Nitric oxide donor increases the efficiency of cytostatic therapy and retards the development of drug resistance

Коновалова, Н. П.; Goncharova, S. A.; Волкова, Л. М.; Rajewskaya, T. A.; Erëmenko, L. T.; Королев, А. М.

doi:10.1016/s1089-8603(02)00142-8

Cited by 54 publications

(24 citation statements)

References 14 publications

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“…On the other hand, an in vitro study of Lue and Vincent [42] demonstrated a potent inhibition of NOS by DOX. The observed elevation in cardiac NO may support the important contribution of NO in the cytotoxic action of DOX, this was confirmed by the finding of Konovalova et al [13]. Moreover, NO may influence several aspects of tumor biology [12] including modulation of cell growth, apoptosis, differentiation, metastatic capability and, tumor-induced immunosuppression.…”

Section: Discussionsupporting

confidence: 75%

“…Lind et al [12] reported that NO contributes to DOX's antitumor effect. Furthermore, NO donor was shown to increase the effectiveness of antineoplastic agents and inhibit the development of drug resistance [13]. Pacher et al [14] reported that both increased oxidative stress and dysregulation of NO have been implicated in the cardiotoxicity of DOX.…”

Section: Introductionmentioning

confidence: 99%

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Nitric oxide and oxidative stress in brain and heart of normal rats treated with doxorubicin: Role of aminoguanidine

Elgawad

El‐Sawalhi

2004

J Biochem & Molecular Tox

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Doxorubicin (DOX) is a potent antitumor antibiotic drug known to cause severe cardiac toxicity. Moreover, its adverse effects were found to be extended to the cerebral tissue. Several mechanisms for this toxicity have been ascribed. Currently, one of the most accepted mechanisms is through free radicals; however, the exact role of nitric oxide (NO) is still unclear. Accordingly, a NO-synthase inhibitor with some antioxidant property, aminoguanidine (AG), was selected to examine its potential protective effect against DOX-induced toxicity. Male Wistar albino rats (150-200 g) were allocated into a normal control group, DOX-induced toxicity group, and DOX + AG-treated group. DOX was injected i.p. at a dose of 10 mg/kg divided into four equal injections over a period of 2 weeks. AG was injected i.p. at a dose of 100 mg/kg 1 h before each DOX injection. The animals were sacrificed 24 h after the last DOX injection and the following parameters were measured: serum lactate dehydrogenase (LDH) and creatine phosphokinase (CPK) activities, cardiac and cerebral contents of malondialdehyde (MDA), conjugated diene (CD), glutathione (GSH), NO, and cytosolic calcium, as well as superoxide dismutase (SOD) and glutathione peroxidase (GSHP(X)) activities. Cardiotoxicity was manifested by a marked increase in serum LDH and CPK in addition to the sharp increase in MDA reaching eightfolds the basal level. This was accompanied by significant increase in CD, NO, cytosolic calcium, SOD, and GSHP(X) content/activity by 69, 85, 76, 125, and 41% respectively as compared to normal control. On the other hand, GSH was significantly depressed. In brain, only significant increase in MDA and GSHP(X) and decrease in GSH were obtained but to a lesser extent than the cardiac tissue. AG treatment failed to prevent the excessive release of cardiac enzymes; however, it alleviated the adverse effects of DOX in heart. AG administration resulted in marked decrease in the elevated levels of MDA, NO, SOD, and GSHP(X), however, MDA level was still pathological. The altered parameters in brain were restored by AG. It is concluded that, AG could not provide complete protection against DOX-induced toxicity. Therefore, it is recommended that, maintenance of the endogenous antioxidant, GSH, and regulation of calcium homeostasis must be considered, rather than NO formation, to guard against DOX-induced toxicity.

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Section: Discussionsupporting

confidence: 75%

Section: Introductionmentioning

confidence: 99%

Nitric oxide and oxidative stress in brain and heart of normal rats treated with doxorubicin: Role of aminoguanidine

Elgawad

El‐Sawalhi

2004

J Biochem & Molecular Tox

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“…The protocol we used was designed to expose DCs to NO selectively and only ex vivo to minimize the systemic effects of NO in vivo. These effects of NO in the case of tumors are complex, resulting from a combination of cytotoxic and cytostatic actions on tumor cells, and protumorigenic functions, including stimulation of angiogenesis and down-regulation of immune responses (13,14); in addition, systemic NO may change sensitivity to anticancer drugs in vivo (18)(19)(20)(21)(22)(23).…”

Section: Discussionmentioning

confidence: 99%

Nitric Oxide Boosts Chemoimmunotherapy via Inhibition of Acid Sphingomyelinase in a Mouse Model of Melanoma

et al. 2007

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Cisplatin is one of the most effective anticancer drugs, but its severe toxic effects, including depletion of immune-competent cells, limit its efficacy. We combined the systemic treatment with cisplatin with intratumor delivery of dendritic cells (DC) previously treated ex vivo with a pulse of nitric oxide (NO) released by the NO donors (z)-1-[2-(2-aminoethyl)-N-(2-ammonioethyl)amino]-diazen-1-ium-1,2-diolate or isosorbide dinitrate. We found that this chemoimmunotherapy, tested in the B16 mouse model of melanoma, was significantly more efficacious than cisplatin alone, leading to tumor regression and animal survival at low doses of cisplatin that alone had no effect. Tumor cure was not observed when combining cisplatin with DCs not exposed to NO donors, indicating the key role of the pretreatment with NO. We investigated the mechanisms responsible for the synergic effect of NO-treated DCs and cisplatin and found that NO-treated DCs were protected both in vitro and in vivo from cisplatin-induced cytotoxicity. Cisplatin triggered DC apoptosis through increased expression and activation of acid sphingomyelinase; pretreatment of DCs with NO donors prevented such activation and inhibited activation of the downstream proapoptotic events, including generation of ceramide, activation of caspases 3 and 9, and mitochondrial depolarization. The effects of NO were mediated through generation of its physiologic messenger, cyclic GMP. We conclude that NO and NO generating drugs represent promising tools to increase the efficacy of chemoimmunotherapies in vivo, promoting the survival and increasing the function of injected cells by targeting a key pathway in cisplatin-induced cytotoxicity. [Cancer Res 2007;67(16):7559-64]

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“…Furthermore, the sensitization to cis-platin cytotoxicity was shortlived [30]. Since these important observations, a significant amount of research has been carried out showing sensitization to cis-platin and other Pt-based drugs by NO-donors in tumor cells [28,[39][40][41] and in vivo in nude mice. An NO-donor derived from aspirin (NCX-4016) was also effective in sensitizing cisplatin cytotoxicity in both sensitive and cisplatin-resistant cell lines [40].…”

Section: Nitric Oxide In Combination With Antitumor Agentsmentioning

confidence: 99%

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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Nitric oxide donor increases the efficiency of cytostatic therapy and retards the development of drug resistance

Cited by 54 publications

References 14 publications

Nitric oxide and oxidative stress in brain and heart of normal rats treated with doxorubicin: Role of aminoguanidine

Nitric oxide and oxidative stress in brain and heart of normal rats treated with doxorubicin: Role of aminoguanidine

Nitric Oxide Boosts Chemoimmunotherapy via Inhibition of Acid Sphingomyelinase in a Mouse Model of Melanoma

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

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