Exploiting Polyphenol-Mediated Redox Reorientation in Cancer Therapy

Abstract

Polyphenol, one of the major components that exert the therapeutic effect of Chinese herbal medicine (CHM), comprises several categories, including flavonoids, phenolic acids, lignans and stilbenes, and has long been studied in oncology due to its significant efficacy against cancers in vitro and in vivo. Recent evidence has linked this antitumor activity to the role of polyphenols in the modulation of redox homeostasis (e.g., pro/antioxidative effect) in cancer cells. Dysregulation of redox homeostasis could lead to the overproduction of reactive oxygen species (ROS), resulting in oxidative stress, which is essential for many aspects of tumors, such as tumorigenesis, progression, and drug resistance. Thus, investigating the ROS-mediated anticancer properties of polyphenols is beneficial for the discovery and development of novel pharmacologic agents. In this review, we summarized these extensively studied polyphenols and discussed the regulatory mechanisms related to the modulation of redox homeostasis that are involved in their antitumor property. In addition, we discussed novel technologies and strategies that could promote the development of CHM-derived polyphenols to improve their versatile anticancer properties, including the development of novel delivery systems, chemical modification, and combination with other agents.

Keywords: ROS; cancer therapy; drug delivery; oxidative stress; polyphenol.

Figure 1

The basic structure of flavonoids and their six main subgroups. This figure was created using Kingdraw.

Figure 2

Redox homeostasis involved in cancer evolution. Reactive oxygen species (ROS) almost participate in all aspects of cancer, including initiation, proliferation, metastasis, and drug resistance. Cancer cells evolved a set of robust antioxidant system, including reducing power (e.g., NADPH), non-enzymatic and enzymatic antioxidants, and transcription factors, for adapting to oxidative stress.

Figure 3

Outlines of antioxidant properties of polyphenols in cancer therapy. Polyphenols can reinforce the transcriptional activation of the classical antioxidant transcription factor NRF2 to defend against ROS-induced DNA damage, thus preventing oxidative stress-mediated carcinogenesis. Meanwhile, polyphenols could also upregulate/activate antioxidant enzymes or activate antioxidant signaling pathways to restore intracellular homeostasis for enhancing P21-mediated cell cycle arrest and blocking the epithelial mesenchymal transition (EMT) process and matrix metalloproteinase (MMP)-mediated metastasis. In addition, polyphenols are able to manipulate the activity of antioxidant or prooxidant transcription factors, thus overcoming ROS-mediated drug resistance.

Figure 4

Prooxidant roles of polyphenols in cancer therapy. Typically, polyphenols induce glutathione (GSH) depletion, iron overload, lipid peroxidation, autophagosome augmentation, and caspase3 cleavage to trigger programmed death of cancer cells, including ferroptosis, autophagy, apoptosis, and pyroptosis. Moreover, polyphenols evoke endoplasmic reticulum (ER) stress and decrease in mitochondrial membrane potential, which could also induce cell death. On the other hand, polyphenol-induced ROS are capable of cleaving caspase3/8 9 and impairing the activities of MMP2/9, thus suppressing metastasis of cancer cell. In addition, polyphenols could inhibit the transcriptional activity of NRF2 to improve the sensitivity of cancer cells to chemotherapy.

Figure 5

Novel strategies promote the application of polyphenols in cancer therapy. Structural modifications, such as esterification, methylation, and glycosylation, protect polyphenols from rapid degradation and promote their bioactivities. Nanotechnologies can make up the inherent limitations of polyphenols and support targeting delivery of them to specific tumor lesions with minor side effects. Combination therapies achieve efficient tumor eliminate via enhanced ROS-mediated mechanisms.