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Anti-cancer effects of traditional Korean wild vegetables in complementary and alternative medicine
Accepted Manuscript Title: Anti-cancer Effects of Traditional Korean Wild Vegetables in Complementary and Alternative Medicine Author: Hyun-Mok Ju Kwang-Won Yu Sung-Dae Cho Sun Hee Cheong Ki Han Kwon PII: DOI: Reference:
S0965-2299(15)30017-0 http://dx.doi.org/doi:10.1016/j.ctim.2015.11.004 YCTIM 1500
To appear in:
Complementary Therapies in Medicine
Received date: Revised date: Accepted date:
16-12-2014 18-7-2015 26-11-2015
Please cite this article as: Ju Hyun-Mok, Yu Kwang-Won, Cho Sung-Dae, Cheong Sun Hee, Kwon Ki Han.Anti-cancer Effects of Traditional Korean Wild Vegetables in Complementary and Alternative Medicine.Complementary Therapies in Medicine http://dx.doi.org/10.1016/j.ctim.2015.11.004 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Anti-cancer Effects of Traditional Korean Wild Vegetables in Complementary and Alternative Medicine Hyun-Mok Jua, Kwang-Won Yub, Sung-Dae Choc, Sun Hee Cheongd, and Ki Han Kwona,e* a
Division of Food Science and Nutrition, Graduate School of Biohealth Science, Gwangju University, Gwangju 503703, South Korea
b
Department of Food and Nutrition, Korea National University of Transportation, Chungbuk 368-701, South Korea
c
Department of Oral Pathology, School of Dentistry and Institute of Oral Bioscience, Chonbuk National University,
Jeonju 561-756, South Korea d
Department of Biotechnology, Konkuk University, Chungju 380-701, South Korea
e
Department of Food Science and Nutrition, College of Health, Welfare, and Education, Gwangju University, Gwangju 503-703, South Korea
*Corresponding authors: Department of Food Science and Nutrition, College of Health, Welfare, and Education, Gwangju University, 277 Hyodeok-ro, Nam-gu, Gwangju 503-703, South Korea. Tel.: +82 62-670-2708; Fax: +82 62-670-2066. E-mail address: [email protected] (K. H. Kwon)
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Highlights
We introduce traditional Korean wild vegetables for anticancer effects.
A variety of traditional Korean wild vegetables can be used as alternative medicines.
The anticancer effects of traditional Korean medicinal plants were identified various biological markers.
Our study will be the guidelines for cancer prevention and treatment using phytochemicals.
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ABSTRACT This research study explored the anti-cancer effects of natural materials in South Korea. Although South Korea has a long history of traditional medicine, many natural materials of South Korea have not yet been introduced to the rest of the world because of language barriers and inconsistent study conditions. In the past 3 years, 56 papers introducing 56 natural materials, which have anti-cancer effects, have been published by scientists in South Korea. Further, these studies have introduced five kinds of natural materials presented in research papers that were written in Korean and are therefore virtually unknown overseas. The anti-cancer effects were confirmed by 2-3 cancer markers in the majority of the studies, with the most common targets being breast cancer cells and gastric cancer cells. These cancers have the greatest incidence in South Korea. The natural materials studied not only exhibit anti-cancer activity but also display anti-inflammatory, anti-oxidative stress, and anti-diabetic activities. They have not yet been used for the direct treatment of disease but have potential as medicinal materials for alternative and complementary medicine for the treatment of many modern diseases. Many natural materials of South Korea are already known all over the world, and with this study, we hope to further future research to learn more about these natural medicines.
Keywords: Traditional Korean wild vegetables; Anti-cancer effects; Complementary and alternative medicine
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1. Introduction In general, the word “cancer” refers to a malignant tumor.1 Cancer cells proliferate rapidly.2 Although all cells that make up the human body divide, cancer cells do so much more quickly than non-cancerous cells.3 Cancer is a disease in which the cancerous cells have an abnormally long life span.4 Cancer is the leading cause of death in South Korea, followed by brain diseases and heart disease.5 The cancer mortality rate has been increasing every year in South Korea.6 The leading cause of death in the world is heart disease, followed by cancer, diabetes, and chronic lung disease.7 In underdeveloped countries, the highest death rate is among infants8 and mothers9, whereas in developed countries, age-related chronic diseases, including cancer, account for the majority of deaths.10 A comparison of the leading causes of death in underdeveloped countries and developed countries could indirectly point to diseases, such as cancer, as being related to aging in advanced societies.9,10 Like many countries in East Asia, South Korea has a long-lived medical tradition. Hyangyakjipseongbang, Uibangruchue, and Donguibogam are traditional medical books representing East Asia, along with Chinese and Japanese traditional medical books.11 Among them, Donguibogam, which was written in the year 1610, has been recognized as a great medical book. The traditional medical book in South Korea represented cancer as “癰疽, Ongjeo” and introduced 70 different types of “癰疽, Ongjeo (cancer)” and medical treatments.12 Although these treatments represented a commitment to empiricism, the book is a great treasure obtained from a long tradition. The traditional medicinal books of South Korea have attempted to treat cancer with natural materials, including plants that grow in the wild. These natural plant materials have been used as effective cancer treatments since 1610.13 Although the treatments are based in empiricism, many scientists have since conducted research studies with a focus on science in complementary and alternative medicine.
2. Biochemical markers to determine anti-cancer activity In general, higher animals have tumor suppresser genes that are involved in the cell cycle, cell differentiation, and inducing cell suicide (apoptosis).10 However, if these mechanisms are disrupted, the cells may generate cancer.10, 14 When tumor suppresser genes are not expressed due to the effects of external or genetic influences, it brings about the over-proliferation of cells and cancer. p53 is a well-known tumor suppresser gene,14 and 50% of all cases of cancer are attributed to the inhibited expression of p53.15 Immortal cell division, which is normally stopped at checkpoints to resolve whether cell division should be continued or if the cells should enter apoptosis and autophagy, is the major cause of cancer development.16 When this checkpoint does not operate, cells become immortal and proliferative cancer cells.17 In general, cancer cell research is conducted to develop anti-cancer treatments, which can inhibit overproliferative cells or induce apoptosis.16, 17 The development of anti-cancer materials makes use of the cell cycle arrest pathway, inhibiting Cdk, cyclin family protein cell division, or inducing the apoptosis pathway to cause cells to 4
directly enter apoptosis.16 Cyclin D is the marker of the cell cycle, while P-Rb up-regulation prevents protein resolution preceding the G1/G0 phase. In the G2/M phase, up-regulation of the p21 and p27 proteins causes cell cycle arrest.17 Inhibition of the cell cycle through the inhibition or induction of proteins involved in cell division is a basic concept for the development of anti-cancer material.14-16 Following the same concept for promoting apoptosis, anticancer materials are typically developed by inhibiting Bcl2 and Bax, which are suppressors of apoptosis, and also by inducing p53, a regulator of apoptosis.18 Proteins related to p53, including p21, cytochrome c, the caspase family, etc., are used as targets for the development of cancer drugs.15,16 In addition, the induction of necrosis activity and the inhibition of angiogenesis activity are involved in cancer drug development.19 In modern medicine, the development of cancer drugs makes use of the activation or inhibition of anti-cancer factor proteins from drug candidate libraries.20 On the other hand, while chemical drugs are harmless by themselves, they often contain by-products produced in the mass-production process, which can create a number of side effects. In addition, some chemical drugs affect normal cells.18 These drugs are often slow to produce a cure, which causes pain for the patient and also has personal and social costs.21 The clear mechanism of action of anti-cancer substances in traditional natural materials has not yet been determined. It is too early in the study of traditional natural materials to promote them as direct anti-cancer agents, but their use has become increasingly frequent and is continuing through the intake of these natural materials for use as adjuncts in the prevention or treatment of cancer. Natural materials can help to prevent and can also cure cancer in a safer way than synthetic chemical products because plant materials are generally considered safe and have been consumed by humans for a long time.
