Autophagy and intermittent fasting: the connection for cancer therapy?

Abstract

Cancer is a leading cause of death worldwide, and its incidence is continually increasing. Although anticancer therapy has improved significantly, it still has limited efficacy for tumor eradication and is highly toxic to healthy cells. Thus, novel therapeutic strategies to improve chemotherapy, radiotherapy and targeted therapy are an important goal in cancer research. Macroautophagy (herein referred to as autophagy) is a conserved lysosomal degradation pathway for the intracellular recycling of macromolecules and clearance of damaged organelles and misfolded proteins to ensure cellular homeostasis. Dysfunctional autophagy contributes to many diseases, including cancer. Autophagy can suppress or promote tumors depending on the developmental stage and tumor type, and modulating autophagy for cancer treatment is an interesting therapeutic approach currently under intense investigation. Nutritional restriction is a promising protocol to modulate autophagy and enhance the efficacy of anticancer therapies while protecting normal cells. Here, the description and role of autophagy in tumorigenesis will be summarized. Moreover, the possibility of using fasting as an adjuvant therapy for cancer treatment, as well as the molecular mechanisms underlying this approach, will be presented.

Figure 1

Presumable molecular mechanisms induced by fasting and anticancer treatment to promote intracellular changes and autophagy induction in tumor cells. I) Fasting may oppose the Warburg effect (glucose breakdown by glycolysis even in the presence of oxygen), favoring oxidative phosphorylation in tumor cells and resulting in increased ROS production and reduced levels of lactate and possibly ATP. The increase in the ADP/ATP ratio can activate the AMPK pathway, leading to autophagy induction. Moreover, the sustained stressful environment can result in cell death induction. II) Several tumors harbor mutations that favor MAPK pathway hyperactivation, which enables tumor cell growth, survival and proliferation. Therapies targeting this pathway, as well as fasting, may result in the downregulation of this pathway alongside a reduction in AKT and mTOR activation, resulting in autophagy induction and cell death. III) Furthermore, fasting potentiates the detrimental effects of chemotherapy, such as DNA damage, thus activating the cell death machinery, deregulating pro- and antiapoptotic proteins, and inducing mitochondrial alterations and caspase activation, which in turn culminates in apoptosis.