Nitric Oxide: Friend or Foe in Cancer Chemotherapy and Drug Resistance: A Perspective

Abstract

A successful treatment of cancers in the clinic has been difficult to achieve because of the emergence of drug resistant tumor cells. While various approaches have been tried to overcome multi-drug resistance, it has remained a major road block in achieving complete success in the clinic. Extensive research has identified various mechanisms, including overexpression of P-glycoprotein 170, modifications in activating or detoxification enzymes (phase I and II enzymes), and mutation and/or decreases in target enzymes in cancer cells. However, nitric oxide and/or nitric oxide-related species have not been considered an important player in cancer treatment and or drug resistance. Here, we examine the significance of nitric oxide in the treatment and resistance mechanisms of various anticancer drugs. Furthermore, we describe the significance of recently reported effects of nitric oxide on topoisomerases and the development of resistance to topoisomerase-poisons in tumor cells.Nitric oxide is also implicated in cancer cell killing, cancer progression and metastasis and poor survival [13][14][15][16][17]. A poor clinical outcome is believed to result from * NO-induced rapid tumor growth, resulting in hypoxia, nutrient deprivation, poor drug delivery, and selection for drug-resistant tumor cells. In vivo, * NO is formed from L-arginine by nitric oxide synthase (NOS). Three forms of NOS have been identified, including neuronal (nNOS), endothelial (eNOS), and a Ca 2+ -independent inducible isoform (iNOS). High expression of iNOS and increased production of • NO have been described in many human tumors, including breast, prostate and colorectal cancers [17][18][19][20]. Increased and continuous generation of * NO plays a significant role in the regulation of cancer cell progression and carcinogenesis. Hibbs et al. [21,22] and Stuehr and Nathan [23] have shown that co-culturing of leukemia L1210 cells with activated peritoneal macrophages results in the inhibition of L1210 cell proliferation which is correlated with nitrite formation. Inhibitors of NOS (L-NAME) and myoglobin, a scavenger of * NO 2 were effective in inhibiting cell killing actions of the activated macrophages, suggesting that * NO is responsible for the killing actions of activated macrophages towards cancer cells.It is believed that DNA damage and apoptosis induced by * NO in tumor cells cause tumor cell death; studies are needed to explore processes to deliver the highest concentrations of * NO in tumor cells using NO-donors as single chemotherapeutic agents or in combination with other chemotherapeutic agents. While significant progress has been made in the last decade, the role of * NO/ * NO-related species remains poorly understood in chemotherapy and drug resistance. Here, we review the role of * NO/ * NO-related species in cancer chemotherapy

Assessment of Blood Antioxidant Defense and Oxidative Stress in Colorectal Carcinoma Patients Undergoing Capecitabine and Oxaliplatin Combined with Bevacizumab Treatment

“…There are numerous mechanisms of NO stimulating cell proliferation, including increased mitogen-activated protein kinase pathway. A multitude of studies emphasizes that NO alone can induce cell death, and can be combined with several clinical anticancer drugs to enhance/sensitize their activity against a variety of human malignancies (30). A significant dissimilarity is demonstrated in plasma NO concentration between the CRC cases BT and those AT, for both sexes.…”

Nitric oxide reverses drug resistance by inhibiting ATPase activity of p-glycoprotein in human multi-drug resistant cancer cells

“…Nitric oxide ( ● NO), produced intracellularly via NOS catalysis, has been shown to kill tumor cells both in vitro and in vivo [46]. We have shown that ● NO/ ● NO-related species ● NO/ ● NO-related species nitrosylates both topo I and II while inhibiting the functions of only topo II [16, 17].…”

The Potential Role of iNOS in Ovarian Cancer Progression and Chemoresistance

“…Lowering ovarian cancer chemoresistance by NO/RNS involves, among others competition with cisplatin for the glutathione [71], decreasing activity of STAT3 and AKT signaling proteins [48,72], induction of DNA damage [50,51,52], inhibition of DNA repair protein activity [24,52,53], induction of apoptosis through, e.g., activation of p53 pathway, down-regulation of anti-apoptotic proteins or activation of Fas receptor [25,73]. On the other hand, NO/RNS can enhance drug resistance of cancer cells by various mechanisms, such as inhibition of apoptosis through, e.g., inhibition of caspase activity or increase in Bcl-2 expression [22], up-regulation of activity of proteins repairing DNA strand breaks [74] or lowering death receptors (CD95) exposure on cell surface by cGMP-dependent phosphorylation of syntaxin 4 [75] [Figure 4].…”