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

Table 1

Reactive oxygen species and hydroxyurea main functions and effects on tumorigenesis.

Function	Cellular and molecular effects	Ref.
Reactive oxygen species
Intracellular signaling pathway regulation	Cell proliferation and survival, cell motility, invasiveness, and metastasis	[140]
Senescence induction	Telomere-dependent mechanism and telomere-independent mechanism; (i) Double-strand DNA breaks induction; (ii) DNA lesions due to 8-oxo-2-deoxyguanosine generation; (iii) Genomic instability; (iv) Gene mutations implicated in the following: (a) Inhibition of tumor suppressor genes; (b) Activation of oncogenes	[143–147]
Regulation of cellular proliferation	H2O2, superoxide (O2·^-), and hydroxyl radical (OH·) reduce cell proliferation	[148, 149]
Hydroxyurea and reactive oxygen species
Cytotoxicity	Cytotoxicity and teratogenicity due to radical chain reactions, via H2O2, initiated by HU hydroxylamine group to form R-HṄOH^+ radical and generation of NO	[150, 151]
DNA damage by increasing oxidative stress	Thymidine and cytosine damage via increasing NO and H2O2 and fork collapse	[6, 45, 55, 152]
Nitric oxide generation	RNR enzyme inhibition via NO and nitrosyl radical ·NO production	[45, 153, 154]
Scavenger protein inhibition	Downregulation of superoxide dismutase-2, peroxiredoxin-1, and Sirtuins	[154–156]