The dual role of iNOS in cancer

Vannini, Federica; Kashfi, Khosrow; Nath, Niharika

doi:10.1016/j.redox.2015.08.009

Cited by 452 publications

(407 citation statements)

References 163 publications

(177 reference statements)

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“…In this study, we describe the cross-talk between treatment resistance and EnR stress, and targeting NOS signaling may overcome this resistance. Cellular regulation of NOS depends on conditions associated to the tumor microenvironment (51,52). In TNBC cell lines, cytokines, hypoxia, nutrient deprivation, and other metabolic factors establish a feed-forward regulatory loop orchestrated by NOS (30,53).…”

Section: Discussionmentioning

confidence: 99%

Pharmacological Inhibition of NOS Activates ASK1/JNK Pathway Augmenting Docetaxel-Mediated Apoptosis in Triple-Negative Breast Cancer

Dávila‐González

Choi

Rosato

et al. 2018

Clinical Cancer Research

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Purpose: Chemoresistance in triple-negative breast cancer (TNBC) is associated with the activation of a survival mechanism orchestrated by the endoplasmic reticulum (EnR) stress response and by inducible nitric oxide synthase (iNOS). Our aim was to determine the effects of pharmacologic NOS inhibition on TNBC.Experimental Design: TNBC cell lines, SUM-159PT, MDA-MB-436, and MDA-MB-468, were treated with docetaxel and NOS inhibitor (L-NMMA) for 24, 48, and 72 hours. Apoptosis was assessed by flow cytometry using Annexin-V and propidium iodide. Western blot was used to assess ER stress and apoptosis, and rtPCR was used to evaluate s-XBP1. TNBC patient-derived xenografts (PDX) were treated either with vehicle, docetaxel, or combination therapy (NOS inhibition þ docetaxel). Mouse weight and tumor volumes were recorded twice weekly. Docetaxel concentration was determined using mass spectrometry. To quantify proliferation and apoptosis, PDX tumor samples were stained using Ki67 and TUNEL assay.Results: In vitro, L-NMMA ameliorated the iNOS upregulation associated with docetaxel. Apoptosis increased when TNBC cells were treated with combination therapy. In TNBC PDXs, combination therapy significantly reduced tumor volume growth and increased survival proportions. In the BCM-5998 PDX model, intratumoral docetaxel concentration was higher in mice receiving combination therapy. Coupling docetaxel with NOS inhibition increased EnR-stress response via coactivation of ATF4 and CHOP, which triggered the pASK1/JNK proapoptotic pathway, promoting cleavage of caspases 3 and 9.Conclusions: iNOS is a critical target for docetaxel resistance in TNBC. Pharmacologic inhibition of NOS enhanced chemotherapy response in TNBC PDX models. Combination therapy may improve prognosis and prevent relapse in TNBC patients who have failed conventional chemotherapy.

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Section: Discussionmentioning

confidence: 99%

Pharmacological Inhibition of NOS Activates ASK1/JNK Pathway Augmenting Docetaxel-Mediated Apoptosis in Triple-Negative Breast Cancer

Dávila‐González

Choi

Rosato

et al. 2018

Clinical Cancer Research

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“…Given that NF-κB is often implicated in iNOS expression (23,36,37) and that Brd4 can serve as a NF-κB co-activator (30,31), we asked whether the observed JQ1 enhancement of PDT cytotoxicity could be explained on this basis. We looked first at the effects of low level JQ1 on U87 iNOS expression after a PDT challenge compared with that in a dark control.…”

Section: Jq1 Inhibition Of Inos Expression -mentioning

confidence: 99%

“…Low level reactive oxygen species (ROS) as well as nitric oxide (NO) generated by inducible nitric oxide synthase (iNOS/NOS2) play important roles in many of these processes (3)(4)(5)(6). There is now compelling evidence that endogenous iNOS/NO not only supports growth and progression of many tumors, but also plays a key role in pro-tumor immunosuppression (7,8) as well as resistance to chemotherapeutic and radiotherapeutic interventions (9)(10)(11).…”

