Open access peer-reviewed chapter

Ginkgo biloba: A Potential Anti-Cancer Agent

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Jian-Shu Lou, Die Hu, Hao-Jie Wang, Li-Ping Zhao, Jun-Hu Hu and Zhao-Huang Zhou

Submitted: 20 March 2022 Reviewed: 04 April 2022 Published: 02 November 2022

DOI: 10.5772/intechopen.104788

From the Edited Volume

Medicinal Plants

Edited by Sanjeet Kumar

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Abstract

Ginkgo biloba is generally considered as safe herbal extract in clinical application. Ginkgo Folium is a living fossil plant, which has been used in record by over few thousands of years. The extract of G. biloba, has been used extensively for the treatment of diseases related to the central nervous system and psychiatric disorders. Recently, different lines of evidence indicated that G. biloba exhibited anti-cancer effects. The potential therapeutic effect may due to antioxidant, anti-angiogenic and gene regulatory actions. In addition, Ginkgo Folium was studied in pharmacodynamic interactions induced by herb-drug interactions. These studies indicated that G. biloba usually exhibits synergistic effect. The extracts derived from G. biloba exhibits promising anticancer effect, including flavonoids, ginkgolide, and phenolic acids etc. This chapter will discuss the anticancer effect and mechanism of extracts derived from various parts of G. biloba, the possible usage as an adjuvant therapy in cancer treatment, and the development of G. biloba as potential novel anticancer drugs.

Keywords

  • Ginkgo biloba
  • cancer
  • natural products
  • herbal extract

1. Introduction

Almost everyone talks about cancer discoloration, and no matter what kind of cancer it is, it can be life-threatening. But fortunately, cancer can also be treated, in addition to mastering the rhythm of life, you can also choose Chinese herbal medicine to strengthen the immunity and enhance the ability to anti-cancer. The active gradients from several plants have anticancer effect, such as Elemene, vincristine and ginsenosides [1, 2, 3, 4, 5, 6]. Elemene, isolated from the volatile oil of traditional Chinese medicine Curcuma wenyujin, has broad-spectrum anticancer activities and mild side effects. Vincristine is derived from periwinkle, which is used for the treatment of acute lymphoblastic leukemia, breast cancer. Ginsenosides is extracted from ginseng. Ginseng has been regarded as a famous traditional Chinese medicine since ancient times. After treatment with ginsenosides, ginsenosides inhibited cancer cell proliferation, invasion, and migration in several cancers, such as breast, brain, liver, gastric, and lung cancer [5].

In recent years, more and more studies have shown that G. biloba also has anti-tumor effects. G. biloba appeared on earth more than 200 million years ago and is the only living species in the order Ginkgoales [7, 8, 9]. Once G. biloba was growing everywhere on earth, but it became nearly extinct during the last ice age, and only survived in Asia. G. biloba has been used as a medicinal plant for a long time. It was firstly recorded in “Shennong Ben Cao Jing, but the medicinal value of ginkgo leaves recorded from the Song Dynasty. The medical use of G. biloba was first recorded in “Ben Cao Gang Mu” by Li Shizhen in Ming Dynasty [10]. G. biloba leaves are fan-shaped, flat, and have an indentation in the middle, giving birth to a species name “Biloba,” a Latin word meaning bi-lobed [11]. Male flower pollens are carried by the wind to the female tree, which produces ovules that fertilize and grow into seeds. G. biloba takes 15 to 20 years to produce fruits, which have a rancid, nasty odor. However, the seeds contain certain mild toxic chemicals [12, 13, 14]. G. biloba has been a beloved plant in Asian countries as an ornamental tree in the gardens and as a medicinal plant, particularly in China, Korea, and Japan [15, 16].

Scientists from Japan and Germany made pioneering and important contributions to research and development. The development history of G. biloba fully embodies the determination of innovation and has become a model for the research and development of traditional Chinese medicine and botanic medicine. In 1929, the Japanese first isolated a flavonoid from G. biloba leaves [17]. In the 1960s, Dr. Schwab firstly extracted the active ingredients (ginkgo flavone and terpenoid lactone) from Chinese G. biloba leaves, which were processed into tablets. These active ingredients quickly became the first world’s plant medicine, which were listed as the third generation of G. biloba leaves preparation. In 1972, Dr. Willmar Schwabe Company developed EGb761, a patent extract of G. biloba leaves. EGb761 contains 24% flavonoids and 6% terpenoids, which is widely used today [18]. From the 1920s to the 1930s, Chinese herbal medicine research upsurge, medical scholars began to analyze the chemical components of G. biloba, pharmacodynamics and toxicology research, with G. biloba tablet, known as the first generation of preparation. In the 1970s, Germany, France and other European countries carried out in-depth research on G. biloba leaves. Flavonoids and lactones extracted G. biloba have therapeutic effects on cardiovascular and cerebrovascular diseases [19]. In the 1990s, Professor Xie Delong, director of Shanghai Institute of Traditional Chinese Medicine, discovered a safer and more effective combination than the German ginkgo leaf invention patent, and innovated the process to raise the clear effective component of the extract to more than 50%, which was listed as the fifth generation of ginkgo leaf preparation.