3. Anti-cancer effects of traditional herbal medicine in South Korea A variety of natural materials that can be used as alternative medicines, including traditional plants of South Korea, has been introduced. Using plant materials of South Korea as the criteria for selection, 49 total traditional medicinal plants were identified in PubMed Central, the National Center for Biotechnology Information, and the U.S. National Library of Medicine (Table 1). Natural plant materials native to South Korea, such as ginseng, are currently being studied as alternative cancer treatments in other parts of the world. However, while many other materials have been of interest to the scientists of South Korea, they are not widely known to most people around the world. Antitumor activity was found only in accordance with the conditions of the study, where most researchers conducted research in vitro. In vivo activity should be used to confirm that the natural materials have potential anti-cancer activity. The data can be used by many researchers worldwide to study the excellent traditional material available in South Korea. Similarly, most traditional plant materials have been found to potentially be useful for anti-cancer activity studies, which test for various cancer markers, such as the induction of apoptosis and autophagy; and the inhibition of cell migration, angiogenesis, cell adhesion, and the cell cycle. After an analysis of the natural materials, 18 papers 5
were selected that identified materials that have anti-apoptotic effects, while 7, 7, 8, and 7 papers described materials involved in cell cycle arrest, anti-metastasis, anti-proliferation, and autophagy, respectively. There was also 1 paper each that presented materials regarding anti-angiogenesis, anti-migration, anti-differentiation, cellular energy homeostasis, and acetylation of core histone activity. The natural materials presented were Naematoloma sublateritium (hazel mushroom),21 Panax ginseng (ginseng),55 Samsoeum,30 cantharidin,31 Dipsacus asperoides (teasel),35 purple bamboo salt,39 Pulsatilla koreana (wind flower),43 Cryptomeria japonica (Japan cedar),46 Artemisia princeps Pampanini cv. Sajabal (mugwort),47 Cirsium japonicum (thistle),51 Venenum Bufonis (toad venom),58 Rhus verniciflua (rhus),27,62 Selaginella tamariscina (purple loosestrife),67 Siegesbeckia glabrescens (Siegesbeckia herb),26, 37, 69 and Albizzia julibrissin (silk tree).70 Naematoloma sublateritium (hazel mushroom)22 was found to induce apoptosis and autophagy through the inhibition of TNF-a expression in TNK and p38 mitogen-activated protein kinase (MARK) pathway modulations in MDA-MB-231 breast cancer cells. Panax ginseng (ginseng), Samsoeum, and Pulsatilla koreana (wind flower) showed anti-cancer effects by inducing apoptosis and autophagy. Cantharidin,31 Dipsacus asperoides,35 purple bamboo salt,39 Pulsatilla koreana (wind flower),43 Cryptomeria japonica (Japan cedar),46 Artemisia princeps Pampanini cv. Sajabal (mugwort),47 Cirsium japonicum (thistle),51 Venenum Bufonis (toad venom),58 Rhus verniciflua (rhus),27, 62 Selaginella tamariscina (purple loosestrife),67 Siegesbeckia glabrescens (Siegesbeckia herb),26, 37, 69 and Albizzia julibrissin (silk tree)69 were determined to have anti-cancer effects solely through the induction of apoptosis. The cancer markers for confirming the induction of apoptosis were the inhibition of Bax and Bcl-2 and the induction of p53 and p38 in the apoptosis pathway. p53 and other genes in its family are important therapeutic targets for a number of metabolic homeostasis disorders. p53 and its family members p63 and p73 influence cell growth and mTOR signaling, carbohydrate metabolism, cellular redox, lipid metabolism, mitochondrial maintenance, and autophagy. In pathways associated with apoptosis, p53, which maintains its inactive state in conjunction with MDM2 and MDM2 binding, is released in response to DNA damage or other stress. Activation of p53 induces the progression of the pathway to apoptosis and inhibits the cell cycle to allow adequate time for DNA repair. Bcl 2-c and Bcl-XL are important proteins that directly prevent apoptosis by inhibiting cytochrome c. Stimulation with stress, such as response cytokines, ultraviolet irradiation, heat shock, and osmotic shock in the cell cycle, induces apoptosis by p38 MARK. Further necrosis mechanisms were induced by the activation of the caspase family. Antrodia camphorate,32 Gleditsia sinensis thorns (piece chair wood),39 Citrus aurantium L. (Korean orange),48, 57
Curcuma longa (curcuma),63 Strychni semen (verbena),61 and Inonotuso bliquus (Chaga mushroom)64 were
determined to have anti-cancer effects by arresting the cell cycle. Apoptosis was induced through the inhibition of checkpoint proteins involved in the cell cycle phase. The cancer markers for confirming cell cycle arrest include the inhibition of Cyclin B1, Cdk 2, Cdk 25c, cyclin D1, and PARP. When cell cycles go beyond this phase, checkpoints lead to apoptosis and autophagy in response to external stress and DNA damage. p21, p27, p53, cyclin E, and CDK-2 are involved in the G1/G0 phase, while G2/M is associated with cyclin A and CDK-1. Specifically, the p21 protein is induced by p53, and it activates cell cycle arrest and inhibits apoptosis. p27 has dual functions. Cdk4-cyclin D1-bound 6
p27 induces cell cycle arrest by phosphorylation of pRB in the cytoplasm, while p27 induces activation of the Cdk3cyclin complex, which goes on to induce cell cycle arrest by the multi-phosphorylation of pRB. The materials confirmed to have anti-metastasis effects were Scutellaria baicalensis Georgi (skullcap),30 Ilex kudingcha C.J. Tseng (Kudingcha) (sickle neofinetia)36 bamboo salt,41 Asiasari radix (Siebold’ieboldi radix),42 Lithospermum erythrorhizon (red-root lithospermum),44 Eriobotrya japonica (Korean mandolin),49 and Platycodon grandiflorum (balloon flower).66 Bamboo salt, Asiasari radix (Siebold’ieboldi radix),42 and Lithospermum erythrorhizon (red-root lithospermum)44 were confirmed to have anti-cancer effects through apoptosis. These three materials increased the percentage of cells in the sub-G1 phase and regulated apoptotic Bax protein expression; they also exhibited downregulation of anti-apoptotic Bcl-2 family proteins. In addition, Ilex kudingcha C.J. Tseng (Kudingcha) (sickle neofinetia)36 was confirmed to have anti-cancer effects associated with it; it induced apoptosis, displayed anti-inflammatory activities with the expression of the NF-κB, iNOS, and COX-2 genes, and exerted antimetastatic effects in tumor-bearing mice by upregulating Bax, caspase-3, and caspase-9, and downregulating Bcl-2.36 Scutellaria baicalensis Georgi (skullcap),30 Eriobotrya japonica (Korean mandolin),49 and Platycodon grandiflorum (balloon flower)
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were confirmed to have only anti-metastatic effects. The induction of apoptosis was
determined by the inhibition of Bax and Bcl-2 activity, while the induction of necrosis was identified by the activation of the caspase family. Though the inhibition of angiogenesis has a close relationship with anti-metastatic activity, materials possessing such an effect have not yet been identified. All materials that exhibit anti-cancer effects were confirmed to act through the induction of apoptosis, the induction of cell cycle arrest, and the inhibition of metastasis. The anti-cancer activities of Sipjeondaebo-tang52 and Curcuma xanthorrhiza (curcuma)63 were determined in vivo. The activity of Sipjeondaebo-tang52 was verified with an analysis of the serum levels of IL-6, MCP-1, and TNF-a in CT-26 tumor-bearing mice; the activity of Curcuma xanthorrhiza (curcuma)63 was confirmed in TPA-induced mouse ear edema and ODC expression. The reasons for determining the in vivo activity of the majority of the materials were that they are new materials being considered as anti-cancer drugs (studied recently within the past 3 years). Additional in vivo confirmation of many of the materials will be required before their use as anti-cancer drugs can be approved. Samsoeum30 Oyaksungisan38 Sipjeondaebo-tang,52 and Bojungikki-tang53 are traditional herbal cocktails made by boiling various medicinal herbal plants. Such traditional herbal cocktails have been called HanYak (韓藥, Traditional Korean Medicine) and are distinguished from Chinese herbal cocktails (HanYak, 漢藥, Traditional Chinese Medicine). Despite being around for a long time in South Korea, the medicinal uses of traditional Korean medicine have not been confirmed. To address these weaknesses, studies have been performed at the Korea Institute of Oriental Medicine (Daejeon, South Korea). Bamboo salt39 and purple bamboo salt41 are not plant materials but are natural minerals instead. Bamboo salt is a powder obtained by repeatedly (nine times) baking salt at high heat in a solar salt compacted bamboo tube. However, bamboo salt has not yet been scientifically proven to be effective in improving immune, anti-inflammatory, or 7
gastrointestinal diseases. The most commonly used cancer cell lines were breast cancer cells, followed by human gastric cancer, human colon cancer, and human acute leukemia jurkat T cells. Men in South Korea experience upper gastric cancer most frequently, followed by prostate, colon, and liver cancer. The most common cancer in South Korean women is upper thyroid cancer, followed by gastric, breast, colon, and lung cancer. Because of the uniqueness of breast cancer in women, the activity of many materials for breast cancer has been confirmed.
