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.
Highlights
Hydroxyurea (HU), called hydroxycarbamide, is a simple hydroxylated compound with the molecular formula CH4N2O2, structurally an analog of urea and initially synthesized in 1869 [1,2,3,4]
HU as a nonalkylating antiproliferative agent is still used to manage a variety of disease conditions in both neoplastic and nonneoplastic settings, and it is listed as an essential medicine by WHO
This drug can function as a cytoreductive agent because of its cytostatic properties; in this sense, as is analyzed in this review, HU can induce cellular senescence in both cancer cells and nontransformed cells, which profoundly affects tumor growth and homeostatic function of normal cells
Summary
Hydroxyurea (HU), called hydroxycarbamide, is a simple hydroxylated compound with the molecular formula CH4N2O2, structurally an analog of urea and initially synthesized in 1869 [1,2,3,4]. HU has an acceptable short-term toxicity profile in most patients and is currently used as the first-line of chemotherapy in hematological malignancies such as myeloproliferative neoplasm (MPN) characterized by a mutation in Janus kinase 2 (JAK2), calreticulin (CALR), and myeloproliferative leukemia virus oncogene (MPL) genes [8,9,10,11]. This agent is indicated to treat sickle-cell anemia, HIV infection, and thrombocythemia [2, 3, 12]. Because of its positive effects of therapy, this drug is defined as an “essential medicine” by the World Health Organization [17]
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