At present, flavonoids (quercetin, kaempferol, isorhamnetin, lignin, etc.) and terpenoids (ginkgolide A, Ginkgolide B, ginkgolide C, ginkgolide J, etc.) have been found to be active pharmacological components in G. biloba [20]. It is recorded in Chinese Pharmacopoeia that G. biloba has the effects on promoting blood circulation and removing stasis, clearing collaterals and relieving pain, strengthening lungs and relieving asthma, removing turbidity and lowering lipids, and is used to treat blood stasis and blocking collaterals, chest paralysis and heartache, stroke hemiplegia, lung deficiency, cough and asthma, hyperlipidemia and other diseases [21, 22, 23]. In recent years, studies have also found that the pharmacological effect of G. biloba lies in the synergistic effect of various components, rather than a component to play a determined role. Studies have shown that G. biloba extract plays a significant role in the treatment of Alzheimer’s disease, neurodegenerative diseases, brain dysfunction, eye diseases, cardiovascular diseases and other diseases. Moreover, recent studies have shown that extract from different part of G. biloba may also be useful in treating cancer [24].

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2. Anticancer effect of extracts derived from various parts of G. biloba

Plants have provided a rich source of therapeutic agents and bases for synthetic drugs. G. biloba is dioecious. Male ginkgo biloba release pollen in spring to fertilize the female ginkgo biloba, which produces a large amount of ginkgo drup-like seeds in fall [25]. The seeds of G. biloba have been used for the treatment of cancer thousands of years ago in China [26], which is first mentioned in herbals in the Yuan dynasty. Mature ginkgo seeds covered with a fleshy thick outer layer, which named as exocarps, or seed coat, sarcotesta in some research papers. Seed mainly consists of mesosperm, membranous endopleura and kernel. The mesosperm is hard and white shell. The innermost layer of the seed is membranous endopleura, which is red and consists of 1–2 layers of parenchymal cells. The kernal of G. biloba is fleshy and pale yellowish-green, consisting of endosperm and embryo, which is an edible part of the seed. The leaves of G. biloba (Ginkgo folium) are fan-shaped, which are unique among seed plants.

Studies reported that extract or active ingredient from different parts of G. biloba, including seeds, exocarps, kernel and flowers exert anticancer effect. In recent years, the anticancer effect of Ginkgo folium was extensively reported. We summarized the current reports on the anticancer effect and potential mechanism of the extracts from the different parts of G. biloba.

2.1 The anticancer effect of G. biloba seeds

G. biloba seeds have been used in traditional Chinese medicine for centuries. The seeds have orange flesh shell, which are toxic as raw forms. The annual global yield of seeds is over 14 kt, more than 90% of which is produced in China [27]. As a traditional Chinese medicinal material, the ginkgo seeds have been used for clinical diseases such as asthma, coughs, cancers and etc. G. biloba seeds formed by the development of a fertilized ovule, contains an embryo and nutrient reserves that enable a new plant to grow. Only a few researches on the anticancer effects of G. biloba seeds extract. G. biloba seeds extracts positively induce cytochrome P450 (CYP) 1B1 expression, inhibiting the proliferation of breast cancer cells [28]. In this vitro study, polysaccharide derived from G. biloba seeds was isolated by ethanol fractionation, which decrease the percentages of G2-M cells, inhibiting the hepatoma cells proliferation. In addition, G. biloba seeds polysaccharides also make microvilli thinner and form apoptosis bodies on and around the spherical cells to promote apoptosis in hepatoma cells. While the hepatoma cells without G. biloba seeds polysaccharide treatment were of shuttle shape and small proportion of cells was of spherical shape [29].

2.2 The anticancer effect of G. biloba exocarps extract

G. biloba exocarp is the outermost layer of seeds, which was also called seed coat or sarcotesta in some studies. Exocarp was previously regarded as a waste material. It smells of rancid butter, causesing air pollution. Phenolic acid in exocarp can contaminate soil and poison fish and shrimp [30, 31]. Exocarp is rich in nutrients: the percent of polysaccharide is 10% and ginkgolic acids is more than 4%. Recently, constituents extracted from the exocarp shows antitumor effect [32].

The extracts prepare from the exocarps of G. biloba (GBEE) enhanced the ratio of Bax/Bcl-2. Meantime, the translocation of Bax/Bcl-2 to mitochondria was also increased accompanied by the release of cytochrome C. Consequently, the protein expression of cleaved-caspase-3, Fas, FasL, p-p38, and the mRNA levels of Fas were all increased, finally inducing apoptosis in lewis lung carcinoma cells (LLC). In vivo study further demonstrated the anticancer effect of GBEE on LLC [33]. GBEE increased the activation of acidic vacuole, the content of Atg5 protein and the ratio of LC3-II/LC3-I protein by AMPK induced inactivation on mTOR/p70S6k, which promoted the formation of autophagosomes in LCC, finally it induced autophagic cell death in LCC [34].