4. Unknown materials with anti-cancer effects for international study South Korea had achieved rapid scientific growth by the end of the 20th century, especially in the field of biological technology. However, it was difficult to find advanced domestic materials that were not accompanied by the introduction of a national study. Because the level of scientists in South Korea has risen significantly enough to enable them to contribute directly to the Science Citation Index (SCI) and Science Citation Index Expand (SCIE) papers, it is rare even for native plants not to have been introduced by a national study. Therefore, only 6 materials native to South Korea were identified that had not been introduced in a national study (Table 2). The extracts of Amphitrite albicostatu (barnacle),72 Euphorbia Supina (spurge),73 and Diospyros kaki cv. Hachiya (Persimmon)74 were confirmed to have anti-cancer effects in liver and breast cancer. Because they had not yet been introduced by SCI or SCIE papers, only the cytotoxicity for their anti-cancer effect was confirmed by MTT assay without the use of other cancer markers. The results of this study do not rule out the possibility that these substances may be cytotoxic to normal cells. Presumably, ensuring only their cytotoxic effects and not checking for other cancer markers was due to insufficient cancer research. Lepidium virginicum L. (poor man's pepper)76 was determined to have apoptosis effects on human colon cancer, as confirmed by the markers Bcl-2, Bcl-XL, and caspase-3. Other papers have suggested that only the cytotoxic effects to cancer cells had been determined. Since these papers were written in Korean, their results should be confirmed with the use of other cancer markers and should be published in English.74, 77 5. Conclusion The uniqueness of South Korea’s culture and technology has spread actively around the world. However, there are still barriers to globalization because of the different letters in the Korean and English alphabets. As a result, Koreans devote a lot of time and money to learning English. However, language barriers have forced excellent research results to be rejected or to remain unknown. Traditional herbal plants of South Korea, which have effective physiological activities, have also not been introduced around the world. South Korea has a long history of traditional medicine. In medicinal books, such as Donguibogam, about 400 species of South Korean medicinal plants and their medicinal effects were confirmed. Many parts, such as the roots, stems, leaves, and flowers, have been used for various purposes. South Korea has about 4,500 species of native plants, including more than 1,000 species of trees and 3,500 species of grasses. The effects of around 1,000 of the medicinal 8
plants have been confirmed, though only 600 species are currently used in pharmacognosy. Only 50 of these species can be cultivated, and the remaining 550 species must be gathered directly from their natural habitat. In studies of the anti-cancer properties of traditional herbs in South Korea, the materials utilized in the development of cancer drugs have been based on studies about apoptosis and cell cycle arrest. Anticancer, antiinflammatory, anti-oxidative stress, and anti-diabetic materials have been actively studied in South Korea. All materials presented herein are from a number of studies, which were conducted in South Korea as well as in China and Japan. Modern society and medicine focus on preventing diseases, and natural materials have shown potential for preventive medicine. Many people have invested great efforts in consuming the healthy components of these plants, such as phytochemicals. These efforts generate a lot of interest in complementary and alternative medicine. Nevertheless, many active materials are not yet being used to treat diseases directly because they have not been extensively studied. Their potential uses as both food and functional ingredients following chemotherapy to help prevent disease and promote healing are great. In addition, a single compound that is effective against disease will require study to determine its physiological activities. There is great potential for traditional native herbal plants in America and Asia, including South Korea, as alternative and complementary medicines for treating many modern diseases, such as cancer. Due to increased interest in medicinal herbs and traditional treatments, we hope there will be support for research around the world that will lead to the introduction of the traditional herbs of South Korea. Conflict of interest statement The authors declare that there is no conflict of interest regarding the publication of this paper.
Acknowledgments This research was supported by Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education, Science and Technology (NRF-2013R1A1A4A01013550). Moreover, this study was conducted in part by research funds from Gwangju University, South Korea in 2015.
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47. Woo HJ, Jun do Y, Lee JY, Woo MH, Yang CH, Kim YH. Apoptogenic activity of 2α,3α -dihydroxyurs-12-ene28-oic acid from Prunella vulgaris var. lilacina is mediated via mitochondria-dependent activation of caspase cascade regulated by Bcl-2 in human acute leukemia Jurkat T cells. J Ethnopharmacol 2011;135(3):626-35. 48. Kim DY, Kang SH, Ghil SH. Cirsium japonicum extract induces apoptosis and anti-proliferation in the human breast cancer cell line MCF-7. Mol Med Rep 2010;3(3):427-32. 49. Choi YK, Jung KY, Woo SM, Yun YJ, Jun CY, Park JH, et al. Effect of Sipjeondaebo-tang on cancer-induced anorexia and cachexia in CT-26 tumor-bearing mice. Mediators Inflamm 2014;2014:736563. 50. Jeong JS, Ryu BH, Kim JS, Park JW, Choi WC, Yoon SW. Bojungikki-tang for cancer-related fatigue: a pilot randomized clinical trial. Integr Cancer Ther 2010;9(4):331-8. 51. Shin EM, Kim S, Merfort I, Kim YS. Glycyrol induces apoptosis in human Jurkat T cell lymphocytes via the FasFasL/caspase-8 pathway. Planta Med 2011;77(3):242-7. 52. Park HJ, Han ES, Park DK. The ethyl acetate extract of PGP (Phellinus linteus grown on Panax ginseng) suppresses B16F10 melanoma cell proliferation through inducing cellular differentiation and apoptosis. J Ethnopharmacol 2010;132(1):115-21. 53. Hu W, Lee SK, Jung MJ, Heo SI, Hur JH, Wang MH. Induction of cell cycle arrest and apoptosis by the ethyl acetate fraction of Kalopanax pictus leaves in human colon cancer cells. Bioresour Technol 2010;101(23):936672. 54. Lee S, Ra J, Song JY, Gwak C, Kwon HJ, Yim SV, Hong SP, et al. Extracts from Citrus unshiu promote immunemediated inhibition of tumor growth in a murine renal cell carcinoma model. J Ethnopharmacol 2011;133(3):973-9. 55. Yun HR, Yoo HS, Shin DY, Hong SH, Kim JH, Cho CK, et al. Apoptosis induction of human lung carcinoma cells by Chan Su (Venenum Bufonis) through activation of caspases. J Acupunct Meridian Stud 2009;2(3):210-7. 56. Yoon SR, Lee GD, Park JH, Lee IS, Kwon JH. Ginsenoside composition and antiproliferative activities of explosively puffed ginseng (Panax ginseng C.A. Meyer). J Food Sci 2010 ;75(4):C378-82. 57. Lee DS, Lee MK, Kim JH. Curcumin induces cell cycle arrest and apoptosis in human osteosarcoma (HOS) cells. Anticancer Res 2009;29(12):5039-44. 58. Lee SM, Kwon JI, Choi YH, Eom HS, Chi GY. Induction of G2/M arrest and apoptosis by water extract of Strychni Semen in human gastric carcinoma AGS cells. Phytother Res 2008;22(6):752-8. 59. Kim JH, Go HY, Jin DH, Kim HP, Hong MH, Chung WY, et al. Inhibition of the PI3K-Akt/PKB survival pathway enhanced an ethanol extract of Rhus verniciflua Stokes-induced apoptosis via a mitochondrial pathway in AGS gastric cancer cell lines. Cancer Lett 2008;265(2):197-205. 60. Park JH, Park KK, Kim MJ, Hwang JK, Park SK, Chung WY. Chung. Cancer chemoprotective effects of Curcuma xanthorrhiza. Phytother Res 2008;22(5):695-8. 61. Youn MJ, Kim JK, Park SY, Kim Y, Kim SJ, Lee JS, et al. Chaga mushroom (Inonotus obliquus) induces G0/G1 arrest and apoptosis in human hepatoma HepG2 cells. World J Gastroenterol 2008;14(4):511-7. 13
