ChemistrySelect Review doi.org/10.1002/slct.202403648 www.chemistryselect.org Generation and Application of Reactive Oxygen Radicals in Cancer Treatment Taniya Patial, [a] Niharika Sharma, [b] Kunal Sharma,* [c] and Vivek Mishra* [b] Reactive oxygen species (ROS) play a dual role in cancer, influencing both tumor growth and regression. Their intricate involvement in cellular processes underscores the necessity of maintaining a delicate ROS balance for normal cellular func- tion. Intriguingly, while ROS contribute to tumor progression, they also exhibit the potential to selectively kill cancer cells. Emerging therapeutic strategies focus on modulating ROS levels within cancer cells, considering the type of radicals generated, their site of formation, and concentration gradients. This review delves into recent advancements in understanding the impact of ROS on the tumor microenvironment and cancer treatment. By exploring the interplay between ROS dynamics and therapeutic outcomes, this study provides a comprehensive perspective on the pivotal role of oxygen-related free radicals in cancer therapy and highlights the innovative approaches and insights shaping this rapidly evolving field. 1. Introduction Cancer remains one of the most formidable and life-threatening diseases, exerting a profound impact on global public health. [ 1 ] Consequently, the prevention and treatment of cancer is one of the current areas of research. Numerous strategies have been proposed to prevent tumors from developing, growing, and spreading beyond. It is one of the worst illnesses in both economically developed and developing nations, despite ongo- ing efforts to create alternative treatments. [ 2–4] Several disease processes, including carcinogenesis, aging, as well as several problems related to cancer treatment have been linked to oxygen-free radicals. As a result, using antioxidants or free rad- ical scavengers to treat free radical-induced disease has become a popular therapeutic option. Many physiological decisions in cells are influenced by free radicals. Free radicals are known to cause DNA damage, contribute to DNA instability and muta- tion, and thus tend to support carcinogenesis because they are toxic to cellular components. ROS are Oxygen (O 2 )- derived free radicals; O 2 molecule is a biradical; however, non-radical derivatives of O 2 exist, such as H 2 O 2 . Over the last few years, compelling evidence has accumulated suggesting Oxygen free radicals (OFRs) represent a major category of carcinogens and produced aerobically by cellular respiration. [ 5–11 ] Numerous cel- lular physiological processes are impacted by free radicals. [ 12 ] Free radicals are known to induce DNA damage, contribute to [a] T. Patial Department of Chemistry, University of Delhi, New Delhi 110007, India [b] N. Sharma, Dr. V. Mishra Amity Institute of Click Chemistry Research and Studies, Amity University Uttar Pradesh, Noida, Uttar Pradesh 201313, India E-mail: vmishra@amity.edu [c] Dr. K. Sharma Department of Pharmacology, Government Medical College, Nainital, Haldwani, Uttarakhand 263139, India E-mail: doctorkunalsharma@gmail.com DNA instability and mutation, and because they are toxic to cellular components, they tend to promote carcinogenesis. ROS are free radicals formed from Oxygen (O 2 ); the O 2 molecule is biradical, however there are nonradical derivatives of O 2 , such as H 2 O 2 . [ 9,13–15 ] Inside the cells there is a diverse defense system that helps eliminate endogenous ROS overproduction using sev- eral antioxidant molecules and enzymes like glutathione (GSH). Reactive oxygen species are naturally occurring by products of cellular metabolism. Because of their highly reactive nature, it can lead to destruction of proteins, DNA, and lipids. ROS has a peculiar impact that they can induce disease while also acting as a chemotherapeutic agent. In normal cells, moderate levels of ROS are required for normal functioning and cellular pro- liferation, but overproduction leads to tumor progression. [ 16,17 ] In cancer patients, ROS is created by physical agents (ultravio- let radiation, heat) as well as by radiation and chemotherapy. When ROS production increases or the amount of ROS that are scavenged decreases, cells are considered to be under oxida- tive stress. [ 18,19] Consequently, high quantities of ROS can induce apoptosis, but chronically low levels of ROS cause a variety of diseases and carcinogenesis, depending on the degree of ROS encountered. [ 16] Thus, these cancer cells adapt to the excessive generation of ROS and maintain the redox balance by raising the levels of antioxidant processes, and variations on these oxy- gen species can be employed to induce cancer cell death. ROS play a dual role in cancer, capable of both promoting tumor growth and inducing cell death. The balance of ROS within cel- lular environments is crucial for normal cellular functions, and its dysregulation can significantly impact cancer dynamics. Several external or internal stimuli raise the ROS level, which leads to oxidative stress and the activation of signaling path- ways for programmed cell death (apoptosis), eventually resulting in cell death. [ 6,21,22 ] Figure 1 depicts the two basic activities of ROS that are critical to the therapeutic uses of nanomedicines for cancer. This review offers a novel perspective by delving into recent research that examines the modulation of ROS levels in cancer ChemistrySelect 2024, 9, e202403648 (1 of 16) © 2024 Wiley-VCH GmbH