Despite of the directly effect on inducing cancer cell death, GBEE can also suppress the processes of angiogenesis and metastasis. It was reported that GBEE inhibited tumor metastasis in LLC mice model, characterized by the suppression on CD34 and microvessel density (MVD). This anti-metastasis effect might be due to the inhibition on angiogenesis, which mediated by downregulation on Wnt/β-catenin- vascular endothelial growth factor (VEGF) signaling pathway, including the inhibition on Wnt3a, β-catenin, VEGF, VEGF2 and p-AKT/AKT [35]. The suppression of GBEE on CD34 and MVD was also found in B16 melanoma. Meanwhile, GBEE attenuated the mRNA and protein levels of VEGF, hypoxia inducible factor-1α (HIF-1α), vascular endothelial growth factor receptor 2 (VEGFR2), p-PI3K and p-Akt. Finally, it exerted antiangiogenesis by inhibiting PI3K/Akt/HIF-1α/VEGF signaling pathways [36]. G. biloba exocarp extracts also have anti-metastasis effect in skin cancer via perturbing the expression of p-PI3K, p-Akt, NF-κB, and MMP-9 [37].

The polysaccharides isolated from G. biloba exocarp (GBEP) had therapeutic effect on cancer patients [33, 38, 39]. For instance, the area of tumors in patients with GBEP capsules were significantly reduced. Meanwhile, the ultrastructural of tumor cells in these patients observed by transmissional electron microscope revealed that abundant heterochromatins were observed in nuclei, swollen mitochondria and dilated rough endoplasmic reticulum were observed in cytosol, indicating apoptosis was triggered by GBEP [40]. The anticancer effect of GBEP was demonstrated in tumor bearing mice [39]. The mechanism involved in the anticancer effect of GBEP was illustrated in gastric cancer. GBEP downregulated the expression of c-myc and bcl-2, upregulated the level of c-fos genes, which inhibited proliferation and induced apoptosis on gastric cancer [40].

Botanical constituents extracted from the exocarp of G. biloba promoted ROS generation, which inducing G0/G1 phase arrest, apoptosis and autophagy in colon cancer cells. RT-qPCR analysis showed that Ginkgolic acid (GA) decreased Cyclin D1, CDK2, CDK4, and Cyclin E1 mRNA levels. The study also found that decreased p-mTOR, pp70s6k and p-pras40 protein levels induced by GA were reversed by NAC pretreatment [41]. GA extracted from the G. biloba exocarp promoted the activation of AMPK, decreased the level of acetyl-CoA carboxylase (ACC) and fatty acid synthase (FASN) involved in lipogenesis. Finally, it plays a positive role in inhibiting pancreatic cancer cells proliferation, migration and invasion. The study examined the effects of GA on the viability of pancreatic cancer cell by MTT assay, found that GA can inhibit the growth of pancreatic cancer cells. Wound-scratch assay and scratch assay showed that GA inhibited the migration and invasion capacities of pancreatic cancer cells in vitro [42]. GA activated caspase-3, decreased the expression of Bcl-2 protein and increased the expression of Bax protein, finally causing apoptosis in laryngeal cancer cells [43]. GA also had positive anticancer effects in gastric cancer cells and liver cancer [44, 45]. After treatment with GA, the morphology of liver cancer cell was shrinkage and formed nuclear fragmentation, activating caspases-3 and promoting Bax expression. Finally, it induced apoptosis in liver cancer cells [45]. GA perturbed the proliferation of human cervical cancer cells and enhanced immune function on immunocompromised S180. But the correlation of GA promoting S180 immune function needs to be further studied [46]. A vitro experiment verified that with the increase of GA concentration on cancer cells, GA inhibited the growth of cancer cells but the toxic effect on normal cells also increases. The anti-tumor effect of GA needs to be further proved by animal experiments [47].

2.3 The anticancer effect of G. biloba kernel extract

G. biloba kernels called Baiguo in China are the main edible part of the seed, which consist of endosperm and embryo [48]. Ginkgo kernel is consumed as a delicious food in China, Japan and Korea after grilled or boiled [49]. Ginkgo kernels contain 60–70% starch, 10–20% protein, 2–4% lipids, 0.8–1.2% pectin, and about 6% sucrose [50, 51]. Raw or cooked the ginkgo kernel has been shown to cause allergic reactions or death [52]. The medicinal value of ginkgo kernel was overlooked. A few studies shed light to the anticancer effect of kernel. The medicinal value of ginkgo kernel was overlooked. A few studies shed light to the anticancer effect of kernel [53]. However, the role of total G. biloba kernel extract on anticancer was reported recently. A study firstly reported that G. biloba kernel extracts exhibited cytotoxic effects in colon cancer and melanoma, characterized by inhibiting cancer cells proliferation and vitality [54]. Melanoma cells are more sensitive to kernel extracts. Meantime, the cytotoxic effect was not found in normal cell line McCoy-Plovdive. However, the anticancer effect of kernel extract needs to be observed in other cancer types, and the molecular mechanism remains to be observed in detail in future.