62. Jeong JB, Jeong HJ, Park JH, Lee SH, Lee JR, Lee HK, et al. de Lumen Cancer-preventive peptide lunasin from Solanum nigrum L. inhibits acetylation of core histones H3 and H4 and phosphorylation of retinoblastoma protein (Rb). J Agric Food Chem 2007;55(26):10707-13 63. Lee KJ, Kim JY, Choi JH, Kim HG, Chung YC, Roh SH, et al. Inhibition of tumor invasion and metastasis by aqueous extract of the radix of Platycodon grandiflorum. Food Chem Toxicol 2006;44(11):1890-6. 64. Ahn SH, Mun YJ, Lee SW, Kwak S, Choi MK, Baik SK, et al. Selaginella tamariscina induces apoptosis via a caspase-3-mediated mechanism in human promyelocytic leukemia cells. J Med Food 2006;9(2):138-44. 65. Lee HJ, Lee EO, Rhee YH, Ahn KS, Li GX, Jiang C, et al. An oriental herbal cocktail, ka-mi-kae-kyuk-tang, exerts
anti-cancer
activities
by
targeting
angiogenesis,
apoptosis
and
metastasis,
Carcinogenesis
2006;27(12):2455-63. 66. Jun SY, Choi YH, Shin HM. Siegesbeckia glabrescens induces apoptosis with different pathways in human MCF7 and MDA-MB-231 breast carcinoma cells. Oncol Rep 2006;15(6):1461-7. 67 Won HJ, Han CH, Kim YH, Kwon HJ, Kim BW, Choi JS, et al. Induction of apoptosis in human acute leukemia Jurkat T cells by Albizzia julibrissin extract is mediated via mitochondria-dependent caspase-3 activation. J Ethnopharmacol 2006;106(3):383-9. 68. Kim DH, Na HK, Oh TY, Shin CY, Surh YJ. Eupatilin inhibits proliferation of ras-transformed human breast epithelial (MCF-10A-ras) cells. J Environ Pathol Toxicol Oncol 2005;24(4):251-9 69. Shin HJ, Shin MO. Antimicrobial and anticarcinogenic activities of Amphitrite albicostatu Fractions. Journal of life science 2010;20(10):1505-10. 70. Choi HM, Lim SY. Fatty acid composition and antiproliferative activity of extracts from Euphorbia supine. Journal of life science 2014;24(1):1505-10. 71. Choi YH, Park JW, Lee JM, Ahn KH, Park HR, Lee SC. Antioxidant and Anticancer Activities of Methanol Extracts Prepared from Different Parts of Jangseong Daebong Persimmon (Diospyros kaki cv. Hachiya). Journal of life science 2011;24(1)1505-10. 72. Kim JH, Suh JK, Kang YH. Anticancer Effects of the Extracts of Oriental Melon (Cucumis melo L. var makuwa Makino) Seeds. Korea journal of plant research 2012;25(5):647-51. 73. Chae YH, Shin DY, Park C, Lee YT, Moon SG, Choi YH. induction of apoptosis in human colon carcinoma hct116 cells using a water extract of Lepidium virginicum L. Korea journal of society food science nutrition 2011;40(5):649-59. 74. Woo KS, Chun A, Oh SK, Kim KJ, Kim DJ, Yang CI, et al. antioxidant and antitumor activities of ethanol extracts from unhulled and hulled rice hiami (Oryza sativa L. cv. Hiami). Korea journal of society food science nutrition 2010;39(2):179-85 14
Table 1: Anti-cancer effects of traditional herbal medicine of South Korea. Scientific Name
Common Name in Korean
Common Name in English
Target Cancer
Target Cell Lines
Naematoloma sublateritium
Gaeambeoseos
Hazel mushroom
Breast cancer cells
MDA-MB-231
Scutellaria baicalensis Georgi
Hwanggeum
Skullcap
Hepatocellular carcinoma
Saussurea lappa
Moghyang
Elecampane
Redroot Gromwell
Jichi
Gromwell.
Siegesbeckia glabrescens
Rhus verniciflua
Panax ginseng
Jindeukchal
Ochnamu
Insam
-
Rhus
Ginseng
Panax ginseng
Hongsam
Red ginseng
Samsoeum
Samsoeum
Samsoeum
Target Cancer Effects
Cancer Markers
Apoptosis
JNK
Autophagy
p38 pathways.
HepG2
Anti-metastasis
FOXM1
20
Breast cancer cells
MCF-7
-
MMP-9
21
Breast cancer cells
MCF-7
metalloproteinase-9
22
Non-small cell lung cancer
H1299
Anti-migration Anti-invasion Anti-proliferation Anti-invasion
References 19
p53 p70
23
p38
Breast cancer cells
MCF-7
Cellular energy homeostasis
AMPK-pathway
Human gastric cancer cells
AGS
Apoptosis
Human colon cancer
HCT 116
Autophagy
Promyelocytic leukemia cell
APL
Anti-proliferation
MYC-SKP2-CDKN1Baxis
Human gastric cancer cells
AGS
Apoptosis
Akt/mTOR
Human fibrosarcoma
HT1080
Autophagy
activating the JNK pathway
24
p38 JNK
25
LC3-II 26 27
HSP70 cantharidin
-
-
-
-
Apoptosis
Bcl-2-associated athanogene
28
domain 3 Antrodia camphorata
Jangjibeoseos
-
Human colon carcinoma
Cell cycle arrest
β-catenin signaling
29
Anti-prolieration
protein 1
30
BT-474
Anti-proliferation
SREBP-1
HER2 expression MCF-7
Apoptosis
FAS
HT-29
Apoptosis
OSCCs Solanum Integrifolium
Hobagnamu
Silver magnolia
Oral squamous cancer
HN-22 HSC-4 HER2-overexpressing SKBR3
Piper longum
Huchu
Black pepper
Breast cancer cells
31
MDA-MB-23 Dipsacus asperoides
Ilex kudingcha C.J. Tseng (Kudingcha)
Euleumdeonggul
Gojeong
Akebi
Sickle neofinetia
Human gastric cancer cells
AGS
Human breast adenocarcinoma
MCF-7
cells
15
Apoptosis
Anti-metastasis Autophagy
caspase-3 MAPK
32
Bax Bcl-2 caspase-3 and -9
33
EGFR Siegesbeckia glabrescens
Jindeugchal
Siegesbeckia herb
Human ovarian cancer cells
SKOV-3
Anti-proliferation
VEGFR-2
34
FGFR-1 Oyaksungisan
Oyagsungisan
-
Human colon cancer cells
HCT116
Purple bamboo salt
Jajudaenamu salt
Bamboo salt
Human tongue carcinoma cells
TCA8113
Gleditsia sinensis thorns
Jogagjanamu
Piece chair wood
Breast cancer cells
SNU-5
Anti-proliferation
LC3-II
Autophagy
LC3-I/3-MA
Apoptosis
Bax Bcl-2
Cell cycle arrest
CDKs/TNF-α
Apoptosis
MMP-9
35
36
37
Bax Bamboo salt
Jugyeom
Bamboo salt
Human colon cancer cells
HCT-116
Anti-metastasis
caspase-3 and -9
Apoptosis
Bcl-2
38
mmp Bax Asiasari radix
Jogdulipul
Siebold’s wild ginger
Human colon cancer cells
HCT-116
Anti-metastasis
caspase-3 and -9
Apoptosis
Bcl-2
39
mmp Pulsatilla koreana
Halmikkoch
Wind flower
Thyroid cancer
ATC
Apoptosis
HIF-1α
Autophagy
VEGF
40
Bax Lithospermum erythrorhizon
Jacho
Red-root lithospermum
Murine melanoma
B16F10
Anti-metastasisA
caspase-3 and -9
poptosis
Bcl-2
41
mmp Korean Angelica gigas Nakai (AGN) and its major
Danggwi
Angelica
pyranocoumarin
Human breast adenocarcinoma
-
cells
-
-
42
caspases Cryptomeria japonica
Samnamu
Japan cedar
KB cells
-
Apoptosis
Bcl-2
43
Bax Artemisia princeps Pampanini cv. Sajabal
Ssug
Mugwort
Human cervical cancer
HeLa
Apoptosis
caspase-3 and -9 PARP
44
Cyclin B1 Cdc 2 Cdc 25c/ Citrus aurantium L.
Gyul
Orange
Human gastric cancer
AGS
Cell cycle arrest
procaspase-3 procaspase -6 procaspase -8 procaspase -9
16
45
Eriobotrya japonica.
Bipanamu
Korean mandolin
Murine melanoma cells
HT-1080
Human fibrosarcoma cells
B16F10
Anti-metastasis
mmP-2 mmP -9
46
caspase -3 caspase -7 Prunella vulgaris var. lilacina
Kkulpul
Self-heal
Human acute leukemia Jurkat
-
T cells
-
caspase -8 caspase -9
47
PARP Fas Cirsium japonicum
Eonggeongkwi
Thistle
Breast cancer cells
MCF-7
Apoptosis
-
48
Sipjeondaebo-tang
Sibjeondaebotang
-
CT-26 tumor-bearing mice
-
Anorexia and cachexia,
-
49
Bojungikki-tang
Bojungiggitang
Bojungiggitang
-
-
-
-
50
Glycyrrhiza uralensis
Gamcho
Licorice root
-
Apoptosis
Fas-FasL/caspase-8 pathway
51
Mogjiljinheulgbeoseos
-
Differentiation
p53
Aapoptosis
p21
Phellinus linteus grown on Panax ginseng
Kalopanax pictus leaves
Eumnamu
Cheesewood
Citrus unshiu
Gyul
Korean Orange
Venenum Bufonis
Sumso
Toad venom
Panax ginseng
Insam
Ginseng
Human acute leukemia Jurkat T cells Melanoma cell
B16F10
Human colon cancer cells
HT-29
Human stomach cancer cells
NCI-N87
Human breast cancer cells
MDA-MB231
Murine renal cell carcinoma
Cell cycle arrest Apoptosis
-
model Human lung carcinoma cells
HeLaMCF-7 HepG2
52
-
53
-
54
Apoptosis
Bax
Anti-proliferation
Bcl-2
Anti-proliferation
-
55
56
cyclin D1
Curcuma longa
Ganghwang
Curcuma
Human osteosarcoma cells
HOS
Cell cycle arrest Apoptosis
cdc2 cyclin B1
57
procaspase-3 PARP cyclinA
Strychni Semen
Mapyeoncho
Verbena
Human gastric carcinoma
AGS
cells
Cell cycle arrest
Cdc2
Apoptosis
p53
58
p21 Rhus verniciflua
Ochnamu
Rhus
Curcuma xanthorrhiza.
