Solid tumor physiology and hypoxia-induced chemo/radio-resistance: novel strategy for cancer therapy: nitric oxide donor as a therapeutic enhancer

Abstract

Hypoxia exists in solid tumor tissues due to abnormal vasculature, vascular insufficiency, treatment or malignancy related anemia, and low intratumor blood flow. Hypoxic status in solid tumor promotes accumulation of hypoxia-inducible factor-1 alpha which is promptly degraded by proteasomal ubiquitination under normoxic conditions. However, under hypoxic conditions, the ubiquitination system for HIF-1 alpha is inhibited by inactivation of prolyl hydroxylase which is responsible for hydroxylation of proline in the oxygen-dependent degradation domain of HIF-1 alpha. HIF-1 alpha is an important transcriptional factor that codes for hundreds of genes involved in erythropoiesis, angiogenesis, induction of glycolytic enzymes in tumor tissues, modulation of cancer cell cycle, cancer proliferation, and cancer metastasis. Hypoxia and accumulation of HIF-1 alpha in solid tumor tissues have been reported to associate with resistance to chemotherapy, radiotherapy, and immunotherapy and poor prognosis. Production of vascular endothelial growth factor (VEGF) in cancer cells is regulated by the activated HIF-1 mediated system. An increase in VEGF levels subsequently induces HIF-1 alpha accumulation and promotes tumor metastasis by angiogenesis. Recently, angiogenesis targeting therapy using humanized VEGF antibody and VEGF receptor tyrosine kinase inhibitors have been used in solid cancer therapy. Nitric oxide (NO) is a unique chemical gaseous molecule that plays a role as a chemical messenger involved in vasodilator, neurotransmitter, and anti-platelet aggregation. In vivo, NO is produced and released from three different isoforms of NO synthase (NOS) and from exogenously administered NO donors. In cancer science, NO has been mainly discussed as an oncogenic molecule over the past decades. However, NO has recently been noted in cancer biology associated with cancer cell apoptosis, cancer cell cycle, cancer progression and metastasis, cancer angiogenesis, cancer chemoprevention, and modulator for chemo/radio/immuno-therapy. The presence and activities of all the three isoforms of NOS and were detected in cancer tissue components such as cancer cells, tumor-associated macrophages, and vascular endothelium. Overexpression of iNOS in cancer tissues has been reported to associate with poor prognosis in patients with cancers. On the other hand, NO donors such as nitroglycerin have been demonstrated to improve the effects of cancer therapy in solid cancers. Nitroglycerin has been used safely for a long time as a potent vasodilator for the treatment of ischemic heart diseases or heart failure. Therefore, we think highly of clinical use of nitroglycerin as a novel cancer therapy in combination with anticancer drugs for improvement of cancer therapeutic levels. In this review article, we demonstrate the unique physiological characteristics of malignant solid tumors, several factors in solid tumors resulting in resistance for cancer therapies, and the effects of NO from NOS or exogenous NO-donating drugs on malignant cells. Furthermore, we refer to promising therapeutic roles of NO and NO-donating drugs for novel treatments in solid tumors.