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Anti-Cancer Agents in Medicinal Chemistry


ISSN (Print): 1871-5206
ISSN (Online): 1875-5992

Research Article

Anti-cancer Effects of a Neutral Triterpene Fraction from Ganoderma lucidum and its Active Constituents on SW620 Human Colorectal Cancer Cells

Author(s): Peng Li, Lingxue Liu, Sheng Huang, Yonghong Zhang, Jianhua Xu* and Zhiqiang Zhang*

Volume 20, Issue 2, 2020

Page: [237 - 244] Pages: 8

DOI: 10.2174/1871520619666191015102442

Price: $65


Background: Ganoderma lucidum (Leyss. ex Fr.) Karst. (G. lucidum, GL) belongs to the family of Ganodermataceae (Basidiomycetes), and possesses activities including antitumor, antimicrobial, antiviral, and antiaging activities. Triterpenoids are typical chemical constituents in G. lucidum, and play an important role in the anti-cancer effects. According to the substituent group at the carbon 26 position, GL total triterpenes fraction can be divided into two types, Neutral Triterpene Fraction (NTF) and an Acidic Triterpene Fraction (ATF). The anti-cancer effects of total triterpenes fraction and total acidic triterpene fraction extracted from G. lucidum have been widely known in vivo and in vitro, whereas few have focused on total neutral triterpene fraction.

Objective: The aim of this study was to evaluate the anti-cancer effects of NTF extracted from G. lucidum in vitro and in vivo and explore its anti-cancer active constituents on SW620 human colorectal cancer cells.

Methods: NTF and ATF were extracted from the dry fruiting body of G. lucidum by impregnation method with 90% ethanol, and further isolated by using alkaline extraction and acid precipitation method. The total triterpenoid content of NTF and ATF was determined by using ultraviolet-visible spectrophotometry. The cytotoxic effects on human colon cancer cells SW480, SW620, SW1116, and mouse embryonic fibroblast cell line NIH3T3 were evaluated by using the MTT method. The anti-cancer activity of NTF in vivo was evaluated in Athymic nude mice against SW620 cells. An activity-guided separation and purification process were used to identify the anti-cancer active constituents of NTF by column and preparative high-performance liquid chromatography. Structures of the constituents were confirmed by 1H-NMR, 13C-NMR and MS. Protein expression was performed by Western blotting.

Results: The percentage of total triterpenoids was 46.7% and 57.6% in ATF and NTF, respectively. Both fractions could reduce the viability of SW480, SW620, and SW1116 cells in vitro, whereby NTF exhibited a stronger effect than ATF. NTF markedly inhibited the growth of SW620 cell xenografts in mice at doses (250, 500mg/kg) during the treatment. Furthermore, a new garnoderic alcohol, named as ethyl ganoderate A and eight known ganoderic alcohols were isolated and identified from NTF by a bioassay-guided separation process. All of these compounds possessed anti-cancer activities against SW620 cells in vitro. As a representative ganoderma alcohol, ganodermanondiol significantly reduced the viability of SW620 cells through the induction of apoptosis, which was associated with the upregulated the levels of cleaved-poly (ADP-ribose) polymerase (PARP), cleaved-caspase-3, and -9. In addition, ganodermanondiol showed low cytotoxic activity against normal NIH3T3 cells.

Conclusion: NTF are potential anti-cancer agents against colon cancer and the active constituents may be ganoderic alcohols whose inhibitory mechanism of anti-cancer action may be related to the activation of a mitochondrial- dependent pathway.

Keywords: Ganoderma lucidum, anti-cancer, triterpene, cytotoxicity, in vivo, in vitro.