Ganghwang
Curcuma
Human gastric carcinoma cells ICR mice
17
AGS
Apoptosis
-
-
PI3K-Akt/PKB survival pathway ODC
59 60
p53 pRb p27 Chaga mushroom (Inonotus obliquus)
Chagabeoseos
Chaga mushroom
Human hepatoma cells
HepG2
Cell cycle arrest Apoptosis
Cdk2 Cdk 4
61
Cdk 6 Cyclin D1 Cyclin D2 Cyclin E
Solanum nigrum L.
Kkamajung
Nightshade
-
-
Acetylation of core histones
-
62
Platycodon grandiflorum.
Dolaji
Balloon flower
Melanoma cells
B16-F10
Anti-metastasis
adhesine
63
Selaginella tamariscina
Bucheoson
Purple loosestrife
-
Apoptosis
Human promyelocytic leukemia cells
caspase-3-mediated mechanism
64
ERK1/2
Ka-mi-kae-kyuk-tang
Ka-mi-kae-kyuk-tang
-
-
-
Anti-angiogenesis Apoptosis
AKT bFGF
65
KMKKT VEGF procaspase-9
Siegesbeckia glabrescens
Jindeugchal
-
MCF-7
Breast cancer cells
MDA-MB-231
Apoptosis
procaspase -3 poly(ADP-ribose)
66
polymerase (PARP) Albizzia julibrissin
Jakwinamu
Silk tree
Artemisia princeps Pamp
Yakssuk
Moxa
Human acute leukemia Jurkat T cells Ras-transformed human breast epithelial cells
18
-
Apoptosis
MCF-10A-ras
Anti-proliferation
mitochondria-dependent caspase-3 activation p21waf1/Cip
67
68
Table 2: Unknown materials of anti-cancer effects to international study Scientific Name
Common Name in Korean
Common Name in English
Target Cancer
Target Cell Lines
Target Cancer Effects
Cancer Markers
References
Amphitrite albicostatu
Ttagaebi
Barnacle
Human hepatocellular
HepG2
Cytotoxicity
Quinone reductase
69
carcinoma
Euphorbia Supina
Aegittangbindae
Spurge
Hepatocellular carcinoma
HT-29 and AGS
Cytotoxicity
-
70
Diospyros kaki cv. Hachiya
Daebonggam
Persimmon
Breast cancer cells
HT-29
Cytotoxicity
-
71
Cucumis melo L. var makuwa
Chamoe
East melons
Breast cancer cells
MCF-7
Cytotoxicity
-
72
Kongdadagnaengi
Poor man's pepper
Human colon cancer
HCT116
Apoptosis
-
73
-
74
Makino
Lepidium virginicum L.
Autophagy
Oryza sativa L. cv. Hiami
Jeongjo
Brown rice
Human hepatocellular
HepG2
carcinoma
19
Cytotoxicity
S0965-2299(15)30017-0 http://dx.doi.org/doi:10.1016/j.ctim.2015.11.004 YCTIM 1500
To appear in:
Complementary Therapies in Medicine
Received date: Revised date: Accepted date:
16-12-2014 18-7-2015 26-11-2015
Please cite this article as: Ju Hyun-Mok, Yu Kwang-Won, Cho Sung-Dae, Cheong Sun Hee, Kwon Ki Han.Anti-cancer Effects of Traditional Korean Wild Vegetables in Complementary and Alternative Medicine.Complementary Therapies in Medicine http://dx.doi.org/10.1016/j.ctim.2015.11.004 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Anti-cancer Effects of Traditional Korean Wild Vegetables in Complementary and Alternative Medicine Hyun-Mok Jua, Kwang-Won Yub, Sung-Dae Choc, Sun Hee Cheongd, and Ki Han Kwona,e* a
Division of Food Science and Nutrition, Graduate School of Biohealth Science, Gwangju University, Gwangju 503703, South Korea
b
Department of Food and Nutrition, Korea National University of Transportation, Chungbuk 368-701, South Korea
c
Department of Oral Pathology, School of Dentistry and Institute of Oral Bioscience, Chonbuk National University,
Jeonju 561-756, South Korea d
Department of Biotechnology, Konkuk University, Chungju 380-701, South Korea
e
Department of Food Science and Nutrition, College of Health, Welfare, and Education, Gwangju University, Gwangju 503-703, South Korea
*Corresponding authors: Department of Food Science and Nutrition, College of Health, Welfare, and Education, Gwangju University, 277 Hyodeok-ro, Nam-gu, Gwangju 503-703, South Korea. Tel.: +82 62-670-2708; Fax: +82 62-670-2066. E-mail address: [email protected] (K. H. Kwon)
1
Highlights
We introduce traditional Korean wild vegetables for anticancer effects.
A variety of traditional Korean wild vegetables can be used as alternative medicines.
The anticancer effects of traditional Korean medicinal plants were identified various biological markers.
Our study will be the guidelines for cancer prevention and treatment using phytochemicals.
2
ABSTRACT This research study explored the anti-cancer effects of natural materials in South Korea. Although South Korea has a long history of traditional medicine, many natural materials of South Korea have not yet been introduced to the rest of the world because of language barriers and inconsistent study conditions. In the past 3 years, 56 papers introducing 56 natural materials, which have anti-cancer effects, have been published by scientists in South Korea. Further, these studies have introduced five kinds of natural materials presented in research papers that were written in Korean and are therefore virtually unknown overseas. The anti-cancer effects were confirmed by 2-3 cancer markers in the majority of the studies, with the most common targets being breast cancer cells and gastric cancer cells. These cancers have the greatest incidence in South Korea. The natural materials studied not only exhibit anti-cancer activity but also display anti-inflammatory, anti-oxidative stress, and anti-diabetic activities. They have not yet been used for the direct treatment of disease but have potential as medicinal materials for alternative and complementary medicine for the treatment of many modern diseases. Many natural materials of South Korea are already known all over the world, and with this study, we hope to further future research to learn more about these natural medicines.
Keywords: Traditional Korean wild vegetables; Anti-cancer effects; Complementary and alternative medicine
3
1. Introduction In general, the word “cancer” refers to a malignant tumor.1 Cancer cells proliferate rapidly.2 Although all cells that make up the human body divide, cancer cells do so much more quickly than non-cancerous cells.3 Cancer is a disease in which the cancerous cells have an abnormally long life span.4 Cancer is the leading cause of death in South Korea, followed by brain diseases and heart disease.5 The cancer mortality rate has been increasing every year in South Korea.6 The leading cause of death in the world is heart disease, followed by cancer, diabetes, and chronic lung disease.7 In underdeveloped countries, the highest death rate is among infants8 and mothers9, whereas in developed countries, age-related chronic diseases, including cancer, account for the majority of deaths.10 A comparison of the leading causes of death in underdeveloped countries and developed countries could indirectly point to diseases, such as cancer, as being related to aging in advanced societies.9,10 Like many countries in East Asia, South Korea has a long-lived medical tradition. Hyangyakjipseongbang, Uibangruchue, and Donguibogam are traditional medical books representing East Asia, along with Chinese and Japanese traditional medical books.11 Among them, Donguibogam, which was written in the year 1610, has been recognized as a great medical book. The traditional medical book in South Korea represented cancer as “癰疽, Ongjeo” and introduced 70 different types of “癰疽, Ongjeo (cancer)” and medical treatments.12 Although these treatments represented a commitment to empiricism, the book is a great treasure obtained from a long tradition. The traditional medicinal books of South Korea have attempted to treat cancer with natural materials, including plants that grow in the wild. These natural plant materials have been used as effective cancer treatments since 1610.13 Although the treatments are based in empiricism, many scientists have since conducted research studies with a focus on science in complementary and alternative medicine.
