Mechanisms of Hydroxyurea-Induced Cellular Senescence: An Oxidative Stress Connection?

Abstract

Hydroxyurea (HU) is a water-soluble antiproliferative agent used for decades in neoplastic and nonneoplastic conditions. HU is considered an essential medicine because of its cytoreduction functions. HU is an antimetabolite that inhibits ribonucleotide reductase, which causes a depletion of the deoxyribonucleotide pool and dramatically reduces cell proliferation. The proliferation arrest, depending on drug concentration and exposure, may promote a cellular senescence phenotype associated with cancer cell therapy resistance and inflammation, influencing neighboring cell functions, immunosuppression, and potential cancer relapse. HU can induce cellular senescence in both healthy and transformed cells in vitro, in part, because of increased reactive oxygen species (ROS). Here, we analyze the main molecular mechanisms involved in cytotoxic/genotoxic HU function, the potential to increase intracellular ROS levels, and the principal features of cellular senescence induction. Understanding the mechanisms involved in HU’s ability to induce cellular senescence may help to improve current chemotherapy strategies and control undesirable treatment effects in cancer patients and other diseases.

Watery Rose Apple: A Comprehensive Review of Its Traditional Uses, Nutritional Value, Phytochemistry, and Therapeutic Merits against Inflammation-Related Disorders

“…A state of oxidative stress is generated when the balance between ROS and cellular antioxidant enzyme levels is disturbed, resulting in potential cell damage. This oxidative stress could be a major contributor to the pathophysiology of several pathological disorders such as diabetes, inflammatory and neurodegenerative diseases, skin aging, and cancer [ 1 , 2 ]. Natural products, delivered to the human body through diet and/or exogenous food supplements and considered nonenzymatic antioxidants, have been reported to either inhibit the production of ROS and/or scavenge them, thus preventing the development of ROS-mediated diseases [ 3 – 5 ].…”

Selenylated Imidazo[1,2-a]pyridine Induces Cell Senescence and Oxidative Stress in Chronic Myeloid Leukemia Cells

“…In addition, a review study on hydroxyurea (HU), an antineoplastic drug widely used in neoplastic and non-neoplastic conditions, reported that the compound is able to reduce cell proliferation as it can induce a state of cell senescence [ 39 ]. According to some related studies, HU promotes a deficiency of proteins that regulate oxidative stress, thus contributing to the elevation of ROS and, consequently, to the establishment of cellular senescence [ 40 , 41 , 42 ].…”

Investigation of the Effect of Imatinib and Hydroxyurea Combination Therapy on Hematological Parameters and Gene Expression in Chronic Myeloid Leukemia (CML) Patients

“…The mechanism of action of HU is that it is an efficient ribonucleotide reductase (RNR) inhibitor that diminishes intracellular deoxynucleotide triphosphate pools and effects as an S-phase-specific agent with DNA synthesis suppression, which ultimately leads to cell cytotoxicity. The main reason for using this agent in leukemia patients is to reduce or prevent the growth of tumor cells in the body [ 23 ]. IM is used in a clinical setting to prevent a BCR-ABL protein from exerting its role in the oncogenic pathway in CML.…”