Development of the plant-derived peptide lunasin as an anticancer agent Saleha B Vuyyuri 1,2 , Chris Shidal 3 and Keith R Davis 1,2 The health benefits of soy consumption have long been recognized. An important potential benefit is the linkage of soy consumption with reduced cancer risk. One emerging factor that may confer the anticancer effects of soy is the peptide lunasin. Lunasin has both chemopreventive and therapeutic activities against a variety of carcinogens and cancer types. A novel feature of lunasin is that it contains multiple functional domains that can modulate gene expression through effects on histone acetylation and integrin signaling. Recent studies suggest that lunasin effects on integrin signaling in cancer stem cells reduce expression of stemness factors with a concomitant reduction in metastatic potential. Here, we highlight recent studies of the potential use of lunasin as an anticancer agent and its mode of action. Addresses 1 Biotechnology Program, Department of Biology, Indiana University, Bloomington, IN, USA 2 Medical Sciences Program, Indiana University School of Medicine, Bloomington, IN, USA 3 Department of Pathology, Microbiology and Immunology, University of South Carolina, Columbia, SC, USA Corresponding author: Davis, Keith R (keirdavi@indiana.edu) Current Opinion in Pharmacology 2018, 41[1_TD$DIFF]:27–[2_TD$DIFF]33 This review comes from a themed issue on Cancer Edited by Elizabeth Yeh For a complete overview see the Issue and the Editorial Available online 22nd May 2018 https://doi.org/10.1016/j.coph.2018.04.006 1471-4892/ã 2018 Elsevier Ltd. All rights reserved. Introduction Plants have long been a source of medicinal compounds and major efforts have been focused on identifying plant- derived compounds for the treatment and prevention of cancer [1–3]. We have been intrigued by epidemiological studies that correlated high levels of soybean consump- tion with lowered incidence and mortality due to breast, prostate, colon and lung cancer [4–13]. The anticancer effects of soy components, particularly in breast cancer, have been attributed to secondary metabolites such as isoflavones [14–16]. Although there has been substantial effort to understand the potential anticancer effects of isoflavones, there has been little clinical success in translating this knowledge. However, it is acknowledged that not all of the anticancer effects associated with soy consumption are likely due to isoflavones [17  ]. There is now extensive evidence that a significant component of the anticancer activity of soy is due to the presence of the bioactive peptide lunasin [18–22]. Lunasin is a 44 amino acid peptide component of the 2S albumin seed protein that has three putative functional domains: an aspartic acid tail, an RGD domain, and a chromatin-binding helical domain (Figure 1)[23  ,24]. These domains all appear to be functional; the aspartic acid tail affects histone acetylation via interactions with core histones H3 and H4; the RGD domain mediates both internaliza- tion and modulation of integrin signaling; and the chro- matin-binding domain provides an immunomodulatory function [25  ,26,27,28,29,30  ,31]. Notably, one of the first biological activities attributed to lunasin was its chemopreventive activity [32,33,34  ]. Sur- prisingly, very little has been done to explore this impor- tant facet of lunasin biology. Early studies demonstrated that lunasin has the ability to suppress transformation of cultured mammalian cells by oncogenes (E1A-mediated and Ras-mediated) and chemical carcinogens 7,12- dimethylbenz(a)anthracene (DMBA) and 3-methylcho- lanthrene (MCA), as well as DMBA-induced skin tumor- igenesis in a mouse model [35–39]. A later study indicated that the ability of lunasin to inhibit foci formation in MCA and DMBA NIH/3T3 cells was enhanced when com- bined with aspirin [40]. Other than the DMBA-skin tumorigenesis study mentioned above, there is only one other in vivo chemoprevention study published. This study demonstrated that a 2-month pretreatment of nude mice with lunasin caused a 33-44% reduction in tumor incidence caused by MDA-MB-231 breast cancer cells [41]. In addition, lunasin was shown to be bioavailable and accumulated in numerous tissues, including the mammary gland. A preliminary study has indicated that dietary lunasin is bioavailable in humans [42], suggesting the potential for developing oral formulations that deliver efficacious levels of lunasin. These initial chemopreven- tion studies are promising and provide support for further studies on the potential use of lunasin as a chemopreven- tion agent. Therapeutic activity of lunasin Much of the recent research on lunasin has focused on its therapeutic activity. The cancer therapeutic activity of lunasin in both in vitro and in vivo models is quite broad and extends to lung cancer, colon cancer, leukemia, Available online at www.sciencedirect.com ScienceDirect www.sciencedirect.com Current Opinion in Pharmacology 2018, 41:27–33