2.4 The anticancer effect of G. biloba flowers extract

G. biloba is an ancient dioecious gymnosperm, which apply to worldwide for landscaping and medical usage. The male flowers with catkin blossom from late March to the middle of April for only three to seven days, varying in different areas of China [55]. The chemical constituents and bioactivities of the flowers contain high contents of nutritional and medicinally relevant components, such as amino acids, vitamins, unsaturated fatty acids, flavonoids, and lactones [56]. The extracts of ginkgo flowers can exhibit anticancer effects. Some phytochemical studies of G. biloba flowers enrich the diversity of Ginkgo chemical constituents and broaden its application in phytotherapy. The bioflavonoids from G. biloba male flowers promoted cell cycle arrest in the G2/M phase, inhibiting the proliferation of cervical cancer cells [57]. A study showed that biflavonoids bilobetin and isoginkgetin isolated from G. biloba flowers exhibited cytotoxic activities on cervical cancer, pancreatic cancer, lung cancer, Lymphoma, and ovarian cancer. The most sensitive cancer cell to these two compounds is cervical cancer. Furthermore, the morphological changes, apoptosis and cell cycle arrest were observed in cervical cancer cell. After treated with bilobetin and isoginkgetin, nuclear condensation together with the decrease on the ratio of Bcl2/BAX and the increase on cleaved-caspase 3, apoptosis rates were observed, indicating that apoptosis was triggered with these two compounds. In addition, cell cycle arrest via promoting G2/M phase arrest was also found in cervical cancer cell treated with bilobetin and isoginkgetin [55].

2.5 The anticancer effect of Ginkgo Folium extract

The anticancer effect of Ginkgo Folium was studied extensively in recent years. The tumor inhibition effect of Ginkgo Folium was demonstrated in mouse S180 mouse sarcoma, which might be due to the elevation on free radical scavenger enzymes [58]. The main reported death way induced by Ginkgo Folium is caspase dependent apoptosis that was observed in several cancer types, including cervical cancer [59], colon cancer [60], gastric cancer [61], melanoma [62]. The mechanism responsible for Ginkgo Folium induced apoptosis is the disruption on the balance of antiapoptotic protein Bcl-2 and proapoptotic protein BAX, characterized by the decrease on Bcl-2 and the increase on BAX.

Despite of apoptosis, Ginkgo Folium can also arrest cell cycle and inhibit cancer cell migration and invasion. The cell cycle arrest induced by Ginkgo Folium was due to the suppression on G0/G1 phase in gastric cancer [61, 63]. The suppression on cancer cell migration and invasion were observed in several cancer types through multiple ways. First, upregulation on E-cadherin via lincRNA-p21 mediated suppression on E-cadherin degradation in colon cancer [64]. Second, downregulation on ERK/NF-kB signaling in gastric cancer [65]. Third, inhibition on heat-shock protein 27 (HSP27) mediated by AKT and p38 MAPK pathways in NSCLC [66].

The extracts of Ginkgo Folium can combine with herbal formulation to exhibit synergistic effect on anticancer. For instance, it was reported that a new formulation consisted of Ginkgo Follium and an herbal mixture Yu Ping Feng San can sensitize cisplatin resistant lung cancer cells through WT1/MVP mediated stabilization on mTOR/AKT pathway [67]. There are few clinical studies on anticancer effect of Ginkgo. Considering Ginkgo Folium extract has the standard commercial product EGb761, thus, it will be alliable to conduct clinical research with EGb761 to observe whether Ginkgo could serve as an adjuvant therapy on anticancer.

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3. Conclusions

G. biloba has been used to treat age-related disorders and improve blood circulation. Recently, the extract from ginkgo exocarp, seed, kernel, flowers and Folium showed anticancer effect in various cancer types. The reported researches are mainly focus on the in vitro and in in vivo studies. Clinical studies are need to be further conducted to verify their anticancer effect. Furthermore, the detailed mechanism and the active ingredient responsible for the anticancer effect are still need to be elucidated.

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Acknowledgments

This work is supported by the Key Programme of National Natural Science Foundation of China [81730108, 81973635]; the National Natural Science Foundation of China [82174024]; the Natural Science Foundation of Zhejiang Province [LY20H280011]; and the Medical Health Science and Technology Project of Zhejiang Provincial Health Commission [2020367195, 2022508369].

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Conflict of interest

The authors declare no conflict of interest.

