Implications of reactive oxygen species in lung cancer and exploiting it for therapeutic interventions

Abstract

Lung cancer is the second (11.4%) most commonly diagnosed cancer and the first (18%) to cause cancer-related deaths worldwide. The incidence of lung cancer varies significantly among men, women, and high and low-middle-income countries. Air pollution, inhalable agents, and tobacco smoking are a few of the critical factors that determine lung cancer incidence and mortality worldwide. Reactive oxygen species are known factors of lung carcinogenesis resulting from the xenobiotics and their mechanistic paths are under critical investigation. Reactive oxygen species exhibit dual roles in cells, as a tumorigenic and anti-proliferative factor, depending on spatiotemporal context. During the precancerous state, ROS promotes cancer origination through oxidative stress and base-pair substitution mutations in pro-oncogenes and tumor suppressor genes. At later stages of tumor progression, they help the cancer cells in invasion, and metastases by activating the NF-kB and MAPK pathways. However, at advanced stages, when ROS exceeds the threshold, it promotes cell cycle arrest and induces apoptosis in cancer cells. ROS activates extrinsic apoptosis through death receptors and intrinsic apoptosis through mitochondrial pathways. Moreover, ROS upregulates the expression of beclin-1 which is a critical component to initiate autophagy, another form of programmed cell death. ROS is additionally involved in an intermediatory step in necroptosis, which catalyzes and accelerates this form of cell death. Various therapeutic interventions have been attempted to exploit this cytotoxic potential of ROS to treat different cancers. Growing body of evidence suggests that ROS is also associated with chemoresistance and cancer cell immunity. Considering the multiple roles of ROS, this review highlights the exploitation of ROS for various therapeutic interventions. However, there are still gaps in the literature on the dual roles of ROS and the involvement of ROS in cancer cell immunity and therapy resistance.

Discovery of a novel ROS-based signature for predicting prognosis and immunosuppressive tumor microenvironment in lung adenocarcinoma

“…In the early stages of cancer development, ROS facilitate the onset of cancer by inducing oxidative stress and causing mutations in both pro-oncogenes and genes that suppress tumors. As tumors evolve, ROS contribute to cancer cell invasion and spread by stimulating the NF-κB and MAPK signaling pathways 51 . Conversely, at very advanced disease stages, an excess of ROS can halt the cell cycle and trigger apoptosis in malignant cells.…”

“…Conversely, at very advanced disease stages, an excess of ROS can halt the cell cycle and trigger apoptosis in malignant cells. ROS initiate extrinsic apoptosis via death receptors and intrinsic apoptosis via mitochondrial routes 51 . Additionally, ROS increase levels of beclin-1, an essential autophagy initiator 52 , and participate in a critical step of necroptosis 53 .…”

“…These processes have been associated with LUAD development. Prior research indicates that ROS—molecules rich in oxygen that can damage cells in high concentrations—play a critical role in the emergence and progression of LUAD 51 . Normally, cells strike a delicate balance between ROS production and elimination.…”

Multifunctional nanoparticle-mediated combining therapy for human diseases

“… 106 At the early stage, oxidative stress (OS) initiates the pathological transformation of the physiological signaling network to induce cell oncogenic mutations; at the later stage, they drive cell proliferation by promoting the mitotic signaling cascade; when the tumor progresses to the advanced stage, ROS exceeds the critical value, promoting DNA double-strand breaks and the 8-oxodG formation and leading to apoptosis. 107 , 108 Despite the paradox, the ROS pathway still provides a strategy for developing safe and effective anticancer therapies. 109 As a result, targeting ROS in tumor cells using responsive drug delivery systems is a commonly reported approach.…”

Insulin resistance in NSCLC: unraveling the link between development, diagnosis, and treatment

“…It has been proposed that ROS can induce DNA damage, gene mutations, and apoptosis, which are all significant factors in the development of cancer ( 74 ). Furthermore, there is evidence suggesting that ROS can impact the progression and prognosis of lung cancer ( 75 ).…”