Send Orders of Reprints at bspsaif@emirates.net.ae 186 Current Medicinal Chemistry, 2013, 20, 186-221 0929-8673/13 $58.00+.00 © 2013 Bentham Science Publishers Assessment of the Antineoplastic Potential of Chalcones in Animal Models B.I. Roman a,c , T.S.A. Heugebaert a,c , M.E. Bracke b and C.V. Stevens* ,a a Research Group SynBioC, Department of Sustainable Organic Chemistry and Technology, Faculty of Bioscience Engineering, Ghent University, Coupure Links 653, B-9000 Ghent, Belgium; b Laboratory of Experimental Cancer Research, Department of Radiation Oncology and Experimental Cancer Research, Ghent University Hospital, De Pintelaan 185, B-9000 Ghent, Belgium; c Research Foundation – Flanders (FWO - Vlaanderen) Abstract: One part of chemical space that is endowed with interesting biological properties is the area of the chalcones. With this review, we provide a comprehensive overview of the numerous in vivo animal studies on the antineoplastic potential of both natural and synthetic members of this flavonoid subclass (covering: up to mid-2011). The thus far identified modes of action of these compounds are also dis- cussed. We hope that this overview may stimulate deeper investigations into the biochemical mechanisms by which chalcones exert their antineoplastic action. As a result, in the foreseeable future, chalcones may prove suitable lead molecules or early drug candidates for the prevention or treatment of various neoplastic diseases. Keywords: Angiogenesis, animal models, antitumor agents, cancer, cell cycle, chalcones, chemoprevention, cytotoxicity, invasion, in vivo, metastasis, mitosis, natural products, phytochemicals, xenograft experiments. INTRODUCTION In recent years, our labs have been involved in the directed de- velopment of novel anti-invasive chalcones, suitable for further advancement into drug candidates [1]. In the course of these inves- tigations, we were confronted with the problem of selecting a proper model for the in vivo evaluation of a number of appealing lead candidates. During our literature survey, we came across a significant number of papers dealing with the assessment of the in vivo antineoplastic potential of natural and unnatural chalcones in mice and rats, but it struck us that no comprehensive review of these trials had been compiled. As a consequence, we hereby pre- sent our attempt at producing such an overview, covering – to the best of our knowledge – all experiments reported to date on the in vivo anticancer effects of chalcones. CHALCONES ARE THERAPEUTICALLY RELEVANT NATURAL PRODUCTS As natural products are situated at the intersect of biological and chemical space, they constitute an evident source of therapeu- tics. Indeed, the use of natural products as pharmaceuticals dates back to the very advent of prehistoric medicine. The first docu- mented application of drugs can be found in the ‘Kahun Gynaeco- logical Papyrus’, which prescribes the use of natural materials as contraceptive agents and substances for pain management, amongst others. Even today, because of tradition and/or poverty, a substan- tial part of the world’s population (up to 80% of the inhabitants of some Asian and African countries) relies on folk medicine for pri- mary health care [2]. Empirical knowledge on herbal drugs plays a key role in such traditional healing practices, and represents a wealthy source of information for the pharmaceutical community [3]. The assets of natural substances were justly put into the spot- lights in the seminal paper of Newman and Cragg, which indicated that nature had a hand in half of the output of the pharmaceutical industry between the 1980s and today [4]. Furthermore, when zoomed in on anticancer drugs, natural products represent 14% of the oncologist’s arsenal. Combined with ‘nature inspired’ and ‘de- rived natural’ substances, not less than 57% of the anticancer drugs on the market are – at least partly – furnished by nature. 4 A compa- rable distribution was reported by Reichert for the period 1990- 2006 [5]. *Address correspondence to this author at the Research Group SynBioC, Department of Sustainable Organic Chemistry and Technology, Faculty of Bioscience Engineering, Ghent University, Coupure Links 653, B-9000 Ghent, Belgium; Tel: +32 9 264 6243; Fax: +32 9 264 6243; E-mail: Chris.Stevens@UGent.be One part of chemical space that is endowed with interesting biological properties is the area of the chalcones. This flavonoid subclass has a 1,3-diphenylpropenone moiety at its core, which can be considered a privileged scaffold. Chalcones have been the sub- ject of sizeable interest from the 1950s onward, and most certainly during the last decade (Fig. 1) [6]. In 2010 alone, over 800 papers appeared mentioning the concept ‘chalcone’. A similar upward trend, albeit with a delay of about 20 years, can be appreciated when looking at the amount of scientific output containing both the terms ‘chalcone’ and ‘cancer’. Chalcones have been found to exhibit a myriad of biological ac- tivities in vitro. Depending on their substitution pattern, they are endowed with antibacterial, antiviral, anti-inflammatory, antifungal or antiprotozoal activity, amongst others [7]. Moreover, sofalcone 1 is currently on the market as an anti-ulcer and mucoprotective drug (Fig. 2; Solon ® , Taisho Pharmaceutical Co., Ltd., Japan) and hes- peridin methyl chalcone 2 is used for the treatment of chronic ve- nous insufficiency (Cyclo3 Fort ® , Laboratoires Pierre Fabre, France). Suitably decorated chalcones have also proved potent anti- neoplastic agents. As a result, a large number of chalcones have been taken forward into animal testing. With this review, we intend to summarize the numerous in vivo animal studies on the anticancer activities of chalcones. On the one hand, this overview should help the researcher, faced with the chal- lenge of choosing a good in vivo model, in understanding which models have proven successful so far, and can thus serve as a start- ing point for the design of a new study. Indeed, the transition from in vitro assays to in vivo models rep- resents a critical step in every drug discovery process. When choos- ing an initial animal model, great care should be taken to minimize the chance for false positive and false negative outcomes. Animal strain, cell line, route of administration and treatment regimen are only a few of the interplaying factors that should match in order to obtain a satisfactory outcome. Furthermore, the choice of a suitable end point (e.g. increase in lifetime, tumor growth rate, number of metastases) is critical to be able to investigate the correlation be- tween the outcome of the study and a presumed molecular mecha- nism. On the other hand, from a medicinal chemistry perspective, we would like to provide an overview of the in vivo potency of anti- neoplastic chalcones, briefly discuss their origin, and present their putative mode of action. We will solely focus on potency, structure and molecular targets; other pharmacological properties will be discussed further throughout the text. Moreover, the effects of plant extracts containing chalcones are not incorporated into this over- view if the effect of the isolated chalcone was not determined as