**14.5. Autophagy**

a. Autophagy as a protective mechanism

A large series of anticancer drugs (both clinically approved and experimental) are able to induce a significant accumulation of autophagosomes in tumour cells both *in vitro* and *in vivo* [201]. For many years, it was thought that these therapies may kill tumours through autophagy and this massive vacuolization of the cytoplasm has been considered a manifestation of **autophagic cell death**. According to this notion, autophagy would represent another mechanism of cell death and the inhibition of autophagy would protect the cell from dying. However, this perspective is nowadays rather discredited, as the majority of the literature has reported that specific inhibition of autophagy (through siRNA) contributes to cell death during cancer treatment [202-204]. Besides, it is now well accepted that acquired resistant to chemotherapeutic drugs is, in part, due to the adaptive prosurvival response conferred by autophagy. Also, several studies have shown that inhibition of autophagy by pharmacological inhibitors such as Bafilomycin A1, cloroquine, or 3 methyladenine can enhance and accelerate cytotoxic cancer therapy in several tumours [205- 207]. In particular, some reports show that chloroquine as a single agent is sufficient to promote tumour regression in transplanted cancer models [208,209]. Moreover, chloroquine is a well-tolerated nontoxic drug that has entered a clinical trail as monotherapy for pancreatic cancer treatment [78]. This clearly indicates that the induction of autophagy represents an

attempt of the cells to cope with the stress induced by cytotoxic drugs and suggests that the inhibition of the autophagic process might be beneficial in cancer treatment.

Cell Death and Cancer, Novel Therapeutic Strategies 97

autophagy depends on various factors: energy/ATP availability, extent of the stress and the damage and presence of inhibitors of particular pathways (e. g. caspases inhibitors) [214]. ATP depletion activates autophagy, but if autophagy fails to maintain energy levels, necrosis/necroptosis results [215]. Apoptosis is usually triggered with sufficient ATP levels to trigger caspases. If the damage is severe necrosis prevails over apoptosis [216,217]. Hence, apoptosis is the first choice in most circumstances and necroptosis is triggered only as a backup alternative to guarantee that cell death takes place. However, in some cases (e.g. viral infection) TNF-mediated necroptosis predominate [218]. Apoptosis can inhibit autophagy through Bcl-2-mediated sequestration [155,156] or caspase-dependent cleavage of Beclin 1 [219,220,220], and conversely, autophagy can inhibit apoptosis by caspase-8

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

*Instituto de Biología Molecular y Celular, Universidad Miguel Hernández, Elche (Alicante), Spain* 

*Instituto de Biología Molecular y Celular, Universidad Miguel Hernández, Elche (Alicante), Spain* 

*Instituto de Biología Molecular y Celular, Universidad Miguel Hernández, Elche (Alicante), Spain* 

*Instituto de Biología Molecular y Celular, Universidad Miguel Hernández, Elche (Alicante), Spain* 

*Unidad AECC de Investigación Traslacional en Cáncer, Hospital Universitario Virgen de la* 

*Unidad de Investigación, Hospital General Universitario de Elche, Elche (Alicante), Spain* 

*Centro Nacional de Investigaciones Cardiovasculares, Departamento de Desarrollo y Reparación* 

Silvina Grasso, Estefanía Carrasco-García, Lourdes Rocamora-Reverte,

Leticia Mayor-López, Elena Tristante, Isabel Martínez-Lacaci\*

*Arrixaca, Instituto Murciano de Investigación Biosanitaria, Murcia, Spain* 

degradation [221].

**Author details** 

**15. Concluding remarks** 

personalized approach to the disease.

M. Piedad Menéndez-Gutiérrez

*Cardiovascular, Madrid, Spain* 

 \*

Corresponding Author

Pilar García-Morales and Miguel Saceda

Ángeles Gómez-Martínez and José A. Ferragut

b. Autophagy as a death mechanism

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].
