Autophagy and cancer 115 Table 3. Proposed anti ‐cancer therapeutic strategy modulating autophagy Cell types Functional status Autophagy Apoptosis Normal Cancer I II III IV +: functional, -: defective + + + - - + + - + - Therapeutic strategy modulating autophagy Activation of autophagy Induction of apoptosis via inhibition of autophagy Induction of autophagic cell death via over ‐stimulation of autophagy Induction of apoptosis using genotoxic and/or metabolic stress ‐inducing anti‐cancer agents Induction of non‐apoptotic cell death using genotoxic and/or metabolic stress ‐inducing anti‐cancer agents Establishment of effective combinatorial therapeutic strategies using inhibitors of autophagy Several agents that were previously identified as inducers of autophagy (mainly by LC3-based auto- phagic assays), including thapsigargin (Høyer- Hansen et al., 2007) and imatinib (Ertmer et al., 2007), were recently reported to inhibit the lysosomal steps (autophagosomal-lysosomal fusion or lysosomal degradation) in different experimental settings (Yogalingam and Pendergast, 2008; Ganley et al., 2011). Inhibitors of autophagy (e.g., HCQ) are already being used in clinical trials along with various chemotherapeutic agents. Thus, when seeking to modulate autophagy in order to increase treatment efficacy, we should first evaluate whether the potentially co-treated anti-cancer drug increases or inhibits the autophagic flux in the target cancers. The abrogation of autophagy often tends to sensitize therapeutic agent-resistant cancer cells to various anti-cancer treatments (Chen et al., 2010). Notably, however, blocking autophagy at different steps (i.e., inhibiting the autophagosome-formation step with 3-MA versus inhibiting the autophago- some-lysosome fusion step with CQ or HCQ) can have different or even opposing outcomes. Temo- zolomide- or imatinib-induced cytotoxicity was attenuated by the inhibition of autophagy at an early stage, but augmented by inhibition of autophagy at a late stage (Kanzawa et al., 2004; Shingu et al., 2009). At present, we do not clearly understand how the inhibition of autophagy stage-specifically affects cytotoxicity. Comparative studies on the effects of various combined therapies with agents that inhibit different autophagic stages may contribute to the rational design of combined regimens against cancer. Although autophagic manipulation by inhibitors such as CQ and HCQ is already being used in clinical trials, these agents are known to have additional effects, such as immunomodulation and the possible induction of DNA damage at higher doses (Chen and Karantza, 2011). Thus, the side- effects of these autophagic inhibitors (e.g., potential induction of genomic instability, and adverse effect on the central nervous and cardiovascular systems) may make them suitable for only certain clinical situations. Furthermore, when we target the auto- phagic system for anti-cancer efforts, we must carefully consider the multifaceted nature of auto- phagy and its diverse crosstalk with other biological processes, including metabolism and the cell death pathways. Conclusion The molecular mechanisms underlying the regulation of autophagy and the role of autophagy in cancer cells are not completely understood. However, the pharmacological modulation of autophagy appears to have significant clinical potential as a novel therapeutic strategy for cancer eradication. The induction of autophagy may be useful for cancer chemoprevention in normal cells or triggering an alternative cell death mechanism in certain cancer cells, especially those with compromised apoptotic functions. In addition, suppression of the autophagic pathway may be combined with conventional antitumor regimens to achieve increased efficacy, representing a valuable therapeutic strategy for radio- and chemosensitization. In the future, we should seek to identify novel biomarkers for assessing dynamic autophagic processes and to establish new methods to assess autophagy in clinical samples. These efforts will help us understand the complicated role of autophagy in cancer and facilitate the rational design of combinatorial strategies aimed at modulating autophagy. Further- more, future efforts toward universally modulating autophagy for maximum therapeutic benefit should focus on elucidating the genetic and physiological conditions that determine the pro-survival or pro-