Targeting Autophagy In Cancer Therapy

MARIA I. VACCARO; CLAUDIO D. GONZALEZ

Frontiers in Anti-Cancer Drug Discovery

Bentham Publishers

Año: 2018; p. 91 - 110

Frontiers in Anti-Cancer Drug DiscoveryTARGETING AUTOPHAGY IN CANCER THERAPYAuthor: Maria Ines Vaccaro, PhD, AGAF Institute of Biochemistry and Molecular Medicine. (CONICET) School ofPharmacy and Biochemistry, University of Buenos Aires. 956 Junin #5- 1113 Buenos Aires, ArgentinaTe. +5411 5287 4517 mvaccaro@ffyb.uba.ar ; maria.vaccaro@gmail.comCo-Author: Claudio Daniel Gonzalez, MD University Institute of the Centre for Medical Education and ClinicalResearch (CEMIC)Macroautophagy is a physiological cellular process that sequesters senescent or damaged organelles and proteinsin autophagosomes for recycling of their products. Autophagy is also involved in the removal of cells that haveundergone classical type 1 apoptosis. Hence, autophagy can be generally considered as a protector of cells againstvarious stressors and a cellular response to routine wear-and-tear. Paradoxically, autophagy may also lead to a formof non-apoptotic cell death, which is called type 2 programmed cell death. Thus, autophagy can either protect cellsor promote cell death, depending on the cellular and environmental context. So far, contradictory data are availableregarding the activity of autophagy and its regulation in cancer cells. In nonmalignant healthy tissues, autophagyseems to suppress the transition of normal to cancer cells. In addition, an exaggerated autophagy rate might driveneoplastic cells to death trough several mechanisms, many of them still to be elucidated. On the other hand,experimental evidence pointed at autophagy as a cancer cell mechanism to survive under adverse environmentalconditions, or as a defective programmed cell death mechanism that favors cancer cell resistance to treatment. Atthe end, the role of autophagy in cancer is complex and it seems to depend on histology, stage, and a plethora ofgenetic variations and epigenetic changes. The tumor surrounding micro-environment exhibits a very complex setof interactions with autophagy at cancer tissues and represents another factor able to regulate tumor cell-kineticsand growth as well as the response to therapies. In summary, while there is certainly evidence that autophagy mayact as a barrier to tumor initiation in certain tissues, there is mounting evidence that autophagy has a significant pro-tumorigenic role in established cancers. Cancer therapies, including chemotherapy, radiotherapy andimmunotherapy, are also associated with relevant changes into the autophagy intensity and flow. Someantineoplastic agents increase the autophagy rate; some other are associated with a reduction of the autophagyrate. Autophagy may modulate anticancer immunity by affecting several cellular and humoral mechanismsinvolvedat these critical processes and immunotherapeutic agents recently introduced in oncology clearly induce relevantmodifications on autophagy flow in several tumor types. In addition, it has been demonstrated that certain non-antineoplastic drugs may exert some autophagy inducing effect on cancer cells. In reverse, other agents blockautophagy flow synergizing with the effect of some antineoplastic agents. Autophagy modulation is at this momenta clear target for further developments for cancer therapy. A description of the mechanismsthat regulate autophagyin cancer cells and their surrounding micro-environment and the potential consequences of the pharmacologicallyinduced modifications of these processes constitute the main objective of this chapter.