References

  1. 1. Lin L, Li L, Chen X, Zeng B, Lin T. Preliminary evaluation of the potential role of β-elemene in reversing erlotinib-resistant human NSCLC A549/ER cells. Oncology Letters. 2018;16:3380-3388. DOI: 10.3892/ol.2018.8980
  2. 2. Gong M, Liu Y, Zhang J, Gao YJ, Zhai PP, Su X, et al. β-Elemene Inhibits Cell Proliferation by Regulating the Expression and Activity of Topoisomerases I and IIα in Human Hepatocarcinoma HepG-2 Cells. BioMed Research International. 2015;2015:153987. DOI: 10.1155/2015/153987
  3. 3. Han Z, Huang H, Zhang T. Downregulation of DBN1 is related to vincristine resistance in colon cancer cells. Journal of Cancer Research and Therapeutics. 2019;15:38-41. DOI: 10.4103/0973-1482.192766
  4. 4. Becker S, Kiecke C, Schäfer E, Sinzig U. Destruction of a Microtubule-Bound MYC Reservoir during Mitosis Contributes to Vincristine's Anticancer Activity. Molecular Cancer Research. 2020;18:859-872. DOI: 10.1158/1541-7786
  5. 5. Hong H, Baatar D, Hwang SG. Anticancer Activities of Ginsenosides, the Main Active Components of Ginseng. Evidence-based Complementary and Alternative Medicine. 2021;2021:8858006. DOI: 10.1155/2021/8858006
  6. 6. Li X, Chu S, Lin M, Gao Y, Liu Y, Yang S, et al. Anticancer property of ginsenoside Rh2 from ginseng. European Journal of Medicinal Chemistry. 2020;203:112627. DOI: 10.1016/j.ejmech.2020.112627
  7. 7. Zeng Z, Zhu J, Chen L, Wen W, Yu R. Biosynthesis pathways of ginkgolides. Pharmacognosy Reviews. 2013;7:47-52. DOI: 10.4103/0973-7847.112848
  8. 8. Gertz HJ, Kiefer M. Review about Ginkgo biloba special extract EGb 761 (Ginkgo). Current Pharmaceutical Design. 2004;10:261-264. DOI: 10.2174/1381612043386437
  9. 9. Yuan Z, Tian Y, He F, Zhou H. Endophytes from Ginkgo biloba and their secondary metabolites. Chinese Medicine. 2019;14:51. DOI: 10.1186/s13020-019-0271-8
  10. 10. Liu L, Wang Y, Zhang J, Wang S. Advances in the chemical constituents and chemical analysis of Ginkgo biloba leaf, extract, and phytopharmaceuticals. Journal of Pharmaceutical and Biomedical Analysis. 2021;193:113704. DOI: 10.1016/j.jpba.2020.113704
  11. 11. Strømgaard K, Nakanishi K. Chemistry and biology of terpene trilactones from Ginkgo biloba. Angewandte Chemie (International Ed. in English). 2004;43:1640-1658. DOI: 10.1002/anie.200300601
  12. 12. Mei N, Guo X, Ren Z, Kobayashi D, Wada K, Guo L. Review of Ginkgo biloba-induced toxicity, from experimental studies to human case reports. Journal of Environmental Science and Health. Part C, Environmental Carcinogenesis & Ecotoxicology Reviews. 2017;35:1-28. DOI: 10.1080/10590501.2016.1278298
  13. 13. Boateng ID, Yang XM. Effect of different drying methods on product quality, bioactive and toxic components of Ginkgo biloba L. seed. Journal of the Science of Food and Agriculture. 2021;101:3290-3297. DOI: 10.1002/jsfa.10958
  14. 14. Zhu JP, Gong H, Labreche F, Kou XH, Wu CE, Fan GJ, et al. In vivo toxicity assessment of 4'-O-methylpyridoxine from Ginkgo biloba seeds: Growth, hematology, metabolism, and oxidative parameters. Toxicon. 2021;201:66-73. DOI: 10.1016/j.toxicon.2021.08.015
  15. 15. Kirschner R, Okuda T. A new species of Pseudocercospora and new record of Bartheletia paradoxa on leaves of Ginkgo biloba. Mycological Progress. 2013;12:421-426. DOI: 10.1007/s11557-012-0849-3
  16. 16. Mahmoudian-Sani MR, Hashemzadeh-Chaleshtori M, Asadi-Samani M, Yang Q. Ginkgo biloba in the treatment of tinnitus: An updated literature review. The International Tinnitus Journal. 2017;21:58-62. DOI: 10.5935/0946-5448.20170011
  17. 17. Isah T. Rethinking Ginkgo biloba L.: Medicinal uses and conservation. Pharmacognosy Reviews. 2015;9:140-148. DOI: 10.4103/0973-7847.162137
  18. 18. Tanaka K, Galduróz RF, Gobbi LT, Galduróz JC. Ginkgo biloba extract in an animal model of Parkinson's disease: a systematic review. Current Neuropharmacology. 2013;11:430-435. DOI: 10.2174/1570159X11311040006