Section: Introductionmentioning

confidence: 99%

Nitric oxide antagonism to glioblastoma photodynamic therapy and mitigation thereof by BET bromodomain inhibitor JQ1

Fahey

Stancill

Smith

et al. 2018

Journal of Biological Chemistry

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Endogenous nitric oxide (NO) generated by inducible NO synthase (iNOS) promotes glioblastoma cell proliferation and invasion, and also plays a key role in glioblastoma resistance to chemotherapy and radiotherapy. Non-ionizing photodynamic therapy (PDT) has anti-tumor advantages over conventional glioblastoma therapies. Our previous studies revealed that glioblastoma U87 cells upregulate iNOS after a photodynamic challenge and that resulting NO not only increased resistance to apoptosis, but rendered surviving cells more proliferative and invasive. These findings were largely based on the effects of inhibiting iNOS activity and scavenging NO. Demonstrating now that iNOS expression in photostressed U87 cells is mediated by NF-κB, we hypothesized that (i) recognition of acetylated lysine (acK) on NF-κB p65/Rel A by bromodomain and extra-terminal (BET) protein Brd4 is crucial, and (ii) by suppressing iNOS expression, a BET inhibitor (JQ1) would attenuate the negative effects of photostress. The following evidence was obtained: (i) Like iNOS, Brd4 protein and p65-acK levels increased several fold in photostressed cells; (ii) JQ1 at minimally toxic concentrations had no effect on Brd4 or p65-acK upregulation after PDT, but strongly suppressed iNOS, survivin, and Bcl-xL upregulation, along with the growth and invasion spurt of PDTsurviving cells; (iii) JQ1 inhibition of NO production in photostressed cells closely paralleled that of growth/invasion inhibition; (iv) At 1% the concentration of iNOS inhibitor 1400W, JQ1 reduced post-PDT cell aggressiveness to a far greater extent. This is the first evidence for BET inhibitor targeting of iNOS expression in cancer cells and how such targeting can markedly improve therapeutic efficacy.

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“…The roles of NOS and NO on DNA damage, apoptosis, cell cycle, enhancement of cell proliferation, angiogenesis and metastasis are currently viewed, and NO was found to be associated with tumor environment, for example, the vasculature cells and other stromal cells [103][104][105]. Research also indicated that NOS2 expression was correlated with tumor vascularization, accumulations of p53 mutations and activation of epidermal growth factor receptor, even could be treated as an independent predictor of poor survival in women with estrogen receptor (ER)-negative breast tumors [106].…”

Section: Role Of Nitric Oxide Synthase In Cancer Biologymentioning

confidence: 99%

Nitric Oxide Synthase in Male Urological and Andrologic Functions

Yu¹,

Li²,

Li³

et al. 2017

Nitric Oxide Synthase - Simple Enzyme-Complex Roles

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Nitric oxide (NO), a crucial signaling molecule, is synthesized by the nitric oxide synthase (NOS) enzyme. The significant effects of NOS are under exploration, and the roles of potential therapy targets for diseases of NOS are widely accepted. In this chapter, we summarized the important roles of NOS mainly on pathogenesis of prostate diseases, male infertility, erectile dysfunction and, addition, the potential therapeutic efficacies of NOS for those diseases.

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The dual role of iNOS in cancer

Cited by 452 publications

References 163 publications

Pharmacological Inhibition of NOS Activates ASK1/JNK Pathway Augmenting Docetaxel-Mediated Apoptosis in Triple-Negative Breast Cancer

Pharmacological Inhibition of NOS Activates ASK1/JNK Pathway Augmenting Docetaxel-Mediated Apoptosis in Triple-Negative Breast Cancer

Nitric oxide antagonism to glioblastoma photodynamic therapy and mitigation thereof by BET bromodomain inhibitor JQ1

Nitric Oxide Synthase in Male Urological and Andrologic Functions

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