia sp. Natural Product Communications 16: 12. doi: 10.1177/1934578X211060924
96. Suhail Y, Cain M P, Vanaja K, Kurywchak P A, Levchenko A, Kalluri R, Kshitiz (2019). Systems biology of cancer metastasis. Cell Systems 9: 109–127. doi: 10.1016/j.cels.2019.07.003
97. Sung H, Ferlay J, Siegel R L, et al. (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. doi: 10.3322/caac.21660
98. Tao Z, Shi A, Lu C, Song T, Zhang Z, Zhao J (2015). Breast cancer: epidemiology and etiology. Cell Biochemistry and Biophysics 72(2): 333–338. doi: 10.1007/s12013-014-0459-6
99. Tian T, Li J, Li B, Wang Y, Li M, et al. (2014). Genistein exhibits anti-cancer effects via down-regulating FoxM1 in H446 small-cell lung cancer cells. Tumour Biology 35: 4137–4145
100. Wang J, Li T, Zhao T, Wu T, Liu C, Ding H, Li Z, Bian J (2019). Design of wogonin-inspired selective cyclin-dependent kinase 9 (CDK9) inhibitors with potent in vitro and in vivo antitumor activity. European Journal of Medicinal Chemistry 178: 782–801. doi: 10.1016/j.ejmech.2019.06.024
101. Wang Z, Ma L, Su M, Zhou Y, Mao K, Li C, Peng G, Zhou C, Shen B, Dou J (2018). Baicalin induces cellular senescence in human colon cancer cells via upregulation of DEPP and the activation of Ras/Raf/MEK/ERK signaling. Cell Death and Disease 9(2): 217. doi: 10.1038/s41419-017-0223-0
102. Wesołowska O, Wiśniewski J, Sroda-Pomianek K, Bielawska-Pohl A, Paprocka M, Duś D, Duarte N, Ferreira M J, Michalak K (2012). Multidrug resistance reversal and apoptosis induction in human colon cancer cells by some flavonoids present in citrus plants. Journal of Natural Products 75(11): 1896–1902
103. Wu B, Liang Y, Tan Y, Xie C, Shen J, Zhang M, Liu X, Yang L, Zhang F, Liu L, et al. (2016). Genistein-loaded nanoparticles of star-shaped diblock copolymer mannitol-core PLGA–TPGS for the treatment of liver cancer. Materials Science and Engineering C 59: 792–800. doi: 10.1016/j.msec.2015.10.087
104. Xu Z, Mei J, Tan Y (2017). Baicalin attenuates DDP (cisplatin) resistance in lung cancer by downregulating MARK2 and pAkt. International Journal of Oncology 50(1): 93–100.
105. Yan W, Ma X, Zhao X, Zhang S (2018). Baicalein induces apoptosis and autophagy of breast cancer cells via inhibiting PI3K/AKT pathway in vivo and vitro. Drug Design, Development and Therapy 12: 3961–3972. doi: 10.2147/DDDT.S181939
106. Yang F, Jin H, Pi J, Jiang J H, Liu L, Bai H H, Yang P H, Cai J Y (2013). Anti-tumor activity evaluation of novel chrysin-organogermanium (IV) complex in MCF-7 cells. Bioorganic and Medicinal Chemistry Letters 23: 5544–5551. doi: 10.1016/j.bmcl.2013.08.055
107. Yang J H, Kwak H W, Kim T G, Han J, Moon S W, Yu S Y (2013). Retinal neurodegeneration in type II diabetic Otsuka Long-Evans Tokushima fatty rats. Investigative Ophthalmology & Visual Science 54(6): 3844–3851. doi: 10.1167/iovs.12-11309
108. Yang Y, An R, Feng T, Qin X, Zhang J, Bo Y, Niu B (2019). Skullcapflavone I suppresses proliferation of human lung cancer cells via down-regulating microRNA-21. Experimental and Molecular Pathology 110: 104285.
109. Yang Y, Cai X, Yang J, Sun X, Hu C, Yan Z, Xu X, Lu W, Wang X, Cao P (2014). Chemoprevention of dietary digitoflavone on colitis-associated colon tumorigenesis through inducing Nrf2 signaling pathway and inhibition of inflammation. Molecular Cancer 13: 48.
110. Ye T, Su J, Huang C, Yu D, Dai S, Huang X, Chen B, Zhou M (2016). Isoorientin induces apoptosis, decreases invasiveness, and downregulates VEGF secretion by activating AMPK signaling in pancreatic cancer cells. OncoTargets and Therapy 9: 7481–7492.
111. Yu L, Chen M, Zhang R, Xu T (2019). Antitumor effects of glychionide-A flavonoid in human pancreatic carcinoma cells are mediated by activation of apoptotic and autophagic pathways, cell cycle arrest, and disruption of mitochondrial membrane potential. Medical Science Monitor 25: 962–969.
112. Yuan C, Chen G, Jing C, Liu M, Liang B, Gong G, Yu M (2021). Eriocitrin, a dietary flavonoid suppressed cell proliferation, induced apoptosis through modulation of JAK2/STAT3 and JNK/p38 MAPKs signaling pathway in MCF-7 cells. Journal of Biochemical and Molecular Toxicology 36: e22943. doi: 10.1002/jbt.22943
113. Zhai K, Mazurakova A, Koklesova L, Kubatka P, Büsselberg D (2021). Flavonoids synergistically enhance the anti-glioblastoma effects of chemotherapeutic drugs. Biomolecules 11(12): 1841. doi: 10.3390/biom11121841
114. Zhang H W, Hu J J, Fu R Q, Liu X, Zhang Y H, Li J, Liu L, Li Y N, Deng Q, Luo Q S, et al. (2018). Flavonoids inhibit cell proliferation and induce apoptosis and autophagy through downregulation of PI3Kγ mediated PI3K/AKT/mTOR/p70S6K/ULK signaling pathway in human breast cancer cells. Scientific Reports 8: 11255. doi: 10.1038/s41598-018-29308-7
115. Zhang H, Liu G, Zeng X, Wu Y, Yang C, Mei L, Wang Z, Huang L (2015). Fabrication of genistein-loaded biodegradable TPGS-b-PCL nanoparticles for improved therapeutic effects in cervical cancer cells. International Journal of Nanomedicine 10: 2461–2473. doi: 10.2147/IJN.S78988
116. Zhang J, Wu D, Song J, Wang J, Yi J, et al. (2015). Hesperetin induces the apoptosis of gastric cancer cells via activating mitochondrial pathway by increasing reactive oxygen species. Digestive Diseases and Sciences 60: 2985–2995
117. Zhou Y, Zheng J, Li Y, et al. (2016). Natural polyphenols for prevention and treatment of cancer. Nutrients 8(8): 515. doi: 10.3390/nu8080515