Targeting the Interplay of Autophagy and ROS for Cancer Therapy: An Updated Overview on Phytochemicals.

Autophagy is an evolutionarily conserved self-degradation system that recycles cellular components and damaged organelles, which is critical for the maintenance of cellular homeostasis. Intracellular reactive oxygen species (ROS) are short-lived molecules containing unpaired electrons that are formed by the partial reduction of molecular oxygen. It is widely known that autophagy and ROS can regulate each other to influence the progression of cancer. Recently, due to the wide potent anti-cancer effects with minimal side effects, phytochemicals, especially those that can modulate ROS and autophagy, have attracted great interest of researchers. In this review, we afford an overview of the complex regulatory relationship between autophagy and ROS in cancer, with an emphasis on phytochemicals that regulate ROS and autophagy for cancer therapy. We also discuss the effects of ROS/autophagy inhibitors on the anti-cancer effects of phytochemicals, and the challenges associated with harnessing the regulation potential on ROS and autophagy of phytochemicals for cancer therapy.

Redox Regulation of Autophagy in Cancer: Mechanism, Prevention and Therapy.

Reactive oxygen species (ROS), products of normal cellular metabolism, play an important role in signal transduction. Autophagy is an intracellular degradation process in response to various stress conditions, such as nutritional deprivation, organelle damage and accumulation of abnormal proteins. ROS and autophagy both exhibit double-edged sword roles in the occurrence and development of cancer. Studies have shown that oxidative stress, as the converging point of these stimuli, is involved in the mechanical regulation of autophagy process. The regulation of ROS on autophagy can be roughly divided into indirect and direct methods. The indirect regulation of autophagy by ROS includes post-transcriptional and transcriptional modulation. ROS-mediated post-transcriptional regulation of autophagy includes the post-translational modifications and protein interactions of AMPK, Beclin 1, PI3K and other molecules, while transcriptional regulation mainly focuses on p62/Keap1/Nrf2 pathway. Notably, ROS can directly oxidize key autophagy proteins, such as ATG4 and p62, leading to the inhibition of autophagy pathway. In this review, we will elaborate the molecular mechanisms of redox regulation of autophagy in cancer, and discuss ROS- and autophagy-based therapeutic strategies for cancer treatment.