Graphical Abstract
Zhao, X.R.; Huo, X.K.; Dong, P.P.; Wang, C.; Huang, S.S.; Zhang, B.J.; Zhang, H.L.; Deng, S.; Liu, K.X.; Ma, X.C. Inhibitory effects of highly oxygenated lanostane derivatives from the fungus Ganoderma lucidum on P-glycoprotein and α-glucosidase. J. Nat. Prod., 2015, 78(8), 1868-1876.
[] [PMID: 26222905]
Paterson, R.R. Ganoderma - a therapeutic fungal biofactory. Phytochemistry, 2006, 67(18), 1985-2001.
[] [PMID: 16905165]
Liu, J.; Shimizu, K.; Kondo, R. The effects of ganoderma alcohols isolated from Ganoderma lucidum on the androgen receptor binding and the growth of LNCaP cells. Fitoterapia, 2010, 81(8), 1067-1072.
[] [PMID: 20603196]
Harhaji Trajković, L.M.; Mijatović, S.A.; Maksimović-Ivanić, D.D.; Stojanović, I.D.; Momcilović, M.B.; Tufegdzić, S.J.; Maksimović, V.M.; Marjanović, Z.S.; Stosić-Grujicić, S.D. Anticancer properties of Ganoderma lucidum methanol extracts in vitro and in vivo. Nutr. Cancer, 2009, 61(5), 696-707.
[] [PMID: 19838944]
Li, P.; Deng, Y.P.; Wei, X.X.; Xu, J.H. Triterpenoids from Ganoderma lucidum and their cytotoxic activities. Nat. Prod. Res, 2013, 27(1), 17-22.
[] [PMID: 22263904]
Li, P.; Shen, C.E.; Nan, T.T.; Xu, J.H. A new lanostanoid from ganoderma lucidum. Chem. Nat. Compd., 2016, 52(1), 71-73.
Gao, J.J.; Min, B.S.; Ahn, E.M.; Nakamura, N.; Lee, H.K.; Hattori, M. New triterpene aldehydes, lucialdehydes A-C, from Ganoderma lucidum and their cytotoxicity against murine and human tumor cells. Chem. Pharm. Bull. (Tokyo), 2002, 50(6), 837-840.
[] [PMID: 12045343]
Wu, J.G.; Kan, Y.J.; Wu, Y.B.; Yi, J.; Chen, T.Q.; Wu, J.Z. Hepatoprotective effect of ganoderma triterpenoids against oxidative damage induced by tert-butyl hydroperoxide in human hepatic HepG2 cells. Pharm. Biol., 2016, 54(5), 919-929.
[] [PMID: 26457919]
Gao, Y.; Zhang, R.; Zhang, J.; Gao, S.; Gao, W.; Zhang, H.; Wang, H.; Han, B. Study of the extraction process and in vivo inhibitory effect of ganoderma triterpenes in oral mucosa cancer. Molecules, 2011, 16(7), 5315-5332.
[] [PMID: 21705972]
Maiyo, F.C.; Moodley, R.; Singh, M. Cytotoxicity, antioxidant and apoptosis studies of quercetin-3-O glucoside and 4-(β-D-glucopyranosyl-1→4-α-L-rhamnopyranosyloxy)-benzyl isothiocyanate from Moringa oleifera. Anticancer. Agents Med. Chem., 2016, 16(5), 648-656.
[] [PMID: 26428271]
Hajjaj, H.; Macé, C.; Roberts, M.; Niederberger, P.; Fay, L.B. Effect of 26-oxygenosterols from Ganoderma lucidum and their activity as cholesterol synthesis inhibitors. Appl. Environ. Microbiol., 2005, 71(7), 3653-3658.
[] [PMID: 16000773]
Niedermeyer, T.H.; Lindequist, U.; Mentel, R.; Gördes, D.; Schmidt, E.; Thurow, K.; Lalk, M. Antiviral terpenoid constituents of ganoderma pfeifferi. J. Nat. Prod., 2005, 68(12), 1728-1731.
[] [PMID: 16378363]
Fujita, A.; Arisawa, M.; Saga, M.; Hayashi, T.; Morita, N. Two new lanostanoids from Ganoderma lucidum. J. Nat. Prod., 1986, 49(6), 1122-1125.
González, A.G.; León, F.; Rivera, A.; Padrón, J.I.; González-Plata, J.; Zuluaga, J.C.; Quintana, J.; Estévez, F.; Bermejo, J. New lanostanoids from the fungus Ganoderma concinna. J. Nat. Prod., 2002, 65(3), 417-421.
[] [PMID: 11908995]
Arisawa, M.; Fujita, A.; Saga, M.; Fukumura, H.; Hayashi, T.; Shimizu, M.; Morita, N. Three new lanostanoids from Ganoderma lucidum. J. Nat. Prod., 1986, 49(4), 621-625.
[] [PMID: 3783158]
