186 Anti-Cancer Agents in Medicinal Chemistry, 2010, 10, 186-195 1871-5206/10 $55.00+.00 © 2010 Bentham Science Publishers Ltd. Silibinin – A Promising New Treatment for Cancer Catherine Wing Ying Cheung 1,* , Norma Gibbons 2 , David Wayne Johnson 1 and David Lawrence Nicol 2 Departments of Renal Medicine 1 and Urology and Transplantation 2 , University of Queensland at Princess Alexandra Hospital, Bris- bane, Queensland, Australia Abstract: Silymarin and its major constituent, Silibinin, are extracts from the medicinal plant Silybum marianum (milk thistle) and have traditionally been used for the treatment of liver diseases. Recently, these orally active, flavonoid agents have also been shown to exert significant anti-neoplastic effects in a variety of in vitro and in vivo cancer models, including skin, breast, lung, colon, bladder, prostate and kidney carcinomas. The aim of the present review is to examine the pharmacokinetics, mechanisms, effectiveness and adverse effects of silibinin’s anti-cancer actions reported to date in pre-clinical and clinical trials. The review will also discuss the results of current re- search efforts seeking to determine the extent to which the effectiveness of silibinin as an adjunct cancer treatment is influenced by such factors as histologic subtype, hormonal status, stromal interactions and drug metabolising gene polymorphisms. The results of these stud- ies may help to more precisely target and dose silibinin therapy to optimise clinical outcomes for oncology patients. Keywords: Silybin, silibinin, cancer, therapeutics, cell biology, pharmacology. INTRODUCTION The potential use of silibinin and the extract silymarin as novel anti-cancer therapies has received considerable interest over the past few years. While many studies described the mechanistic events associated with various cell biological signalling pathways and some groups have presented results where the drug has been used for phase I and II trials, these studies have largely generalised the effects of silibinin in many cancers by dealing with a limited number of cell lines and subjects without correlating the clinical parameters with the response to silibinin treatment. This review presents the current knowledge of the use of silibinin/silymarin in cancer treatment and suggests directions for new areas of research which offer a more comprehensive/holistic approach to drug inves- tigation. 1. SILIBININ AS A POTENTIAL TREATMENT FOR CAN- CER Silibinin: Traditional and Clinical Uses Seeds of the medicinal plant, Silybum marianum (milk thistle), have traditionally been used for more than 2000 years for detoxifi- cation and treatment of liver diseases [1,2] The plant’s main extract is silymarin, of which the flavonolignan silibinin (synonymous with silybin), a mixture of 2 diastereomers (A and B) (Fig. 1), is the major active constituent. Other components of silymarin include isosilibinin, dehydrosilibinin, silidianin, silichristin, taxifolin and quercetin [2] (Fig. 2). In modern medicine, there is emerging evi- dence that silymarin and silibinin have potential clinical value in the treatment of liver disorders, diabetes mellitus, mushroom poiso- ning, neurodegenerative and neurotoxic diseases, certain types of nephrotoxicity and numerous forms of cancer [2-5]. 2. BIOCHEMISTRY, CHEMISTRY AND SYNTHESIS OF SILIBININ ANALOGUES A number of synthetic analogues for silibinin has been devel- oped for improvement of therapeutic activity, hydrophilicity and scavenging/antioxidant potency. Some of these analogues have already been reviewed by Ramasamy and Agarwal [6]. Briefly, the 1-4 dixone ring system of silibinin was important in contributing anti-hepatotoxicity. The generation of synthetic compounds con- taining the 1.4-dixone ring namely 2-hydroxy-4-methoxy-3',4'-(2"- *Address correspondence to this author at the Division of Cancer Services, Princess Alexandra Hospital, Ipswich Road, Woolloongabba, Brisbane Q 4102, Australia; Tel: 61-7-3240 7329; Fax: 61-7-3240 7042; Email: catherine_cheung@health.qld.gov.au hydroxy methyl-1", 4"- dioxano) chalcone (9b) and 2-hydroxy- 4,6- dimethoxy-3', 4'-(2"-hydroxy methyl-1", 4"- dioxano) chalcone (9c) exhibited a potent activity in comparison to standard drug silybon- 70 [7]. For improving hydrophilicity and scavenging/ antioxidant activity), the 2,3 dedroxysilibinin have been synthesised [8]. Various forms of anti-cancer effects have been demonstrated in silibinin analogues. Recently, significantly greater antioxidant and TNF-alpha promoted anticancer activities of 2,3-dehydrosilybin than silibinin were found [9,10]. The more potent anti-cancer ef- fects of the analogue was related to its nature of being a more po- tent topoisomerase I inhibitor than its parental form for sensitisation to TNF-alpha induced-cytotoxicity [11] and the analogue’s ability to inhibit metalloproteinases (MMP)-2,-9, which are proteinases responsible for invasive and metastasis potentials of transformed cell [9]. Similar to synthetic analogues of silibinin, the natural analogues of silibinin also differ in their anti-cancer effects. Dietary feeding of isosilibinin (a 50:50 mixture of isosilibinin A and isosilibinin B, silymarin and silibinin to mice with human prostate cancer (PCa) DU145 xenograft showed better tumour inhibitory effect in isosilibinin-fed mice compared to silymarin- or silibinin-fed mice after 53 days of treatment [12]. A withdrawal of isosilibinin treat- ment for 24 days also showed more prolonged anti-tumour effect compared to withdrawal of silymarin and silibinin, as demonstrated by significant reduction of tumour volume in isosilibinin-treated tumour-bearing mice only [12]. Different natural analogues also exhibit efficacies in inhibiting oxidised low-density lipoprotein (oxLDL) generation and subse- quent scavenger receptor (SR) mediated monocyte adherence to oxLDL, an agent associated with high fat diet. The natural constitu- ents of silymarin extracts; silichristin (SC), silidianin (SD), silibinin (SBN), and isosilibinin (IS), were found to lower oxLDL generation in monocyte/macrophages by 60.0, 28.1, 60.0, and 30.1%, respec- tively. In this case, silichristin (SC) and silibinin (SBN) showed the highest amount of oxLDL generation compared to silidianin (SD) and isosilibinin (IS) [13]. Cell growth and cell cycle regulatory molecules in human pros- tate cancer cells have been differentially inhibited by various sily- marin constituents in human prostate cancer cells. A study on the efficacy of 7 pure flavonolignan compounds isolated from sily- marin, namely silibinin A, silibinin B, isosilibinin A, isosilibinin B, silidianin, isosilidianin, silichristin and isosilichristin, in advanced human PCa PC-3 cells was conducted. Silibinin A, silibinin B, isosilibinin A, isosilibinin B, and silymarin showed strong colony formation and cell cycle arrests by PC-3 cells, while silidianin,