2. Biochemical markers to determine anti-cancer activity In general, higher animals have tumor suppresser genes that are involved in the cell cycle, cell differentiation, and inducing cell suicide (apoptosis).10 However, if these mechanisms are disrupted, the cells may generate cancer.10, 14 When tumor suppresser genes are not expressed due to the effects of external or genetic influences, it brings about the over-proliferation of cells and cancer. p53 is a well-known tumor suppresser gene,14 and 50% of all cases of cancer are attributed to the inhibited expression of p53.15 Immortal cell division, which is normally stopped at checkpoints to resolve whether cell division should be continued or if the cells should enter apoptosis and autophagy, is the major cause of cancer development.16 When this checkpoint does not operate, cells become immortal and proliferative cancer cells.17 In general, cancer cell research is conducted to develop anti-cancer treatments, which can inhibit overproliferative cells or induce apoptosis.16, 17 The development of anti-cancer materials makes use of the cell cycle arrest pathway, inhibiting Cdk, cyclin family protein cell division, or inducing the apoptosis pathway to cause cells to 4
directly enter apoptosis.16 Cyclin D is the marker of the cell cycle, while P-Rb up-regulation prevents protein resolution preceding the G1/G0 phase. In the G2/M phase, up-regulation of the p21 and p27 proteins causes cell cycle arrest.17 Inhibition of the cell cycle through the inhibition or induction of proteins involved in cell division is a basic concept for the development of anti-cancer material.14-16 Following the same concept for promoting apoptosis, anticancer materials are typically developed by inhibiting Bcl2 and Bax, which are suppressors of apoptosis, and also by inducing p53, a regulator of apoptosis.18 Proteins related to p53, including p21, cytochrome c, the caspase family, etc., are used as targets for the development of cancer drugs.15,16 In addition, the induction of necrosis activity and the inhibition of angiogenesis activity are involved in cancer drug development.19 In modern medicine, the development of cancer drugs makes use of the activation or inhibition of anti-cancer factor proteins from drug candidate libraries.20 On the other hand, while chemical drugs are harmless by themselves, they often contain by-products produced in the mass-production process, which can create a number of side effects. In addition, some chemical drugs affect normal cells.18 These drugs are often slow to produce a cure, which causes pain for the patient and also has personal and social costs.21 The clear mechanism of action of anti-cancer substances in traditional natural materials has not yet been determined. It is too early in the study of traditional natural materials to promote them as direct anti-cancer agents, but their use has become increasingly frequent and is continuing through the intake of these natural materials for use as adjuncts in the prevention or treatment of cancer. Natural materials can help to prevent and can also cure cancer in a safer way than synthetic chemical products because plant materials are generally considered safe and have been consumed by humans for a long time.
3. Anti-cancer effects of traditional herbal medicine in South Korea A variety of natural materials that can be used as alternative medicines, including traditional plants of South Korea, has been introduced. Using plant materials of South Korea as the criteria for selection, 49 total traditional medicinal plants were identified in PubMed Central, the National Center for Biotechnology Information, and the U.S. National Library of Medicine (Table 1). Natural plant materials native to South Korea, such as ginseng, are currently being studied as alternative cancer treatments in other parts of the world. However, while many other materials have been of interest to the scientists of South Korea, they are not widely known to most people around the world. Antitumor activity was found only in accordance with the conditions of the study, where most researchers conducted research in vitro. In vivo activity should be used to confirm that the natural materials have potential anti-cancer activity. The data can be used by many researchers worldwide to study the excellent traditional material available in South Korea. Similarly, most traditional plant materials have been found to potentially be useful for anti-cancer activity studies, which test for various cancer markers, such as the induction of apoptosis and autophagy; and the inhibition of cell migration, angiogenesis, cell adhesion, and the cell cycle. After an analysis of the natural materials, 18 papers 5
were selected that identified materials that have anti-apoptotic effects, while 7, 7, 8, and 7 papers described materials involved in cell cycle arrest, anti-metastasis, anti-proliferation, and autophagy, respectively. There was also 1 paper each that presented materials regarding anti-angiogenesis, anti-migration, anti-differentiation, cellular energy homeostasis, and acetylation of core histone activity. The natural materials presented were Naematoloma sublateritium (hazel mushroom),21 Panax ginseng (ginseng),55 Samsoeum,30 cantharidin,31 Dipsacus asperoides (teasel),35 purple bamboo salt,39 Pulsatilla koreana (wind flower),43 Cryptomeria japonica (Japan cedar),46 Artemisia princeps Pampanini cv. Sajabal (mugwort),47 Cirsium japonicum (thistle),51 Venenum Bufonis (toad venom),58 Rhus verniciflua (rhus),27,62 Selaginella tamariscina (purple loosestrife),67 Siegesbeckia glabrescens (Siegesbeckia herb),26, 37, 69 and Albizzia julibrissin (silk tree).70 Naematoloma sublateritium (hazel mushroom)22 was found to induce apoptosis and autophagy through the inhibition of TNF-a expression in TNK and p38 mitogen-activated protein kinase (MARK) pathway modulations in MDA-MB-231 breast cancer cells. Panax ginseng (ginseng), Samsoeum, and Pulsatilla koreana (wind flower) showed anti-cancer effects by inducing apoptosis and autophagy. Cantharidin,31 Dipsacus asperoides,35 purple bamboo salt,39 Pulsatilla koreana (wind flower),43 Cryptomeria japonica (Japan cedar),46 Artemisia princeps Pampanini cv. Sajabal (mugwort),47 Cirsium japonicum (thistle),51 Venenum Bufonis (toad venom),58 Rhus verniciflua (rhus),27, 62 Selaginella tamariscina (purple loosestrife),67 Siegesbeckia glabrescens (Siegesbeckia herb),26, 37, 69 and Albizzia julibrissin (silk tree)69 were determined to have anti-cancer effects solely through the induction of apoptosis. The cancer markers for confirming the induction of apoptosis were the inhibition of Bax and Bcl-2 and the induction of p53 and p38 in the apoptosis pathway. p53 and other genes in its family are important therapeutic targets for a number of metabolic homeostasis disorders. p53 and its family members p63 and p73 influence cell growth and mTOR signaling, carbohydrate metabolism, cellular redox, lipid metabolism, mitochondrial maintenance, and autophagy. In pathways associated with apoptosis, p53, which maintains its inactive state in conjunction with MDM2 and MDM2 binding, is released in response to DNA damage or other stress. Activation of p53 induces the progression of the pathway to apoptosis and inhibits the cell cycle to allow adequate time for DNA repair. Bcl 2-c and Bcl-XL are important proteins that directly prevent apoptosis by inhibiting cytochrome c. Stimulation with stress, such as response cytokines, ultraviolet irradiation, heat shock, and osmotic shock in the cell cycle, induces apoptosis by p38 MARK. Further necrosis mechanisms were induced by the activation of the caspase family. Antrodia camphorate,32 Gleditsia sinensis thorns (piece chair wood),39 Citrus aurantium L. (Korean orange),48, 57
Curcuma longa (curcuma),63 Strychni semen (verbena),61 and Inonotuso bliquus (Chaga mushroom)64 were
determined to have anti-cancer effects by arresting the cell cycle. Apoptosis was induced through the inhibition of checkpoint proteins involved in the cell cycle phase. The cancer markers for confirming cell cycle arrest include the inhibition of Cyclin B1, Cdk 2, Cdk 25c, cyclin D1, and PARP. When cell cycles go beyond this phase, checkpoints lead to apoptosis and autophagy in response to external stress and DNA damage. p21, p27, p53, cyclin E, and CDK-2 are involved in the G1/G0 phase, while G2/M is associated with cyclin A and CDK-1. Specifically, the p21 protein is induced by p53, and it activates cell cycle arrest and inhibits apoptosis. p27 has dual functions. Cdk4-cyclin D1-bound 6