Nishitoba, T.; Oda, K.; Sato, H.; Sakamura, S. Novel triterpenoids from the fungus Ganoderma lucidum. Agric. Biol. Chem., 1988, 52(2), 367-372.
Kikuchi, T.; Kanomi, S.; Kadota, S.; Murai, Y.; Tsubono, K.; Ogita, Z.I. Constituents of the fungus Ganoderma lucidum (FR.) KARST. I.: Structures of ganoderic acids C2, E, I, and K, lucidenic acid F and related compounds. Chem. Pharm. Bull. (Tokyo), 1986, 34(9), 3695-3712.
Tang, Q.J.; Ji, Z.; Hao, R.X.; Liu, Y.F.; Yang, Y.; Zhang, J.S. Inhibition of tumor cell proliferation by a neutral triterpenoid fraction from ganoderma lucidum. Acta Edulis Fungi, 2010, 17(1), 60-64.
Lu, H.; Song, J.; Jia, X.B.; Feng, L. Antihepatoma activity of the acid and neutral components from Ganoderma lucidum. Phytother. Res., 2012, 26(9), 1294-1300.
[] [PMID: 22275242]
Gao, J.J.; Hirakawa, A.; Min, B.S.; Nakamura, N.; Hattori, M. In vivo anti-cancer effects of bitter principles from the antlered form of fruiting bodies of ganoderma lucidum. J. Nat. Med., 2006, 60(1), 42-48.
Cheng, C.R.; Yue, Q.X.; Wu, Z.Y.; Song, X.Y.; Tao, S.J.; Wu, X.H.; Xu, P.P.; Liu, X.; Guan, S.H.; Guo, D.A. Cytotoxic triterpenoids from Ganoderma lucidum. Phytochemistry, 2010, 71(13), 1579-1585.
[] [PMID: 20615519]
Xiong, X.W.; Li, Y.; Li, P.; Yao, G.; Zhang, Z.Q.; Xu, J.H. Chemical constituents from fruiting body of ganoderma lucidum and their anti-cancer activity. Zhongguo Yiyuan Yaoxue Zazhi, 2015, 35(21), 1902-1906.
Zhang, Y.S.; Shen, Q.; Li, J. Traditional Chinese medicine targeting apoptotic mechanisms for esophageal cancer therapy. Acta Pharmacol. Sin., 2016, 37(3), 295-302.
[] [PMID: 26707140]
Fu, C.; Li, J.; Aipire, A.; Xia, L.; Yang, Y.; Chen, Q.; Lv, J.; Wang, X.; Li, J. Cistanche tubulosa phenylethanoid glycosides induce apoptosis in Eca-109 cells via the mitochondria-dependent pathway. Oncol. Lett., 2019, 17(1), 303-313.
[PMID: 30655768]
Herceg, Z.; Wang, Z.Q. Functions of poly(ADP-ribose) polymerase (PARP) in DNA repair, genomic integrity and cell death. Mutat. Res., 2001, 477(1-2), 97-110.
[] [PMID: 11376691]
Garg, G.; Khandelwal, A.; Blagg, B.S. Anticancer inhibitors of Hsp90 function: Beyond the usual suspects. Adv. Cancer Res., 2016, 129, 51-88.
[] [PMID: 26916001]
Zhao, X.; Wang, J.; Xiao, L.; Xu, Q.; Zhao, E.; Zheng, X.; Zheng, H.; Zhao, S.; Ding, S. Effects of 17-allylamino-17-demethoxygeldanamycin on the induction of apoptosis and cell cycle arrest in HCT-116 cells. Oncol. Lett., 2017, 14(2), 2177-2185.
[] [PMID: 28789442]
Eachkoti, R.; Reddy, M.V.R.; Lieu, Y.K.; Cosenza, S.C. Reddy, E.P. Identification and characterisation of a novel heat shock protein 90 inhibitor ONO4140. Eur. J. Cancer, 2014, 50(11), 1982-1992.
[] [PMID: 24835034]
Moser, C.; Lang, S.A.; Kainz, S.; Gaumann, A.; Fichtner-Feigl, S.; Koehl, G.E.; Schlitt, H.J.; Geissler, E.K.; Stoeltzing, O. Blocking heat shock protein-90 inhibits the invasive properties and hepatic growth of human colon cancer cells and improves the efficacy of oxaliplatin in p53-deficient colon cancer tumors in vivo. Mol. Cancer Ther., 2007, 6(11), 2868-2878.
[] [PMID: 18025273]
Mason, T.J.; Matthews, M. Aquatic environment, housing, and management in the eighth edition of the guide for the care and use of laboratory animals: Additional considerations and recommendations. J. Am. Assoc. Lab. Anim. Sci, 2012, 51(3), 329-332.
[PMID: 22776190]

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