**Acknowledgements**

growth, identifying mechanisms of this resistance such as S-nitrosylation may be a key in cancer progression and the development of chemoresistance. S-nitrosylation is reversible and seemingly a specific post-translational modification that regulates the activity of several signaling proteins. S-nitrosylation of the catalytic site cysteine in caspases serves as an on/off switch regulating caspase activity during apoptosis in endothelial cells, lymphocytes, and trophoblasts [147–149]. Targeting MPO may be a potential therapeutic intervention to reverse

It is well established that tumorigenic cells generate high levels of ROS to activate proximal signaling pathways that promote proliferation, survival and metabolic adaptation while also maintaining a high level of antioxidant activity to prevent buildup of ROS to levels that could induce cell death [160]. Moreover, there is evidence that ROS can act as secondary messengers in immune cells, which can lead to hyperactivation of inflammatory responses resulting in tissue damage and pathology [160]. Ovarian cancer is considered an ideal tumorogenic cancer

Effective immunotherapy for ovarian cancer is currently the focus of several investigations and clinical trials. Current immunotherapies for cancer treatment include therapeutic vaccines, cytokines, immune modulators, immune checkpoint inhibitors, and adoptive T cell transfer [162]. The discovery of a monoclonal antibodies (such as bevacizumab) directed against VEGF have been shown to improve progression free survival compared to cytotoxic chemotherapy alone was a major outcome of these clinical trials [163]. Other monoclonal antibodies currently approved for other cancers such as trastuzumab for breast cancer or cetuximab for colon cancer exhibited limited activity in ovarian cancer [163]. Several clinical trials are ongoing for the utilization of immune checkpoint blockade in ovarian cancer immune therapy [164]. Most recently tested were the programmed death (PD)-1 inhibitors, pembrolizumab and nivolumab, which showed a consistent response rate of 10–20% in phase 2 studies and then failed to improve outcomes in confirmatory trials [164]. Ultimately, larger phase 3 studies are needed to validate these findings for checkpoint inhibitors, particularly with regard to the duration of response seen with these agents. Additionally, the direct intraperitoneal delivery of interleukin (IL)-12, a potent immunostimulatory agent, exhibited some potential therapeutic efficacy in ovarian cancer [165]. Recently, targeting folate receptor alpha, which is found to be expressed in ovarian cancer, has shown promising therapeutic value. The targeting of the folate receptor was achieved by either a blocking monoclonal antibody (farletu-

the resistance to apoptosis in sensitive and chemoresistant EOC cells.

98 Ovarian Cancer - From Pathogenesis to Treatment

**13. Ovarian cancer immunotherapy and oxidative stress**

because ovarian cancer cells have no negative impact on immune cells [161].

zumab) or antibody conjugates of folate analogs, such as vintafolide [166].

Oxidative stress has been implicated in the pathogenesis of several malignancies including ovarian cancer. Epithelial ovarian cancer is characterized to manifest a persistent pro-oxidant

**14. Summary and conclusion**

Portions of this chapter contain material that was previously published and is used with permission from Elsevier, IOS Press, and the authors. Reprinted from *Gynecologic Oncology*, 145(3), Saed GM, Diamond MP, Fletcher NM, Updates of the role of oxidative stress in the pathogenesis of ovarian cancer, 2017 Jun;145(3):595-602, with permission from Elsevier, 2017, License number 4091940523932; Reprinted from *Gynecologic Oncology*, 116(2), Saed GM, Ali-Fehmi R, Jiang ZL, Fletcher NM, Diamond MP, Abu-Soud HM, Munkarah AR, Myeloperoxidase serves as a redox switch that regulates apoptosis in epithelial ovarian cancer, 2010 Feb;116(2):276- 81, with permission from Elsevier, 2017, License 4091940340178; Reprinted from *Free Radical Biology and Medicine*, 102, Fletcher NM, Belotte J, Saed MG, Memaj I, Diamond MP, Morris RT, Saed GM, Specific point mutations in key redox enzymes are associated with chemoresistance in epithelial ovarian cancer, 2017 Jan;102:122-132, with permission from Elsevier, 2017, License 4091940462337; Reprinted from *Gynecologic Oncology,* 122(2), Jiang Z, Fletcher NM, Ali-Fehmi R, Diamond MP, Abu-Soud HM, Munkarah AR, Saed GM, Modulation of redox signaling promotes apoptosis in epithelial ovarian cancer cells, 2011 Aug;122(2):418-23, with permission from Elsevier, 2017, License 4091940941920; Fletcher NM1, Jiang Z, Ali-Fehmi R, Levin NK, Belotte J, Tainsky MA, Diamond MP, Abu-Soud HM, Saed GM. Myeloperoxidase and free iron levels: potential biomarkers for early detection and prognosis of ovarian cancer. Reprinted from Cancer Biomark. 2011-2012;10(6):267-75 with permission from IOS Press. The final publication is available at IOS Press through http://dx.doi.org/10.3233/CBM-2012-0255.
