Effects of Reduced Extracellular Sodium Concentrations on Cisplatin Treatment in Human Tumor Cells: The Role of Autophagy.

Hyponatremia is the prevalent electrolyte imbalance in cancer patients, and it is associated with a worse outcome. Notably, emerging clinical evidence suggests that hyponatremia adversely influences the response to anticancer treatments. Therefore, this study aims to investigate how reduced extracellular [Na+] affects the responsiveness of different cancer cell lines (from human colon adenocarcinoma, neuroblastoma, and small cell lung cancer) to cisplatin and the underlying potential mechanisms. Cisplatin dose-response curves revealed higher IC50 in low [Na+] than normal [Na+]. Accordingly, cisplatin treatment was less effective in counteracting the proliferation and migration of tumor cells when cultured in low [Na+], as demonstrated by colony formation and invasion assays. In addition, the expression analysis of proteins involved in autophagosome-lysosome formation and the visualization of lysosomal areas by electron microscopy revealed that one of the main mechanisms involved in chemoresistance to cisplatin is the promotion of autophagy. In conclusion, our data first demonstrate that the antitumoral effect of cisplatin is markedly reduced in low [Na+] and that autophagy is an important mechanism of drug escape. This study indicates the role of hyponatremia in cisplatin chemoresistance and reinforces the recommendation to correct this electrolyte alteration in cancer patients.

Hyponatremia Promotes Cancer Growth in a Murine Xenograft Model of Neuroblastoma.

In cancer patients, hyponatremia is detected in about 40% of cases at hospital admission and has been associated to a worse outcome. We have previously observed that cancer cells from different tissues show a significantly increased proliferation rate and invasion potential, when cultured in low extracellular [Na+]. We have recently developed an animal model of hyponatremia using Foxn1nu/nu mice. The aim of the present study was to compare tumor growth and invasivity of the neuroblastoma cell line SK-N-AS in hyponatremic vs. normonatremic mice. Animals were subcutaneously implanted with luciferase-expressing SK-N-AS cells. When masses reached about 100 mm3, hyponatremia was induced in a subgroup of animals via desmopressin infusion. Tumor masses were significantly greater in hyponatremic mice, starting from day 14 and until the day of sacrifice (day 28). Immunohistochemical analysis showed a more intense vascularization and higher levels of expression of the proliferating cell nuclear antigen, chromogranin A and heme oxigenase-1 gene in hyponatremic mice. Finally, metalloproteases were also more abundantly expressed in hyponatremic animals compared to control ones. To our knowledge, this is the first demonstration in an experimental animal model that hyponatremia is associated to increased cancer growth by activating molecular mechanisms that promote proliferation, angiogenesis and invasivity.

The Yin and Yang Effect of the Apelinergic System in Oxidative Stress.

Apelin is an endogenous ligand for the G protein-coupled receptor APJ and has multiple biological activities in human tissues and organs, including the heart, blood vessels, adipose tissue, central nervous system, lungs, kidneys, and liver. This article reviews the crucial role of apelin in regulating oxidative stress-related processes by promoting prooxidant or antioxidant mechanisms. Following the binding of APJ to different active apelin isoforms and the interaction with several G proteins according to cell types, the apelin/APJ system is able to modulate different intracellular signaling pathways and biological functions, such as vascular tone, platelet aggregation and leukocytes adhesion, myocardial activity, ischemia/reperfusion injury, insulin resistance, inflammation, and cell proliferation and invasion. As a consequence of these multifaceted properties, the role of the apelinergic axis in the pathogenesis of degenerative and proliferative conditions (e.g., Alzheimer's and Parkinson's diseases, osteoporosis, and cancer) is currently investigated. In this view, the dual effect of the apelin/APJ system in the regulation of oxidative stress needs to be more extensively clarified, in order to identify new potential strategies and tools able to selectively modulate this axis according to the tissue-specific profile.

Hyponatremia and Cancer: From Bedside to Benchside.

