epigallocatechin-3-gallate (EGCG) have demon- strated chemopreventive activities in many preclinical and clinical studies (Davis 2007; Pan and Ho, 2008). Their antioxidant, anti-inflammatory, and pro-apoptotic activities appear to be important for preventing, suppressing, or reversing the develop- ment of carcinogenesis (Tan et al., 2011). Both in vitro and animal studies have demonstrated that a number of phytochemicals (curcumin, resveratrol, EGCG, sulforaphane and silibinin) show preferential cytotoxicity to malignant cancer cells over normal cells, suggesting that they might safely be used for both cancer chemoprevention and cancer therapy (Nair et al., 2007; Mann et al., 2009). Interestingly, a number of dietary phytochemicals, including quercetin, apigenin, genistein, hesperetin, and luteolin were recently shown to induce autophagy in both normal cells and several cancer cell types (Singletary and Milner, 2008; Hannigan and Gorski, 2009). Furthermore, pharmacological activation of autophagy by drugs, such as rapamycin analogs (mTOR inhibitors, (Harrison et al., 2009)), class I PI3K inhibitors (Levine and Kroemer, 2008) and metformin (an AMPK activator, (Buzzai et al., 2007)) were demonstrated to inhibit malignant transformation (Evans et al., 2005). The possibility of preventing cancer by activating autophagy is very intriguing. However, it is not yet clear whether the enhancement of autophagy is a potentially critical mechanism for the chemopreventive and/or chemotherapeutic actions of these agents. Future work will be required to determine whether the up-regulation of autophagy is a safe and effective approach for cancer prevention. Inhibiting autophagy to enhance the efficacy of anticancer therapies Despite recent advances in cancer treatment, many tumors still exhibit unsatisfactory responses to chemotherapy and/or radiation, either recurring or continuing to grow after treatment (Chen et al., 2010). Autophagy is commonly up-regulated in both tumor and normal cells exposed to cancer therapies, but the greater reliance of tumor cells (versus normal cells) on the cytoprotective effects of autophagy provides a novel therapeutic opportunity (White and DiPaola, 2009). Indeed, autophagy is induced as a pro-survival strategy in human cancer cells treated with HDAC inhibitors (Carew et al., 2007), arsenic trioxide (Smith et al., 2010), TNF-α (Moussay et al., 2011), IFN-γ (Ní Cheallaigh et al., 2011), rapamycin (Fan et al., 2010), and anti- estrogen hormonal therapy (Qadir et al., 2008), suggesting that the inhibition of autophagy could sensitize cancer cells to these therapies. Consistent Autophagy and cancer 113 with this notion, siRNA-mediated suppression of ATG5, ATG6, or ATG7 as well as co-treatment with 3-MA or bafilomycin A1 sensitized various cancer cells to various anti-cancer drugs or therapies (Chen et al., 2010). CQ derivatives act as lysosomotropic agents by increasing pH and inhibiting autophagosomal maturation (White and DiPaola, 2009). These oral drugs cross the blood-brain barrier (Amaravadi et al., 2011) and have been prescribed for malaria (O’Neill et al., 1998), rheumatoid arthritis (Kremer, 2001), and HIV (Romanelli et al., 2004), Recently, CQ and HCQ were shown to enhance the cytotoxic effects of chemotherapy or standard cancer therapy in vitro (Amaravadi et al., 2011). In addition, combined treatments with CQ or HCQ plus metabolic stressors (e.g., an angiogenesis inhibitor or 2-deoxyglucose) (Ramakrishnan et al., 2007; Dipaola et al., 2008) or targeted therapeutic drugs (e.g., imatinib, an inhibitor of Bcr-Abl) have been found to potentiate cell death (Shingu et al., 2009; Calabretta and Salomoni, 2011). HCQ is less toxic than CQ (Gunja et al., 2009) but has similar ability to induce autophagy (Amaravadi et al., 2011). Thus, multiple clinical trials are currently assessing the effects of combined treatments with various anti-cancer drugs plus HCQ for patients with various refractory malignancies (http://clinicaltrials.gov) (White and DiPaola, 2009; Levy and Thorburn, 2011). Since the pharmacological modulation of autophagy appears to enhance the efficacy of current anticancer regimens, these new combinatorial strategies may hopefully contribute to cancer eradication in the future. Induction of autophagic cell death as a therapeutic strategy Since defects in apoptosis are often observed in many solid tumor cells and can increase the resistance of tumor cells to various conventional cancer therapies, the targeting of alternative cell death pathways is an attractive strategy for improving anti-tumor therapy (Schleicher et al., 2010). Thus, the induction of cell death by autophagy may serve as a novel therapeutic strategy for eliminating cancer cells, especially those with high thresholds to apoptosis (Gozuacik and Kimchi, 2007). Although several agents, including arsenic trioxide (Kanzawa et al., 2003) and vitamin D analog EB1089 (Høyer-Hansen et al., 2005), were previously reported to induce autophagic cell death in cancer cells in vitro, in these cases, unfortunately, auto- phagic cell death was often determined based on morphological characteristics, meaning that some may not represent true autophagic cell death