Abstract
Reactive oxygen species (ROS) and their products are components of cell signaling pathways and play important roles in cellular physiology and pathophysiology. Under physiological conditions, cells control ROS levels by the use of scavenging systems such as superoxide dismutases, peroxiredoxins, and glutathione that balance ROS generation and elimination. Under oxidative stress conditions, excessive ROS can damage cellular proteins, lipids, and DNA, leading to cell damage that may contribute to carcinogenesis. Several studies have shown that cancer cells display an adaptive response to oxidative stress by increasing expression of antioxidant enzymes and molecules. As a double-edged sword, ROS influence signaling pathways determining beneficial or detrimental outcomes in cancer therapy. In this review, we address the role of redox homeostasis in cancer growth and therapy and examine the current literature regarding the redox regulatory systems that become upregulated in cancer and their role in promoting tumor progression and resistance to chemotherapy.
Highlights
Barbara Marengo,1 Mariapaola Nitti,1 Anna Lisa Furfaro,2 Renata Colla,1 Chiara De Ciucis,1 Umberto Maria Marinari,1 Maria Adelaide Pronzato,1 Nicola Traverso,1 and Cinzia Domenicotti1
Cancer cells with high levels of nuclear factor erythroid 2-related factor 2 (Nrf2) have been shown to be less sensitive to etoposide, cisplatin, and doxorubicin [203] and our studies demonstrated that activation of Nrf2 and of its target genes plays a key role in the resistance of neuroblastoma cells to GSH depletion or proteasome inhibition [85, 204]
Our studies have demonstrated that BSO-induced Reactive oxygen species (ROS) overproduction and apoptosis of neuroblastoma cells is mediated by PKCδ activation [69,70,71,72] which is crucial for the sensitization of cancer cells to BSO and to etoposide [156]
Summary
Reactive oxygen species (ROS) are highly reactive molecules that are principally derived from the oxygen that is consumed in various metabolic reactions occurring mainly in the mitochondria, peroxisomes, and the endoplasmic reticulum. Thioredoxins (Trxs) protect cells from oxidative stress by means of their 2-cysteine active site that reacts with ROS and is able to reduce oxidized proteins They serve as hydrogen donors to the thioredoxin-dependent peroxide reductases. It has been recently demonstrated that the response of myeloma cells to bortezomib could be due to the noncanonical functions of HO1 which translocates to the nucleus where it plays a role in genetic instability, favoring cancer progression independently of its enzymatic activity [65] Within this context, the nuclear localization of HO-1 has been demonstrated to be involved in the gain of resistance to other chemotherapeutic agents such as imatinib in chronic myeloid leukemia [66]. These findings open up a new scenario of the role of HO-1 in cancer cell biology
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