**15. Concluding remarks**

96 Apoptosis and Medicine

self-digestion.

b. Autophagy as a death mechanism

attempt of the cells to cope with the stress induced by cytotoxic drugs and suggests that the

Although there is robust evidence indicating that autophagy has a protective role in cancer therapeutics, in certain cancer treatments, autophagy can kill cells by inducing **autophagic cell death**. For example, Abe and colleagues have demonstrated that harmol, a β-carboline alkaloid, triggered autophagic cell death in human lung carcinoma A549 cells without activation of caspase-3, caspase-8, or caspase-9 or PARP cleavage. Autophagy, but not apoptosis, was detected by electron microscopy in these cancer cells. Furthermore, pretreatment of A549 cells with the autophagy inhibitor 3-methyladenine or siRNAmediated knockdown of LC3 suppressed harmol-induced cell death [210]. Another study shows that L929 fibrosarcoma cells die in a caspase-independent manner involving autophagy and that ATG genes are required for this cell death process [211]. In this model, caspase inhibition induces the selective autophagic degradation of catalase, a major ROS scavenger, and the resulting ROS accumulation promotes autophagic cell death [212].

Autophagy is a process that allows cells to escape death or paradoxically leads to cell death. It is not yet understood what factors determine whether autophagy is cytoprotective or cytotoxic. It has been suggested that autophagy induced under pathological conditions functions as an adaptive cell response, allowing the cell to survive bioenergetic stress. However, autophagy is a process that destroys cellular content and organelles. In this way, it has been suggested that deregulated, excessive or persistent autophagy may lead to autophagic cell death. That is, the destruction of proteins and organelles may pass a threshold, leading to cell death. However, the point at which autophagy becomes autophagic cell death remains unclear. In this perspective, the dissection of the transition from autophagy to autophagic cell death and the cross-talking between apoptosis and autophagy may help to understand this process, leading to more efficacious treatments in cancer. In contrast, a different study has reported that when cells are subjected to prolonged growth factor deprivation or shortage of glucose and oxygen they can lose the majority of their mass via autophagy. However, when these cells are placed in optimal culture conditions, they are able to fully recover [163,213]. This result suggests that cell death via autophagy may not be simply a matter of crossing a quantitative threshold of

inhibition of the autophagic process might be beneficial in cancer treatment.

**14.6. What determines if autophagy is cytoprotective or cytotoxic?** 

**14.7. Interplay among apoptosis, necrosis/necroptosis and autophagy** 

Cell death process *in vivo* involves a complex interaction among apoptosis, necrosis/necroptosis and autophagy [78]. In some situations, a specific stimulus triggers only one mechanism, but in other cases, the same stimulus can evoke more than one cell demise machinery. Therefore, several mechanisms can coexist within a cell, but only one will predominate over the others. The decision to undergo apoptosis, necrosis/necroptosis or Programmed cell death mechanisms are intricate and usually interconnected processes. Evasion of cell death is a common feature of cancer cells leading to chemoresistance. Apoptosis, necrosis/necroptosis and autophagy are the main explored pathways that had gained interest among cancer biologists, as means to develop novel cancer therapeutics. Deeping our knowledge on the nexus between cell death and cancer will enable us to predict in a more refined manner the carcinogenic process and therefore, pave the way for a personalized approach to the disease.