Hyponatremia is the most common electrolyte disorder encountered in hospitalized patients. This applies also to cancer patients. Multiple causes can lead to hyponatremia, but most frequently this electrolyte disorder is due to the syndrome of inappropriate antidiuresis. In cancer patients, this syndrome is mostly secondary to ectopic secretion of arginine vasopressin by tumoral cells. In addition, several chemotherapeutic drugs induce the release of arginine vasopressin by the hypothalamus. There is evidence that hyponatremia is associated to a more negative outcome in several pathologies, including cancer. Many studies have demonstrated that in different cancer types, both progression-free survival and overall survival are negatively affected by hyponatremia, whereas the correction of serum [Na+] has a positive effect on patient outcome. In vitro studies have shown that cells grown in low [Na+] have a greater proliferation rate and motility, due to a dysregulation in intracellular signalling pathways. Noteworthy, vasopressin receptors antagonists, which were approved more than a decade ago for the treatment of euvolemic and hypervolemic hyponatremia, have shown unexpected antiproliferative effects. Because of this property, vaptans were also approved for the treatment of polycystic kidney disease. In vitro evidence indicated that this family of drugs effectively counteracts proliferation and invasivity of cancer cells, thus possibly opening a new scenario among the pharmacological strategies to treat cancer.

Hyponatremia and Oxidative Stress.

Hyponatremia, i.e., the presence of a serum sodium concentration ([Na+]) < 136 mEq/L, is the most frequent electrolyte imbalance in the elderly and in hospitalized patients. Symptoms of acute hyponatremia, whose main target is the central nervous system, are explained by the "osmotic theory" and the neuronal swelling secondary to decreased extracellular osmolality, which determines cerebral oedema. Following the description of neurological and systemic manifestations even in mild and chronic hyponatremia, in the last decade reduced extracellular [Na+] was associated with detrimental effects on cellular homeostasis independently of hypoosmolality. Most of these alterations appeared to be elicited by oxidative stress. In this review, we focus on the role of oxidative stress on both osmolality-dependent and -independent impairment of cell and tissue functions observed in hyponatremic conditions. Furthermore, basic and clinical research suggested that oxidative stress appears to be a common denominator of the degenerative processes related to aging, cancer progression, and hyponatremia. Of note, low [Na+] is able to exacerbate multiple manifestations of senescence and to decrease progression-free and overall survival in oncologic patients.

Low sodium and tolvaptan have opposite effects in human small cell lung cancer cells.

PURPOSE: Hyponatraemia is frequently observed in cancer patients and can be due to the syndrome of inappropriate anti-diuresis (SIAD), related to ectopic vasopressin secretion, particularly in small cell lung cancer (SCLC). Hyponatraemia is associated with a worse outcome in cancer patients. The vasopressin receptor antagonist tolvaptan effectively corrects hyponatraemia secondary to SIAD and there is in vitro evidence that it has also an antiproliferative effect in cancer cells. The purpose of this study was i) to analyse the effect of low serum sodium concentrations ([Na+]) in SCLC cells and ii) to determine whether tolvaptan counteracts tumor progression. METHODS: We evaluated cell proliferation, cell cycle, apoptosis, oxidative stress, invasivity in low [Na+] as well as after exposure to tolvaptan. We also analysed the intracellular signalling pathways involved. RESULTS: In reduced [Na+] cell proliferation was significantly increased compared to normal [Na+] and cells were mostly distributed in the G2/M phase. Apoptosis appeared reduced. In addition, the ability to cross matrigel-coated membranes markedly increased. As observed in other cancer cell models, the expression of the heme-oxigenase-1 gene was increased. Finally, we found that in cells cultured in low [Na+] the RhoA/ROCK1/2 pathway, which is involved in the regulation of actin cytoskeleton, was activated. On the other hand, we found that tolvaptan effectively inhibited cell proliferation, anchorage-independent growth, invasivity and promoted apoptosis. Accordingly, the RhoA/ROCK-1/2 pathway was inhibited. CONCLUSIONS: These findings demonstrate for the first time that low [Na+] favours tumor progression in SCLC cells, whereas tolvaptan effectively inhibits cell proliferation, survival and invasivity.