  19. 19. Zuo W, Yan F, Zhang B, Li J, Mei D. Advances in the Studies of Ginkgo Biloba Leaves Extract on Aging-Related Diseases. Aging and Disease. 2017;8:812-826. DOI: 10.14336/AD.2017.0615
  20. 20. Zhao Y, Sun Y, Li C. Simultaneous determination of ginkgo flavonoids and terpenoids in plasma: ammonium formate in LC mobile phase enhancing electrospray ionization efficiency and capacity. Journal of the American Society for Mass Spectrometry. 2008;19:445-449. DOI: 10.1016/j.jasms.2007.11.015
  21. 21. Wu Y, Wang T, Xin Y, Wang G, Xu LA. Overexpression of GbF3'5'H1 Provides a Potential to Improve the Content of Epicatechin and Gallocatechin. Molecules. 2020;25:4836. DOI: 10.3390/molecules25204836
  22. 22. Wang B, Wei PW, Wan S, Yao Y, Song CR, Song PP, et al. Ginkgo biloba exocarp extracts inhibit S. aureus and MRSA by disrupting biofilms and affecting gene expression. Journal of Ethnopharmacology. 2021;271:113895. DOI: 10.1016/j.jep.2021.113895
  23. 23. Liu PK, Weng ZM, Ge GB, Li HL, Ding LL, Dai ZR, et al. Biflavones from Ginkgo biloba as novel pancreatic lipase inhibitors: Inhibition potentials and mechanism. International Journal of Biological Macromolecules. 2018;118:2216-2223. DOI: 10.1016/j.ijbiomac.2018.07.085
  24. 24. Wang Y, Lv J, Cheng Y, Du J, Chen D, Li C, et al. Apoptosis induced by Ginkgo biloba (EGb761) in melanoma cells is Mcl-1-dependent. PLoS One. 2015;10:e0124812. DOI: 10.1371/journal.pone.0124812
  25. 25. D'Apice G, Moschin S, Araniti F, Nigris S, Di Marzo M, Muto A, et al. The role of pollination in controlling Ginkgo biloba ovule development. The New Phytologist. 2021;232:2353-2368. DOI: 10.1111/nph.17753
  26. 26. Boateng ID, Yang XM. Ginkgo biloba L. seed; A comprehensive review of bioactives, toxicants, and processing effects. Industrial Crops and Products. 2022;176:114281. DOI: 10.1016/j.indcrop.2021.114281
  27. 27. Zhou M, Hua T, Ma X, Sun H, Xu L. Protein content and amino acids profile in 10 cultivars of ginkgo (Ginkgo biloba L.) nut from China. Royal Society Open Science. 2019;6:181571. DOI: 10.1098/rsos.181571
  28. 28. Zhao XD, Dong N, Man HT, Fu ZL, Zhang MH, Kou S, et al. Antiproliferative effect of the Ginkgo biloba extract is associated with the enhancement of cytochrome P450 1B1 expression in estrogen receptor-negative breast cancer cells. Biomed Rep. 2013;1:797-801. DOI: 10.3892/br.2013.150
  29. 29. Chen Q , Yang GW, An LG. Apoptosis of hepatoma cells SMMC-7721 induced by Ginkgo biloba seed polysaccharide. World Journal of Gastroenterology. 2002;8:832-836. DOI: 10.3748/wjg.v8.i5.832
  30. 30. Jiang H, Luan Z, Fan Z, Wu X, Xu Z, Zhou T, et al. Antibacterial, Antibiofilm, and Antioxidant Activity of Polysaccharides Obtained from Fresh Sarcotesta of Ginkgo biloba: Bioactive Polysaccharide that Can Be Exploited as a Novel Biocontrol Agent. Evidence-based Complementary and Alternative Medicine. 2021;2021:5518403. DOI: 10.1155/2021/5518403
  31. 31. Ye J, Ye C, Huang Y, Zhang N, Zhang X, Xiao M. Ginkgo biloba sarcotesta polysaccharide inhibits inflammatory responses through suppressing both NF-κB and MAPK signaling pathway. Journal of the Science of Food and Agriculture. 2019;99:2329-2339. DOI: 10.1002/jsfa.9431
  32. 32. Zhou G, Yao X, Tang Y, Yang N, Pang H, Mo X, et al. Two new nonacosanetriols from Ginkgo biloba sarcotesta. Chemistry and Physics of Lipids. 2012;165:731-736. DOI: 10.1016/j.chemphyslip.2012.08.003
  33. 33. Xu AH, Chen HS, Sun BC, Xiang XR, Chu YF, Zhai F, et al. Therapeutic mechanism of ginkgo biloba exocarp polysaccharides on gastric cancer. World Journal of Gastroenterology. 2003;9:2424-2427. DOI: 10.3748/wjg.v9.i11.2424
  34. 34. Cao C, Han D, Su Y, Ge Y, Chen H, Xu A. Ginkgo biloba exocarp extracts induces autophagy in Lewis lung cancer cells involving AMPK/mTOR/p70S6k signaling pathway. Biomedicine & Pharmacotherapy. 2017;93:1128-1135. DOI: 10.1016/j.biopha.2017.07.036
  35. 35. Han D, Cao C, Su Y, Wang J, Sun J, Chen H, et al. Ginkgo biloba exocarp extracts inhibits angiogenesis and its effects on Wnt/β-catenin-VEGF signaling pathway in Lewis lung cancer. Journal of Ethnopharmacology. 2016;192:406-412. DOI: 10.1016/j.jep.2016.09.018
