Hypoxia and Oxidative Stress in the Pathogenesis of Gynecological Cancers and in Therapeutical Options

Peeter      Karihtala; Ulla      Puistola

Abstract

Reactive oxygen species (ROS) are continuously generated in living cells mainly as a consequence of aerobic metabolism. If ROS production exceeds the capacity of antioxidant systems, oxidative stress may induce damage in all cellular macromolecules. Hypoxia, derived from inappropriate and inadequate vasculature, is a characteristic of rapidly proliferating tumors. A hypoxic environment promotes ROS production which further activates hypoxia-derived pathways, e.g. those regulated by hypoxia inducible factor 1. Based on the increasing and significant amount of data available already, hypoxia and oxidative stress are widely linked to many stages of carcinogenesis. On the other hand, the effects of the major chemotherapeutics, used in the treatment of gynecological cancers, are based directly or indirectly on the excessive production of ROS and high antioxidant levels can increase resistance to these drugs. The measurement of tumor hypoxia, oxidative stress markers and antioxidant levels may become potential predictive and prognostic biomarkers in the future, as already is the case in some types of carcinomas. Either by down or upregulating ROS levels in tumor cells may provide novel pharmacological interventions in the treatment of these malignancies. There are currently several anticancer redox drugs in various phases of pre-clinical and clinical trials which will be discussed in this review.

Keywords: Antioxidant enzymes, breast cancer, chemotherapy, nitric oxide, ovarian cancer, reactive oxygen species, oxygen species, aerobic metabo-lism, superoxide anion, hydroxyl radical, peroxynitrite, mitochondrial electron, UV light, X-rays, tobacco smoking, enzymes, hypoxia, vascular system, hydrogen peroxide, normoxic, transition metals, carcinogenesis, DNA strand, tyrosine, mitochondrial electron transport, hydrolysis, lipid, neutrophils, stroma, antibody, chromatography, HPLC, monolith column, diabetes, immunohistochemical, oxygenation status, metastatic lesions, ovarian carcinomas, growth factor-1, tumor necrosis, oxidative stress, malignant cells, proliferation, cell survival, deat, cytochrome, detoxification, enzyme families, Thioredoxins, cervical cancer, antioxidant, serum levels, isoenzymes, lymphoma, non-malignant cells, tyrosine kinase receptor HER2, follicle rupture, epithelial cells, endometriosis, nonendometriotic, doxorubicin, RNA, wild-type cells, menarche, menopause, obesity, estrogen, HPV infection, squamous intraepithelial, lesions, anticancer drugs, Ototoxicity, nephrotoxicity, Tetrathiomolybdate, mitochondrial, isoform, lung, apoptosis, antioxidant suppressors, Retinoids, retinoic acid, placebo, radiotherapy regimens, thiol, colon car-cinoma cell lines, cytotoxicity, phenylethyl isothiocyanate (PEITC), polymorphism, chemoresistant regulators