p27 induces cell cycle arrest by phosphorylation of pRB in the cytoplasm, while p27 induces activation of the Cdk3cyclin complex, which goes on to induce cell cycle arrest by the multi-phosphorylation of pRB. The materials confirmed to have anti-metastasis effects were Scutellaria baicalensis Georgi (skullcap),30 Ilex kudingcha C.J. Tseng (Kudingcha) (sickle neofinetia)36 bamboo salt,41 Asiasari radix (Siebold’ieboldi radix),42 Lithospermum erythrorhizon (red-root lithospermum),44 Eriobotrya japonica (Korean mandolin),49 and Platycodon grandiflorum (balloon flower).66 Bamboo salt, Asiasari radix (Siebold’ieboldi radix),42 and Lithospermum erythrorhizon (red-root lithospermum)44 were confirmed to have anti-cancer effects through apoptosis. These three materials increased the percentage of cells in the sub-G1 phase and regulated apoptotic Bax protein expression; they also exhibited downregulation of anti-apoptotic Bcl-2 family proteins. In addition, Ilex kudingcha C.J. Tseng (Kudingcha) (sickle neofinetia)36 was confirmed to have anti-cancer effects associated with it; it induced apoptosis, displayed anti-inflammatory activities with the expression of the NF-κB, iNOS, and COX-2 genes, and exerted antimetastatic effects in tumor-bearing mice by upregulating Bax, caspase-3, and caspase-9, and downregulating Bcl-2.36 Scutellaria baicalensis Georgi (skullcap),30 Eriobotrya japonica (Korean mandolin),49 and Platycodon grandiflorum (balloon flower)
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were confirmed to have only anti-metastatic effects. The induction of apoptosis was
determined by the inhibition of Bax and Bcl-2 activity, while the induction of necrosis was identified by the activation of the caspase family. Though the inhibition of angiogenesis has a close relationship with anti-metastatic activity, materials possessing such an effect have not yet been identified. All materials that exhibit anti-cancer effects were confirmed to act through the induction of apoptosis, the induction of cell cycle arrest, and the inhibition of metastasis. The anti-cancer activities of Sipjeondaebo-tang52 and Curcuma xanthorrhiza (curcuma)63 were determined in vivo. The activity of Sipjeondaebo-tang52 was verified with an analysis of the serum levels of IL-6, MCP-1, and TNF-a in CT-26 tumor-bearing mice; the activity of Curcuma xanthorrhiza (curcuma)63 was confirmed in TPA-induced mouse ear edema and ODC expression. The reasons for determining the in vivo activity of the majority of the materials were that they are new materials being considered as anti-cancer drugs (studied recently within the past 3 years). Additional in vivo confirmation of many of the materials will be required before their use as anti-cancer drugs can be approved. Samsoeum30 Oyaksungisan38 Sipjeondaebo-tang,52 and Bojungikki-tang53 are traditional herbal cocktails made by boiling various medicinal herbal plants. Such traditional herbal cocktails have been called HanYak (韓藥, Traditional Korean Medicine) and are distinguished from Chinese herbal cocktails (HanYak, 漢藥, Traditional Chinese Medicine). Despite being around for a long time in South Korea, the medicinal uses of traditional Korean medicine have not been confirmed. To address these weaknesses, studies have been performed at the Korea Institute of Oriental Medicine (Daejeon, South Korea). Bamboo salt39 and purple bamboo salt41 are not plant materials but are natural minerals instead. Bamboo salt is a powder obtained by repeatedly (nine times) baking salt at high heat in a solar salt compacted bamboo tube. However, bamboo salt has not yet been scientifically proven to be effective in improving immune, anti-inflammatory, or 7
gastrointestinal diseases. The most commonly used cancer cell lines were breast cancer cells, followed by human gastric cancer, human colon cancer, and human acute leukemia jurkat T cells. Men in South Korea experience upper gastric cancer most frequently, followed by prostate, colon, and liver cancer. The most common cancer in South Korean women is upper thyroid cancer, followed by gastric, breast, colon, and lung cancer. Because of the uniqueness of breast cancer in women, the activity of many materials for breast cancer has been confirmed.
4. Unknown materials with anti-cancer effects for international study South Korea had achieved rapid scientific growth by the end of the 20th century, especially in the field of biological technology. However, it was difficult to find advanced domestic materials that were not accompanied by the introduction of a national study. Because the level of scientists in South Korea has risen significantly enough to enable them to contribute directly to the Science Citation Index (SCI) and Science Citation Index Expand (SCIE) papers, it is rare even for native plants not to have been introduced by a national study. Therefore, only 6 materials native to South Korea were identified that had not been introduced in a national study (Table 2). The extracts of Amphitrite albicostatu (barnacle),72 Euphorbia Supina (spurge),73 and Diospyros kaki cv. Hachiya (Persimmon)74 were confirmed to have anti-cancer effects in liver and breast cancer. Because they had not yet been introduced by SCI or SCIE papers, only the cytotoxicity for their anti-cancer effect was confirmed by MTT assay without the use of other cancer markers. The results of this study do not rule out the possibility that these substances may be cytotoxic to normal cells. Presumably, ensuring only their cytotoxic effects and not checking for other cancer markers was due to insufficient cancer research. Lepidium virginicum L. (poor man's pepper)76 was determined to have apoptosis effects on human colon cancer, as confirmed by the markers Bcl-2, Bcl-XL, and caspase-3. Other papers have suggested that only the cytotoxic effects to cancer cells had been determined. Since these papers were written in Korean, their results should be confirmed with the use of other cancer markers and should be published in English.74, 77 5. Conclusion The uniqueness of South Korea’s culture and technology has spread actively around the world. However, there are still barriers to globalization because of the different letters in the Korean and English alphabets. As a result, Koreans devote a lot of time and money to learning English. However, language barriers have forced excellent research results to be rejected or to remain unknown. Traditional herbal plants of South Korea, which have effective physiological activities, have also not been introduced around the world. South Korea has a long history of traditional medicine. In medicinal books, such as Donguibogam, about 400 species of South Korean medicinal plants and their medicinal effects were confirmed. Many parts, such as the roots, stems, leaves, and flowers, have been used for various purposes. South Korea has about 4,500 species of native plants, including more than 1,000 species of trees and 3,500 species of grasses. The effects of around 1,000 of the medicinal 8
plants have been confirmed, though only 600 species are currently used in pharmacognosy. Only 50 of these species can be cultivated, and the remaining 550 species must be gathered directly from their natural habitat. In studies of the anti-cancer properties of traditional herbs in South Korea, the materials utilized in the development of cancer drugs have been based on studies about apoptosis and cell cycle arrest. Anticancer, antiinflammatory, anti-oxidative stress, and anti-diabetic materials have been actively studied in South Korea. All materials presented herein are from a number of studies, which were conducted in South Korea as well as in China and Japan. Modern society and medicine focus on preventing diseases, and natural materials have shown potential for preventive medicine. Many people have invested great efforts in consuming the healthy components of these plants, such as phytochemicals. These efforts generate a lot of interest in complementary and alternative medicine. Nevertheless, many active materials are not yet being used to treat diseases directly because they have not been extensively studied. Their potential uses as both food and functional ingredients following chemotherapy to help prevent disease and promote healing are great. In addition, a single compound that is effective against disease will require study to determine its physiological activities. There is great potential for traditional native herbal plants in America and Asia, including South Korea, as alternative and complementary medicines for treating many modern diseases, such as cancer. Due to increased interest in medicinal herbs and traditional treatments, we hope there will be support for research around the world that will lead to the introduction of the traditional herbs of South Korea. Conflict of interest statement The authors declare that there is no conflict of interest regarding the publication of this paper.
Acknowledgments This research was supported by Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education, Science and Technology (NRF-2013R1A1A4A01013550). Moreover, this study was conducted in part by research funds from Gwangju University, South Korea in 2015.
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Table 1: Anti-cancer effects of traditional herbal medicine of South Korea. Scientific Name
Common Name in Korean
Common Name in English
Target Cancer
Target Cell Lines
Naematoloma sublateritium
Gaeambeoseos
Hazel mushroom
Breast cancer cells
MDA-MB-231
Scutellaria baicalensis Georgi
Hwanggeum
Skullcap
Hepatocellular carcinoma
Saussurea lappa
Moghyang
Elecampane
Redroot Gromwell
Jichi
Gromwell.
Siegesbeckia glabrescens
Rhus verniciflua
Panax ginseng
Jindeukchal
Ochnamu
Insam
-
Rhus
Ginseng
Panax ginseng
Hongsam
Red ginseng
Samsoeum
Samsoeum
Samsoeum
Target Cancer Effects
Cancer Markers
Apoptosis
JNK
Autophagy
p38 pathways.
