Applications for nitric oxide in halting proliferation of tumor cells

Reynolds, Melissa M.; Witzeling, Scott D.; Damodaran, Vinod B.; Medeiros, Tysha N.; Knodle, Ryan; Edwards, Melissa A.; Lookian, Pashayar P.; Brown, Mark A.

doi:10.1016/j.bbrc.2013.01.041

Cited by 36 publications

(27 citation statements)

References 61 publications

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“…Nitric oxide, for example, has emerged as a powerful adjuvant for the hyper-sensitization of tumors to more traditional chemo- and radio-therapeutics. Furthermore, emerging evidence indicates that nitric oxide donors have the potential to exert intrinsic antitumor activity in the clinical management of cancer [35]. However, while the above discussion would suggest an overall favorable role for M1 polarization of microglia, it should be taken into account that the latter may also have detrimental effects, as it has been shown that chronic activation of microglia can cause damage to normal neurons through the release of the same substances that are potentially cytotoxic for glioma cells [36].…”

Section: Discussionmentioning

confidence: 99%

The mTOR kinase inhibitors polarize glioma-activated microglia to express a M1 phenotype

Lisi¹,

Laudati²,

Navarra³

et al. 2014

J Neuroinflammation

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BackgroundIncreased activation of mammalian target of rapamycin (mTOR) is observed in numerous human cancers. Recent studies on the glioma kinome have identified several deregulated pathways that converge and activate mTOR. The available evidence on the role of microglia in CNS cancers would suggest a dual role, a tumoricidal role and -on the contrary- a role favoring tumor growth.MethodsIn the present paper, we have compared the effects of μM concentrations of rapamycin (RAPA) and its analog, RAD001 (RAD), on activated microglia; the latter was obtained by exposing cells to conditioned medium harvested either from inflammatory activated glioma cells (LI-CM) or from glioma cells kept under basal conditions (C-CM).ResultsHere we show that the inhibition of mTOR polarizes glioma-activated microglial cells towards the M1 phenotype, with cytotoxic activities, preventing the induction of the M2 status that promotes tumor growth. In fact RAPA and RAD significantly increased iNOS expression and activity, while on the same time significantly reducing IL-10 gene expression induced by C-CM, thus suggesting that the drugs prevent the acquisition of a M2 phenotype in response to glioma factors promoting a classic M1 activation. Similar results were obtained using the conditioned media obtained after glioma stimulation with LPS-IFNγ (LI-CM), which was found to induce a mixture of M1 and M2a/b polarization phenotypes. In these conditions, the inhibition of mTOR led to a significant up-regulation of iNOS, and in parallel to the down-regulation of both ARG and IL-10 gene expression.ConclusionsThese data suggest that mTOR inhibition may prevent glioma induced M2 polarization of microglial cells and increase their cytotoxic potential, possibly resulting in antitumor actions.

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Section: Discussionmentioning

confidence: 99%

The mTOR kinase inhibitors polarize glioma-activated microglia to express a M1 phenotype

Lisi¹,

Laudati²,

Navarra³

et al. 2014

J Neuroinflammation

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“…To overcome these issues, NO donors can be incorporated into, or chemically linked to, the surface of nanomaterials [34,39,40]. In both cases, nanomaterials have been shown to load high levels of NO, are considerably stable, and mimic endogenous NO production by iNOS [40].…”

Section: Advantages Of No-releasing Nanomate-rials In Cancermentioning

confidence: 99%

Nitric Oxide Releasing Nanomaterials for Cancer Treatment: Current Status and Perspectives

Seabra¹,

Lima²,

Calderón

2015

CTMC

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Nitric oxide (NO) is known to have dichotomous effects on cancer biology, acting as a pro- or antineoplastic agent. Low concentrations of NO are reported to promote tumor growth, whereas high NO influx acts as a potent tumor repressor, leading to cytotoxicity and apoptosis. There is increasing interest in developing NO-releasing materials as potent tumoricidal agents in which high and localized concentrations of NO may be directly released in a sustained manner to the tumor site. Nanomaterials allied to NO donors have emerged as a promising strategy in cancer treatment. In this context, this review summarizes the roles of NO in cancer biology and highlights the therapeutic potential effects of NO-releasing nanomaterials based on polymeric nanoparticles, dendritic polymers, liposomes, silica nanoparticles, metallic nanoparticles and quantum dots in combating tumor cells.

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“…Several NO-donors have now been evaluated as anticancer agents in various tumor cell lines, including organic nitrite, glyceryl nitrite, nitrosothiols and diazeniumdiolates. Several excellent reviews are already available highlighting the importance of NO-donors as anticancer agents [15,[25][26][27][28][29]. Therefore, these are not focused on in detail in this review.…”

Section: Becausementioning

confidence: 99%

“…Here, we review the role of * NO/ S-nitrosothiols (sugar-SNAP) that resulted from enhanced uptake of saccharides in tumor cells and delivering * NO directly to tumor cells (34). Reynolds et al [29] have reported synthesis of polysaccharidebased dextran thiomers which contained covalently attached NOdonors. They found that these NO-donor compounds were stable and quantitatively released * NO under normal physiological conditions.…”

Section: +mentioning

confidence: 99%

“…Since the early observations of Wink et al [30] showing that certain NO-donors enhanced the cytotoxicity of cis-platin in Chinese Hamster V79 lung fibroblast cells, extensive research has suggested that the delivery of * NO via NO-donors has been beneficial and/or synergistic with various anticancer drugs in killing tumor cells in vitro and in animal models [15,[25][26][27][28][29]. Interestingly, not all nitric oxide donors are effective in this sensitization of cytotoxicity as it was found to depend upon both the flux of * NO and the reactive species formed.…”

Section: Nitric Oxide In Combination With Antitumor Agentsmentioning

confidence: 99%

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

Sinha

2016

J Cancer Sci Ther

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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

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Applications for nitric oxide in halting proliferation of tumor cells

Cited by 36 publications

References 61 publications

The mTOR kinase inhibitors polarize glioma-activated microglia to express a M1 phenotype

The mTOR kinase inhibitors polarize glioma-activated microglia to express a M1 phenotype

Nitric Oxide Releasing Nanomaterials for Cancer Treatment: Current Status and Perspectives

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

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