Antioxidants and Therapeutic Targets in Ovarian Clear Cell Carcinoma

Abstract

Ovarian clear cell carcinomas (OCCCs) are resistant to conventional anti-cancer drugs; moreover, the prognoses of advanced or recurrent patients are extremely poor. OCCCs often arise from endometriosis associated with strong oxidative stress. Of note, the stress involved in OCCCs can be divided into the following two categories: (a) carcinogenesis from endometriosis to OCCC and (b) factors related to treatment after carcinogenesis. Antioxidants can reduce the risk of OCCC formation by quenching reactive oxygen species (ROS); however, the oxidant stress-tolerant properties assist in the survival of OCCC cells when the malignant transformation has already occurred. Moreover, the acquisition of oxidative stress resistance is also involved in the cancer stemness of OCCC. This review summarizes the recent advances in the process and prevention of carcinogenesis, the characteristic nature of tumors, and the treatment of post-refractory OCCCs, which are highly linked to oxidative stress. Although therapeutic approaches should still be improved against OCCCs, multi-combinatorial treatments including nucleic acid-based drugs directed to the transcriptional profile of each OCCC are expected to improve the outcomes of patients.

Keywords: antioxidant; cancer stemness; endometriosis; ovarian clear cell carcinoma.

Figure 1

Activating pathways and targeting proposals in ovarian clear cell carcinomas. In ovarian clear cell carcinomas, downstream of receptor tyrosine kinases (RTKs), AT-rich interactive domain 1A (ARID1A)-related chromatin remodeling factors, and genomic instability, including MSI-H, are activated. These are currently being targeted. However, other therapeutic strategies, such as nucleic acid-based drugs, RDH10, RECQL1, WRN, and HNF1B, should be targeted in the future to reduce cancer stemness, induce cancer-specific synthetic lethality, and reduce gluconeogenesis, together with a drug repositioning strategy against SOD2 anti-oxidative stress molecules.

Figure 2

Abundant retinol dehydrogenase 10 (RDH10) expression in ovarian clear cell carcinomas. In contrast to SK-OV-3, ovarian serous cell carcinoma (A), ovarian clear cell carcinoma cells, OVISE (B), and TOV-21 (C) express high levels of retinol dehydrogenase 10 (RDH10). Scale bars: 100 μm.