HepG2
Anti-metastasis
FOXM1
20
Breast cancer cells
MCF-7
-
MMP-9
21
Breast cancer cells
MCF-7
metalloproteinase-9
22
Non-small cell lung cancer
H1299
Anti-migration Anti-invasion Anti-proliferation Anti-invasion
References 19
p53 p70
23
p38
Breast cancer cells
MCF-7
Cellular energy homeostasis
AMPK-pathway
Human gastric cancer cells
AGS
Apoptosis
Human colon cancer
HCT 116
Autophagy
Promyelocytic leukemia cell
APL
Anti-proliferation
MYC-SKP2-CDKN1Baxis
Human gastric cancer cells
AGS
Apoptosis
Akt/mTOR
Human fibrosarcoma
HT1080
Autophagy
activating the JNK pathway
24
p38 JNK
25
LC3-II 26 27
HSP70 cantharidin
-
-
-
-
Apoptosis
Bcl-2-associated athanogene
28
domain 3 Antrodia camphorata
Jangjibeoseos
-
Human colon carcinoma
Cell cycle arrest
β-catenin signaling
29
Anti-prolieration
protein 1
30
BT-474
Anti-proliferation
SREBP-1
HER2 expression MCF-7
Apoptosis
FAS
HT-29
Apoptosis
OSCCs Solanum Integrifolium
Hobagnamu
Silver magnolia
Oral squamous cancer
HN-22 HSC-4 HER2-overexpressing SKBR3
Piper longum
Huchu
Black pepper
Breast cancer cells
31
MDA-MB-23 Dipsacus asperoides
Ilex kudingcha C.J. Tseng (Kudingcha)
Euleumdeonggul
Gojeong
Akebi
Sickle neofinetia
Human gastric cancer cells
AGS
Human breast adenocarcinoma
MCF-7
cells
15
Apoptosis
Anti-metastasis Autophagy
caspase-3 MAPK
32
Bax Bcl-2 caspase-3 and -9
33
EGFR Siegesbeckia glabrescens
Jindeugchal
Siegesbeckia herb
Human ovarian cancer cells
SKOV-3
Anti-proliferation
VEGFR-2
34
FGFR-1 Oyaksungisan
Oyagsungisan
-
Human colon cancer cells
HCT116
Purple bamboo salt
Jajudaenamu salt
Bamboo salt
Human tongue carcinoma cells
TCA8113
Gleditsia sinensis thorns
Jogagjanamu
Piece chair wood
Breast cancer cells
SNU-5
Anti-proliferation
LC3-II
Autophagy
LC3-I/3-MA
Apoptosis
Bax Bcl-2
Cell cycle arrest
CDKs/TNF-α
Apoptosis
MMP-9
35
36
37
Bax Bamboo salt
Jugyeom
Bamboo salt
Human colon cancer cells
HCT-116
Anti-metastasis
caspase-3 and -9
Apoptosis
Bcl-2
38
mmp Bax Asiasari radix
Jogdulipul
Siebold’s wild ginger
Human colon cancer cells
HCT-116
Anti-metastasis
caspase-3 and -9
Apoptosis
Bcl-2
39
mmp Pulsatilla koreana
Halmikkoch
Wind flower
Thyroid cancer
ATC
Apoptosis
HIF-1α
Autophagy
VEGF
40
Bax Lithospermum erythrorhizon
Jacho
Red-root lithospermum
Murine melanoma
B16F10
Anti-metastasisA
caspase-3 and -9
poptosis
Bcl-2
41
mmp Korean Angelica gigas Nakai (AGN) and its major
Danggwi
Angelica
pyranocoumarin
Human breast adenocarcinoma
-
cells
-
-
42
caspases Cryptomeria japonica
Samnamu
Japan cedar
KB cells
-
Apoptosis
Bcl-2
43
Bax Artemisia princeps Pampanini cv. Sajabal
Ssug
Mugwort
Human cervical cancer
HeLa
Apoptosis
caspase-3 and -9 PARP
44
Cyclin B1 Cdc 2 Cdc 25c/ Citrus aurantium L.
Gyul
Orange
Human gastric cancer
AGS
Cell cycle arrest
procaspase-3 procaspase -6 procaspase -8 procaspase -9
16
45
Eriobotrya japonica.
Bipanamu
Korean mandolin
Murine melanoma cells
HT-1080
Human fibrosarcoma cells
B16F10
Anti-metastasis
mmP-2 mmP -9
46
caspase -3 caspase -7 Prunella vulgaris var. lilacina
Kkulpul
Self-heal
Human acute leukemia Jurkat
-
T cells
-
caspase -8 caspase -9
47
PARP Fas Cirsium japonicum
Eonggeongkwi
Thistle
Breast cancer cells
MCF-7
Apoptosis
-
48
Sipjeondaebo-tang
Sibjeondaebotang
-
CT-26 tumor-bearing mice
-
Anorexia and cachexia,
-
49
Bojungikki-tang
Bojungiggitang
Bojungiggitang
-
-
-
-
50
Glycyrrhiza uralensis
Gamcho
Licorice root
-
Apoptosis
Fas-FasL/caspase-8 pathway
51
Mogjiljinheulgbeoseos
-
Differentiation
p53
Aapoptosis
p21
Phellinus linteus grown on Panax ginseng
Kalopanax pictus leaves
Eumnamu
Cheesewood
Citrus unshiu
Gyul
Korean Orange
Venenum Bufonis
Sumso
Toad venom
Panax ginseng
Insam
Ginseng
Human acute leukemia Jurkat T cells Melanoma cell
B16F10
Human colon cancer cells
HT-29
Human stomach cancer cells
NCI-N87
Human breast cancer cells
MDA-MB231
Murine renal cell carcinoma
Cell cycle arrest Apoptosis
-
model Human lung carcinoma cells
HeLaMCF-7 HepG2
52
-
53
-
54
Apoptosis
Bax
Anti-proliferation
Bcl-2
Anti-proliferation
-
55
56
cyclin D1
Curcuma longa
Ganghwang
Curcuma
Human osteosarcoma cells
HOS
Cell cycle arrest Apoptosis
cdc2 cyclin B1
57
procaspase-3 PARP cyclinA
Strychni Semen
Mapyeoncho
Verbena
Human gastric carcinoma
AGS
cells
Cell cycle arrest
Cdc2
Apoptosis
p53
58
p21 Rhus verniciflua
Ochnamu
Rhus
Curcuma xanthorrhiza.
Ganghwang
Curcuma
Human gastric carcinoma cells ICR mice
17
AGS
Apoptosis
-
-
PI3K-Akt/PKB survival pathway ODC
59 60
p53 pRb p27 Chaga mushroom (Inonotus obliquus)
Chagabeoseos
Chaga mushroom
Human hepatoma cells
HepG2
Cell cycle arrest Apoptosis
Cdk2 Cdk 4
61
Cdk 6 Cyclin D1 Cyclin D2 Cyclin E
Solanum nigrum L.
Kkamajung
Nightshade
-
-
Acetylation of core histones
-
62
Platycodon grandiflorum.
Dolaji
Balloon flower
Melanoma cells
B16-F10
Anti-metastasis
adhesine
63
Selaginella tamariscina
Bucheoson
Purple loosestrife
-
Apoptosis
Human promyelocytic leukemia cells
caspase-3-mediated mechanism
64
ERK1/2
Ka-mi-kae-kyuk-tang
Ka-mi-kae-kyuk-tang
-
-
-
Anti-angiogenesis Apoptosis
AKT bFGF
65
KMKKT VEGF procaspase-9
Siegesbeckia glabrescens
Jindeugchal
-
MCF-7
Breast cancer cells
MDA-MB-231
Apoptosis
procaspase -3 poly(ADP-ribose)
66
polymerase (PARP) Albizzia julibrissin
Jakwinamu
Silk tree
Artemisia princeps Pamp
Yakssuk
Moxa
Human acute leukemia Jurkat T cells Ras-transformed human breast epithelial cells
18
-
Apoptosis
MCF-10A-ras
Anti-proliferation
mitochondria-dependent caspase-3 activation p21waf1/Cip
67
68
Table 2: Unknown materials of anti-cancer effects to international study Scientific Name
Common Name in Korean
Common Name in English
Target Cancer
Target Cell Lines
Target Cancer Effects
Cancer Markers
References
Amphitrite albicostatu
Ttagaebi
Barnacle
Human hepatocellular
HepG2
Cytotoxicity
Quinone reductase
69
carcinoma
Euphorbia Supina
Aegittangbindae
Spurge
Hepatocellular carcinoma
HT-29 and AGS
Cytotoxicity
-
70
Diospyros kaki cv. Hachiya
Daebonggam
Persimmon
Breast cancer cells
HT-29
Cytotoxicity
-
71
Cucumis melo L. var makuwa
Chamoe
East melons
Breast cancer cells
MCF-7
Cytotoxicity
-
72
Kongdadagnaengi
Poor man's pepper
Human colon cancer
HCT116
Apoptosis
-
73
-
74
Makino
Lepidium virginicum L.
Autophagy
Oryza sativa L. cv. Hiami
Jeongjo
Brown rice
Human hepatocellular
HepG2
carcinoma
19
Cytotoxicity