Revisiting therapeutic strategies for ovarian cancer by focusing on redox homeostasis (Review)

Abstract

Recent advances in molecular genetics have expanded our understanding of ovarian cancer. High levels of reactive oxygen species (ROS) and upregulation of antioxidant genes are common characteristic features of human cancers. This review reconsiders novel therapeutic strategies for ovarian cancer by focusing on redox homeostasis. A literature search was performed for preclinical and clinical studies published between January 1998 and October 2021 in the PubMed database using a combination of specific terms. ROS serves a central role in tumor suppression and progression by inducing DNA damage and mutations, genomic instability, and aberrant anti-and pro-tumorigenic signaling. Cancer cells increase their antioxidant capacity to neutralize the extra ROS. Additionally, antioxidants, such as CD44 variant isoform 9 (CD44v9) and nuclear factor erythroid 2-related factor 2 (Nrf2), mediate redox homeostasis in ovarian cancer. Furthermore, studies conducted on different cancer types revealed the dual role of antioxidants in tumor progression and inhibition. However, in animal models, genetic loss of antioxidant capacity in the host cannot block cancer initiation and progression. Host-derived antioxidant systems are essential to suppress carcinogenesis, suggesting that antioxidants serve a pivotal role in suppressing cancer development. By contrast, antioxidant activation in cancer cells confers aggressive phenotypes. Antioxidant inhibitors can promote cancer cell death by enhancing ROS levels. Concurrent inhibition of CD44v9 and Nrf2 may trigger apoptosis induction, potentiate chemosensitivity and enhance antitumor activities through the ROS-activated p38/p21 pathway. Antioxidants may have tumor-promoting and -suppressive functions. Therefore, an improved understanding of the role of antioxidants in redox homeostasis and developing antioxidant-specific inhibitors is necessary for treating ovarian cancer. Contents 1. Introduction 2. Search strategy and selection criteria 3. Unique redox homeostasis in cancer 4. Targeted therapy for ovarian cancer based on redox modifications 5. Conclusion

CD44 Receptor-Mediated/Reactive Oxygen Species-Sensitive Delivery of Nanophotosensitizers against Cervical Cancer Cells

“…Furthermore, they also showed that H 2 O 2 treatment induces the degradation of nanoparticles and the drug release rate was significantly increased. The fact that the ROS level is normally elevated in tumor tissue can be used as a targeting issue, and this status induces the tumor-specific degradation of nanoparticles to liberate anticancer agents [ 53 , 54 ].…”

Clinicopathological characteristics, molecular features and novel diagnostic strategies for the detection of malignant transformation of endometriosis (Review)

“…In contrast, antioxidants protect cells from DNA damage by neutralizing excess ROS (29). A sublethal dose of iron overload participates in mutagenesis and aberrant pro-tumorigenic signaling to activate cell survival and promote carcinogenesis (29,30). Thus, low to moderate oxidative stress may contribute to the development of EAOC (26,27,(29)(30)(31).…”

“…A sublethal dose of iron overload participates in mutagenesis and aberrant pro-tumorigenic signaling to activate cell survival and promote carcinogenesis (29,30). Thus, low to moderate oxidative stress may contribute to the development of EAOC (26,27,(29)(30)(31). This suggests that not only endometriosis but also conditions of iron overload, such as hemochromatosis, viral hepatitis B and C, and asbestos exposure, are risk factors for cancer development (32).…”

“…Moreover, excessive accumulation of lipid ROS triggers ferroptotic cell death in an iron-dependent manner ( 28 ). In contrast, antioxidants protect cells from DNA damage by neutralizing excess ROS ( 29 ). A sublethal dose of iron overload participates in mutagenesis and aberrant pro-tumorigenic signaling to activate cell survival and promote carcinogenesis ( 29 , 30 ).…”

“…High levels of antioxidants allow EAOC cells to escape the lethal effects of excessive oxidative stress-induced cell death. Thus, iron levels should be maintained within a narrow range to prevent endometriotic cell death, which may in turn increase the risk of cancer progression when the cellular antioxidant capacity exceeds ROS production ( 2 , 6 , 27 , 29 ).…”