  36. 36. Cao CJ, Su Y, Sun J, Wang GY, Jia XQ , Chen HS, et al. Anti-tumor Effect of Ginkgo biloba Exocarp Extracts on B16 Melanoma Bearing Mice Involving P I3K/Akt/HIF-1α/VEGF Signaling Pathways. Iran J Pharm Res. 2019;18:803-811. DOI: 10.22037/ijpr.2019.1100637
  37. 37. Cao C, Su Y, Gao Y, Luo C, Yin L, Zhao Y, et al. Ginkgo biloba Exocarp Extract Inhibits the Metastasis of B16-F10 Melanoma Involving PI3K/Akt/NF-κB/MMP-9 Signaling Pathway. Evidence-based Complementary and Alternative Medicine. 2018;2018:4969028. DOI: 10.1155/2018/4969028
  38. 38. Chen HS, Zhai F, Chu YF, Xu F, Xu AH, Jia LC. Clinical study on treatment of patients with upper digestive tract malignant tumors of middle and late stage with Ginkgo biloba exocarp polysaccharides capsule preparation. Journal of Chinese Integrative Medicine. 2003;1:189-191. DOI: 10.3736/jcim20030313
  39. 39. Xu A, Chen H, Wang L, et al. Influence of Ginkgo biloba L. exocarp polysaccharides on serum superoxide dismutase activity and malondialdehyde level in mice under different states. China Journal of Chinese Materia. Médica. 1998;23:746-747
  40. 40. Cao C, Su Y, Han D, Gao Y, Zhang M, Chen H, et al. Ginkgo biloba exocarp extracts induces apoptosis in Lewis lung cancer cells involving MAPK signaling pathways. Journal of Ethnopharmacology. 2017;198:379-388. DOI: 10.1016/j.jep.2017.01.009
  41. 41. Liu Y, Yang B, Zhang L, Cong X, Liu Z, Hu Y, et al. Ginkgolic acid induces interplay between apoptosis and autophagy regulated by ROS generation in colon cancer. Biochemical and Biophysical Research Communications. 2018;498:246-253. DOI: 10.1016/j.bbrc.2018.01.091
  42. 42. Ma J, Duan W, Han S, Lei J, Xu Q , Chen X, et al. Ginkgolic acid suppresses the development of pancreatic cancer by inhibiting pathways driving lipogenesis. Oncotarget. 2015;6:20993-21003. DOI: 10.18632/oncotarget.3663
  43. 43. Zhou C, Li X, Du W, Feng Y, Kong X, Li Y, et al. Antitumor effects of ginkgolic acid in human cancer cell occur via cell cycle arrest and decrease the Bcl-2/Bax ratio to induce apoptosis. Chemotherapy. 2010;56:393-402. DOI: 10.1159/000317750 Epub 2010 Oct 15
  44. 44. Wu X, Mao G, Zhao T, et al. Isolation, purification and in vitro anti-tumor activity of polysaccharide from Ginkgo biloba sarcotesta. Carbohydrate Polymers. 2011;86:1073-1076. DOI: 10.1016/j.carpol.2011.04.069
  45. 45. Yang XM, Wang YF, Li YY, Ma HL. Thermal stability of ginkgolic acids from Ginkgo biloba and the effects of ginkgol C17:1 on the apoptosis and migration of SMMC7721 cells. Fitoterapia. 2014;98:66-76. DOI: 10.1016/j.fitote.2014.07.003
  46. 46. Yang X, Qian Z, Chen J, Zhu W, Xie J. Study on antitumor activities of ginkgolic acids from Ginkgo sarcotestas in vitro. Journal of Huazhong Agricultural University. 2004;27:40-42. DOI: 10.13300/j.cnki.hnlkxb.2006.04.026
  47. 47. Cao Y, Zhang D, Zheng G, Tang Y, Zhang J. Study on Antitumor and Synergy Effect of "bushen huayu jiedu formula" on Mice Hepatocarcinoma H22. Vol. 27. China: China Academic Publishing House; 2004. pp. 38-40. DOI: 10.13863/j.issn1001-4454.2004.01.022
  48. 48. Lu Y, Hao W, Zhang X, Zhao Y, Xu Y, Luo J, et al. Comparative Study of Physicochemical Properties and Starch Granule Structure in Seven Ginkgo Kernel Flours. Food. 2021;10:1721. DOI: 10.3390/foods10081721
  49. 49. Wang HY, Zhang YQ. The main active constituents and detoxification process of Ginkgo biloba seeds and their potential use in functional health foods. Journal of Food Composition and Analysis. 2019;83:103247. DOI: 10.1016/j.jfca.2019.103247
  50. 50. Singh B, Kaur P, Gopichand SRD, Ahuja PS. Biology and chemistry of Ginkgo biloba. Fitoterapia. 2008;79:401-418. DOI: 10.1016/j.fitote.2008.05.007
  51. 51. Zhang H, Wang Z, Xu SY. Optimization of processing parameters for cloudy ginkgo (Ginkgo biloba Linn.) juice. Journal of food engineering. 2007;80:1226-1232. DOI: 10.1016/j.jfoodeng.2006.09.021
