br Resveratrol trihydroxy trans stilbene is
Resveratrol (3,5,4′-trihydroxy-trans-stilbene) is one of the natural polyphenols produced by several plants, including grapes, blueberries, raspberries as an immune response against to injury or pathogen attack (Frémont, 2001). By regulating diﬀerent molecular targets, it has been shown to involved in various molecular pathways such as inflammation and immunity (Park and Pezzuto, 2015; Švajger and Jeras, 2012). Moreover, a natural plant-derived product resveratrol also constitutes a good example for autophagy-modulated anti-cancer compounds through induction of cell death (Lang et al., 2015; Wang and Feng, 2015). Molecular mechanism behind the activatory eﬀect of resveratrol autophagic cell death was is highly context- and cell type-dependent as it is proposed to be able to aﬀect a vast number of signaling pathways, including Beclin-1 (Scarlatti et al., 2008a, 2008b), DAPK1 (Choi et al., 2013), TIGAR (Kumar et al., 2015), STIM1-mTOR (Selvaraj et al., 2016), PI3K-AKT (Jiang et al., 2009) and WNT/β-Catenin signaling pathways (Fu et al., 2014).
4.2.6. Polygonatum cyrtonema lectin
Polygonatum cyrtonema lectin (PCL) is a mannose/sialic acid-binding plant lectin proposed to activate programmed cell death me-chanisms, including apoptosis and autophagy in various cells, including cancer cells (Wang et al., 2011). PCL-mediated autophagy induction has been linked to PI3K-AKT pathway in murine fibrosarcoma cell line (B. Liu et al., 2010, F. Liu et al., 2010). Additionally, PCL-induced autop-hagy was also occurred through mitochondria linked ROS-p38–p53 pathway in human melanoma cells (Liu et al., 2009). Eventhough currently there is no FDA-approved applications, PCL holds a great potential as a cancer-therapeutic.
Epigallocatechin gallate (EGCG) is a major polyphenol found in green tea has been associated with the induction of Acetylcysteine arrest and apoptosis in human colorectal cancer cells (G. J. Du et al., 2012). On the other hand, a recent study suggested that EGCG suppressed apoptosis and autophagy in oral cancer cells (Irimie et al., 2015). Similarly, EGCG was also linked to increased autophagy and removal of lipids in hepatic cells which may oﬀer new therapeutic approaches for treatment of pathological liver conditions, including liver cancer (Zhou et al., 2014).
Curcumin is another natural polyphenolic compound extracted from Curcuma sp. and linked to cancer treatments due to its antioxidant ef-fects (Rahmani et al., 2014). It has been demonstrated that curcumin induced autophagic cell death in malignant glioma cells in vitro and in vivo through inhibition of AKT/mTOR/p70(S6K) pathway (Aoki et al., 2007; Shinojima et al., 2007). Additionally, curcumin-induced autop-hagy was also linked to activation of the AMPK signaling pathway in lung adenocarcinoma cells (Xiao et al., 2013). Moreover, curcumin was European Journal of Pharmaceutical Sciences 134 (2019) 116–137
found to have a role in cell death decision between apoptosis and au-tophagy through regulating several distinct mechanisms in breast cancer cells (Akkoç et al., 2015). Furthermore, curcumin analogues EF25-(GSH)2 (Zhou et al., 2014) and IHCH (Zhou et al., 2014) were also reported to have an activatory eﬀect on autophagy in liver and lung cancer cells respectively.
Allicin is an ubiquitously found ingredient in garlic and widely used as food supplement all over the world (Lawson and Wang, 2005). As a thiosulfinate, allicin can undergo a redox-reaction with thiol groups in biologically active molecules. In addition to its anti-fungal and anti-bacterial eﬀects allicin is also reported to induce cell death and inhibit proliferation in cancer cells therefore providing an important anti-tu-moral eﬀect (Borlinghaus et al., 2014). Findings also suggested that allicin induced autophagy human liver cancer cells in a p53-dependent mechanism (Chu et al., 2012).
Ginsenosides (panaxosides) are the principal bioactive constituents of ginseng. They are involved in a group of glycosylated triterpenes also known as saponins. Compounds in this family are found in the medic-inal plant Panax (ginseng) (Murthy et al., 2014). A number of diﬀerent biological activities of ginsenosides including anti-cancer eﬀects have been reported (Nag, 2012). Accumulating data also suggested that some of the anti-cancer eﬀects of ginsenosides are attributed to induction of autophagic activity in cancer cells. For example, ginsenoside F2 was shown to induce autophagy in breast cancer stem cells (Mai et al., 2012). Similarly, a ginsenoside Rb1 and its active metabolite compound K, induced autophagy through generation of reactive oxygen species (ROS) and activation of JNK in human colon cancer cells (Kim, 2013).