Send Orders for Reprints to [email protected] 28 Current Bioactive Compounds 2017, 13, 28-40 RESEARCH ARTICLE ISSN: 1573-4072 eISSN: 1875-6646 Ganoderma lucidum (Ling-zhi): The Impact of Chemistry on Biological Activity in Cancer Temitope O. Lawal1, Sheila M. Wicks2 and Gail B. Mahady3,* 1Department of Pharmacy Practice, Clinical Pharmacognosy Laboratories, University of Illinois at Chicago, Chicago, IL 60612, USA and Department of Pharmaceutical Microbiology, University of Ibadan, Ibadan, Nigeria; 2Department of Clinical Anatomy, City Colleges of Chicago and Rush University, Chicago, IL 60612, USA; 3Department of Phar- macy Practice, Clinical Pharmacognosy Laboratories, College of Pharmacy, University of Illinois at Chicago, Chicago, IL 60612, USA Abstract: Background: Ganoderma (Ganodermataceae), a genus of medicinal mushrooms, has been employed as an herbal medicine in Traditional Chinese medicine (TCM) for over 2000 years. The fruiting bodies have been used historically in TCM, while the mycelia, and spores are now also used as a tonic, to stimulate the immune system and treat many diseases, including cancers. Objective: To review the anti-cancer research on G. lucidum (GL) from 2005 up to May 2016 and corre- late these data with analysis of the active chemical constituents. Methods: Literature searches were performed from 2005 to May 2016 in various databases such as Pub- A R T I C L E H I S T O R Y Med, SciFinder, Napralert, and Google Scholar for peer-reviewed research literature pertaining to Gano- Received: January 23, 2016 Revised: June 2, 2016 derma lucidum and cancer. Accepted: June 9, 2016 Results: Of the >200 known Ganoderma species, only two species, G. lucidum (W. Curtis: Fr.) P. Karst DOI: 10.2174/15734072126661606140748 and G. sinense Zhao, Xu et Zhang, are officially recognized as “Ling-zhi” in the Chinese Pharmacopoeia. 01 Both species are thought to have similar biological effects. “Ling-zhi” is purported to have anticancer effects, and is also used in the promotion of health and longevity. Numerous polysaccharides and triterpe- nes have been identified in G. lucidum and have anticancer effects in both cell culture and animal models. Conclusion: The current published literature suggests that G. lucidum extracts have excellent potential for use in cancer therapy, as both the triterpenes and polysaccharides appear to have anti-cancer effects both in vitro and in vivo. However, many problems still exist including significant quality issues including taxonomy and identification of species, parts used, and the production of extracts with active constituents. Keywords: Ganoderma lucidum, Ling-zhi, Ganodermataceae, cancer, polysaccharides, triterpenes. INTRODUCTION Enzymes contained within the mushroom help to pro- mote the breakdown the wood constituents including lignins Ganoderma (Ganodermataceae), a genus of medicinal and cellulose in rotting trees [6]. In terms of distribution, mushrooms has been employed as an herbal medicine in while Ganoderma are primarily used in Asia as medicines, Traditional Chinese medicine (TCM) for over 2000 years [1- these mushrooms are also found in many countries of the 5]. The genus “Ganoderma” was named by Karsten in 1881, world, including Malaysia where they grow on rubber trees. and means "brightness or shiny", and “shiny skin” in Greek To facilitate the identification of the genus and species, [6, 7]. Ganoderma mushrooms are characterized by their many physical and geographical characteristics are used, large basidiocarps [8]. They are leather-like, and may or may including shape and color of the fruiting body, host specific- not have a stem [8]. The fruiting bodies (carpophore, myo- ity as well as place of origin [2]. carp) are generally found growing in a characteristic fan-like shape on the trunks of both live and rotting trees [6]. USE IN TRADITIONAL CHINESE MEDICINE (TCM) The medicinal use of Ganoderma, also commonly re- *Address correspondence to this author at the Director, Clinical Pharma- ferred to as “Reishi” (Japan) or “Ling-zhi” (Chinese) dates cognosy Laboratories, Department of Pharmacy Practice, College of Phar- back more than 2000 years in TCM [9]. The fruiting bodies macy, University of Illinois at Chicago, 833 South Wood St., MC 877, were used in TCM to increase energy, stimulate the immune Chicago, IL 60612, USA; Tel: 312-996-1669; Fax: 312-413-5894; E-mail: [email protected] system and to treat many diseases, including arthritis, asthma and bronchitis, heart disease, hepatitis, hypertension, nephri- 1875-6646/17 $58.00+.00 © 2017 Bentham Science Publishers Current Bioactive Compounds Anti-Cancer Activities of Ganoderma lucidum (Ling-zhi) Current Bioactive Compounds 2017, Vol. 13, No. 1 29 tis, and cancers [2-11]. The term “Ling-zhi” in China indi- ents from Ling-zhi act either additively or synergistically to cates spiritual strength and longevity, and thus Ling-zhi is produce its overall pharmacologic effects. Interestingly, the considered a powerful herbal medicine that enhances well- quantity of triterpenes present in both Ganoderma species ness and long