  52. 52. Wu CE, Yang JT, Fan GJ, Li TT, Tang ZX, Cao FL. Allergic identification for ginkgo kernel protein in guinea pigs. Food Science and Biotechnology. 2016;25:915-919. DOI: 10.1007/s10068-016-0150-3
  53. 53. Chassagne F, Huang X, Lyles JT, Quave CL. Validation of a 16th Century Traditional Chinese Medicine Use of Ginkgo biloba as a Topical Antimicrobial. Frontiers in Microbiology. 2019;10:775. DOI: 10.3389/fmicb.2019.00775
  54. 54. Feodorova Y, Tomova T, Minchev D, Turiyski V, Draganov M, Argirova M. Cytotoxic effect of Ginkgo biloba kernel extract on HCT116 and A2058 cancer cell lines. Heliyon. 2020;6:e04941. DOI: 10.1016/j.heliyon.2020.e04941
  55. 55. Li M, Li B, Xia ZM, Tian Y, Zhang D, Rui WJ, et al. Anticancer Effects of Five Biflavonoids from Ginkgo Biloba L male flowers in vitro. Molecules. 2019;24:1496. DOI: 10.3390/molecules24081496
  56. 56. Li M, Li B, Hou Y, Tian Y, Chen L, Liu S, et al. Anti-inflammatory effects of chemical components from Ginkgo biloba L. male flowers on lipopolysaccharide-stimulated RAW264.7 macrophages. Phytotherapy Research. 2019;33:989-997. DOI: 10.1002/ptr.6292
  57. 57. Li R, Xia Z, Li B, Tian Y, Zhang G, Li M, et al. Advances in Supercritical Carbon Dioxide Extraction of Bioactive Substances from Different Parts of Ginkgo biloba L. Molecules. 2021;26:4011. DOI: 10.3390/molecules26134011
  58. 58. Yamashita T, Sato T, Sakamoto K, Ishii H, Yamamoto J. The free-radical scavenger edaravone accelerates thrombolysis with alteplase in an experimental thrombosis model. Thrombosis Research. 2015 Jun;135(6):1209-1213. DOI: 10.1016/j.thromres.2015.04.011
  59. 59. Xu Z, Feng Q , Wang M, Zhao H, Lin Y, Zhou S. Green Biosynthesized Silver Nanoparticles With Aqueous Extracts of Ginkgo Biloba Induce Apoptosis via Mitochondrial Pathway in Cervical Cancer Cells. Frontiers in Oncology. 2020;10:575415. DOI: 10.3389/fonc.2020.575415
  60. 60. Chen XH, Miao YX, Wang XJ, Yu Z, Geng MY, Han YT, et al. Effects of Ginkgo biloba extract EGb761 on human colon adenocarcinoma cells. Cellular Physiology and Biochemistry. 2011;27:227-232. DOI: 10.1159/000327948
  61. 61. Bai Y, Zhao F, Li Y, Wang L, Fang XJ, Wang CY. Ginkgo biloba extract induce cell apoptosis and G0/G1 cycle arrest in gastric cancer cells. International Journal of Clinical and Experimental Medicine. 2015;8:20977-20982
  62. 62. Park HJ, Kim MM. Flavonoids in Ginkgo biloba fallen leaves induce apoptosis through modulation of p53 activation in melanoma cells. Oncology Reports. 2015;33:433-438. DOI: 10.3892/or.2014.3602
  63. 63. Qian Y, Xia L, Shi W, Sun JJ, Sun YQ. The effect of EGB on proliferation of gastric carcinoma SGC7901 cells. Clinical & Translational Oncology. 2016;18:521-526. DOI: 10.1007/s12094-015-1399-3
  64. 64. Chang L, Liu T, Chai Z, Jie S, Li Z, Liu M, et al. lincRNA-p21 Mediates the Anti-Cancer Effect of Ginkgo Biloba Extract EGb 761 by Stabilizing E-Cadherin Protein in Colon Cancer. Medical Science Monitor. 2018;24:9488-9496. DOI: 10.12659/MSM.911924
  65. 65. Fu Z, Lin L, Liu S, Qin M, He S, Zhu L, et al. Ginkgo Biloba Extract Inhibits Metastasis and ERK/Nuclear Factor kappa B (NF-κB) Signaling Pathway in Gastric Cancer. Medical Science Monitor. 2019;25:6836-6845. DOI: 10.12659/MSM.915146
  66. 66. Tsai JR, Liu PL, Chen YH, Chou SH, Yang MC, Cheng YJ, et al. Ginkgo biloba extract decreases non-small cell lung cancer cell migration by downregulating metastasis-associated factor heat-shock protein 27. PLoS One. 2014;9:e91331. DOI: 10.1371/journal.pone.0091331
  67. 67. Lou JS, Xia YT, Wang HY, Kong XP, Yao P, Dong TTX, et al. The WT1/MVP-Mediated Stabilization on mTOR/AKT Axis Enhances the Effects of Cisplatin in Non-small Cell Lung Cancer by a Reformulated Yu Ping Feng San Herbal Preparation. Frontiers in Pharmacology. 2018;9:853. DOI: 10.3389/fphar.2018.00853

Written By

Jian-Shu Lou, Die Hu, Hao-Jie Wang, Li-Ping Zhao, Jun-Hu Hu and Zhao-Huang Zhou

Submitted: 20 March 2022 Reviewed: 04 April 2022 Published: 02 November 2022