Polyphenols as Modulator of Oxidative Stress in Cancer Disease: New Therapeutic Strategies

Abstract

Cancer onset and progression have been linked to oxidative stress by increasing DNA mutations or inducing DNA damage, genome instability, and cell proliferation and therefore antioxidant agents could interfere with carcinogenesis. It is well known that conventional radio-/chemotherapies influence tumour outcome through ROS modulation. Since these antitumour treatments have important side effects, the challenge is to develop new anticancer therapeutic strategies more effective and less toxic for patients. To this purpose, many natural polyphenols have emerged as very promising anticancer bioactive compounds. Beside their well-known antioxidant activities, several polyphenols target epigenetic processes involved in cancer development through the modulation of oxidative stress. An alternative strategy to the cytotoxic treatment is an approach leading to cytostasis through the induction of therapy-induced senescence. Many anticancer polyphenols cause cellular growth arrest through the induction of a ROS-dependent premature senescence and are considered promising antitumour therapeutic tools. Furthermore, one of the most innovative and interesting topics is the evaluation of efficacy of prooxidant therapies on cancer stem cells (CSCs). Several ROS inducers-polyphenols can impact CSCs metabolisms and self-renewal related pathways. Natural polyphenol roles, mainly in chemoprevention and cancer therapies, are described and discussed in the light of the current literature data.

Figure 1

Dual prooxidant role of ROS level in cancer cells. Prooxidant mechanisms associated with different cellular ROS levels: high levels could induce DNA damage and cell death whereas low levels could induce epigenetic alterations and senescence-like growth arrest. In the figure the classical role of ROS scavengers as antioxidants is also reported.

Figure 2

Targets of polyphenol anticancer therapies. Epigenetic pathways, cellular redox status, and cancer stem cells as therapeutic targets of polyphenol anticancer therapies as extensively discussed in the text. Depending on acute or chronic treatment a prooxidant activity may induce, respectively, high ROS-mediated cytotoxicity or low ROS-mediated cytostasis. According to the figure, several natural compounds as resveratrol, artichoke polyphenols, ginsenoside Rg-3, and quercetin induce a prooxidant apoptotic mechanism at high concentrations whereas low doses and chronic exposure trigger a ROS-epigenetic mediated cellular senescence.