112 Exp. Mol. Med. Vol. 44(2), 109-120, 2012 Table 2. Preclinical studies supporting autophagy induction for cancer treatment Delayed cell death by autophagy inhibition Early step Late step siRNA Reference Cancer type Treatment Prostate cancer Phenethyl isothiocyanate Glioma Lung cancer CML Fisetin Sodium selenite Imatinib Cannabinoid β‐Lapachone Elisidepsin (PM02734) Resveratrol 3‐MA 3‐MA 3‐MA 3‐MA 3‐MA 3‐MA CQ CQ BFA BFA HCQ, E64+Pepstatin A therapy and receptor tyrosine kinase inhibition (Chen et al., 2010). In this respect, the inhibition of autophagy appears to represent a major therapeutic means for sensitizing cells to various anti-cancer therapies. Autophagy as a pro-death mechanism: autophagic cell death Under extreme stress, tumor cells with apoptosis- defective genetic backgrounds die via other mechanisms (Kondo and Kondo, 2006; Gozuacik and Kimchi, 2007). Sustained autophagic activation, which leads to turnover of proteins and organelles beyond a survival threshold, can kill some cancer cells with high apoptotic thresholds, thus enhancing treatment efficacy (Yang et al., 2011). In this case, therefore, cell death via autophagy could provide an alternative therapeutic strategy (Gozuacik and Kimchi, 2007; Eisenberg-Lerner et al., 2009). However, the concept of “autophagic cell death”, also known as type II programmed cell death (Gozuacik and Kimchi, 2004), has been the subject of some controversy. It was initially regarded as a cell death mode that included the presence of autophagosomes (Schweichel and Merker, 1973). In many cases, however, autophagy is presumably activated by dying cells as part of an unsuccessful effort to cope with stress (i.e., as a pro-survival mechanism) (Boya et al., 2005). Increases in auto- phagic markers (e.g., autophagosome accumulation and up-regulation of the LC3 II form) in dying cells following exposure to chemotherapy or molecular targeted therapeutics do not necessarily indicate increases in autophagic flux (Mizushima et al., 2010). Instead, inefficient fusion between autopha- gosomes and lysosomes or reduced lysosomal degradation might lead to massive accumulation of autophagosomes. In this case, inhibition of autophagy would accelerate cell death rather than preventing Beclin 1 ATG5 Bommareddy et al., 2009 Suh et al., 2010 ATG6, ATG7 Kim et al., 2007; Kim and Choi, 2008 ATG5 Shingu et al., 2009 ATG1, ATG5, Salazar et al., 2009 AMBRA1 ATG5, ATG6 Park et al., 2011 ATG5 Ling et al., 2011 ATG5, LC3, p62 Puissant et al., 2010 it (Boya et al., 2005). Since the term “autophagic cell death” is highly prone to misinterpretation from a purely morphological perspective, the Nomenclature Committee on Cell Death very recently suggested that the term should only be used to indicate a cell death that is mediated by autophagy, as assessed based on biochemical and functional considerations (Galluzzi et al., 2012). In other words, “autophagic cell death” should be a cell death mode that is suppressed by inhibition of autophagy by chemicals (e.g., 3-MA) and/or genetic means, such as gene knockout/mutation or RNAi targeting of essential autophagic modulators, such as AMBRA1, ATG5, ATG12 or Beclin 1 (Galluzzi et al., 2012). Recently, Shen and Codogno (2011) also defined “autophagic cell death” as a form of programmed cell death in which autophagy per se serves as a cell death mechanism, in that it is cell death by autophagy, not cell death with autophagy. They proposed that autophagic cell death should meet the following criteria: 1) the cell death occurs without apoptosis; 2) there is an increase of the autophagic flux, not just the autophagic markers, in dying cells; and 3) suppression of autophagy via both pharmacological inhibitors and genetic approaches can rescue or prevent the cell death. Such autophagic cell death has been reported during the in vivo development of D. melanogaster (Berry and Baehrecke, 2007; Denton et al., 2009) and in hippocampal neural stem cells of adult rat brain following insulin withdrawal (Yu et al., 2008). However, the in vivo evidence of autophagic cell death in mammals has been relatively limited to date. Targeting autophagy for cancer therapy Induction of autophagy for cancer prevention Various dietary phytochemicals, including β-carotene, lycopene, lutein, quercetin, resveratrol, curcumin and