life [2]. known as “Ling-zhi” is significantly different, and it is re- ported that G. sinense has a much lower percentage of triter- Of the >200 known Ganoderma species, only two spe- penes than G. lucidum [12-15]. cies, G. lucidum (W. Curtis: Fr.) P. Karst and G. sinense Zhao, Xu et Zhang, are officially recognized as “Ling-zhi” In the study by Da et al., [15], the chemistry of the two in the Chinese Pharmacopoeia, and research suggests that official species of Ling-zhi in the Chinese Pharmacopoeia they may have similar pharmacological effects [12]. Ling-zhi was investigated to compare the types of chemical constitu- was also mentioned in the “Classic of the Materia Medica” ents present in both G. sinense and G. lucidum. Thirty-two (502-536 AD) and a book entitled the “Ben Cao Gang Mu”, batches of commercial Ling-zhi samples were tested using which was thought to be one of the initial Chinese pharma- multiple-optimized chromatographic and spectroscopic copoeias (1590 AD) [2]. Ganoderma mushrooms are primar- methods, to determine the chemical variances between these ily cultivated in Sichuan, Zhejiang, Jiangxi and Hunan prov- species. Results from this study showed definite differences inces, although wild collection is also still performed [1]. between G. sinense and G. lucidum in terms of the types of chemical constituents present and their quantity [15]. The In TCM, Ling-zhi is a medicinal herb used for nourishing most striking difference in the chemistry was the lack of the and tonifying chi of zang organs, as well as nourishing chi most common triterpenes in G. sinense, while analysis of G. and blood [1]. Ling-zhi has also been used to treat stress, lucidum (GL), showed hundreds of triterpenes, including the weakness, as well as mental fatigue. Ling-zhi may be em- ganoderic acids (G) A, B, C2, D, F, G, H and K and gan- ployed alone, or in combination with other herbs to increase oderenic acids (GE) A-D (Fig. 1) many of which possessed its therapeutic efficacy [1]. Ling-zhi has also been used for antitumor activities. A difference in the types of polysaccha- the treatment of anxiety, heart palpitations, lack of sleep and rides contained in G. lucidum and G. sinense was not directly poor sleep quality [1]. Thus, the therapeutic effects of Ling- observed, however in the principle component analysis, a zhi include tonifying effects, energy-enhancing activities, difference in the polysaccharide content was also shown for improving heart activity, improving memory, as well as re- the two species [15]. ducing the ageing process [2]. In 2010, excerpts from the Chinese Pharmacopoeial monograph for Ling-zhi state that it In a 2012 investigation, Xie et al., [12] found similarities “acts to replenish Qi, ease the mind, and relieve cough and in the polysaccharide content of the two species of Ling-zhi asthma, and it is recommended for dizziness, insomnia, pal- that were obtained from various areas in China. Using high pitations, and shortness of breath” [2]. performance size exclusion chromatography-evaporative light scattering detection (HPSEC-ELSD) and HPSEC- Among cultivated mushrooms, Ling-zhi is unique in that MALLS-RI (multi-angle laser light scattering analyses), this it is used more as a medicinal agent rather than a food. In group showed that both experimentally generated profiles, terms of commercial production, G. lucidum (GL) products and the molecular weights of isolated polysaccharides were are available in many forms including crude drug, dried comparable. Analysis of digested polysaccharides (using the preparations, phytomedicines, and teas. Such products are enzymes pectinase and dextranase) also showed similarity in manufactured from the mycelium, and fruiting bodies of the the structures of the monosaccharides [15]. However, the mushroom. Reported therapeutic effects of Ling-zhi include polysaccharide content may not be as important as the struc- a reduction in blood sugar levels for the treatment of diabe- ture of the polysaccharides present. Polysaccharides contain tes, enhancement of immune function, liver protection, an- large numbers of single sugars (monosaccharides) that are timicrobial, as well as possible adjunct therapy for cancer. joined through O-glycoside linkages [16]. Polysaccharides The mushroom is commonly used to make soup in southern exist in two forms: homo-polysaccharides are repeating units China, and it is marketed as a botanical dietary supplement of one monosaccharide, while hetero-polysaccharides are worldwide [13]. It is purported to have anticancer effects and composed of more than two types of monosaccharides. In is also used to increase overall well being as well as increase medicinal mushrooms, the primary polysaccharides include life span. The goal of this review was to review the in vitro the glucans that contain varying kinds of glycosidic linkages, and in vivo effects of GL on cancer from 2005 up to 2016, including (1-3)-, (1-6)- glucans or (1-3)--glucans. In addi- and to correlate these data with chemical analysis of the ac- tion, heteroglycans may also occur in medicinal mushrooms.