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Nitric oxide: role in tumour biology and iNOS/NO-based anticancer therapies

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Abstract

Purpose

The diatomic radical nitric oxide (NO) has been the cause of intense debate with implication in carcinogenesis, tumour progression, invasion, angiogenesis and modulation of therapeutic responses. The tumour biology of NO is highly complex, and this review summarises the various protective and damaging mode of action of NO.

Methods

We reviewed all published literature addressing the complexities of the role of NO in the altered biology of cancer and evaluating promising therapeutic roles of NO/iNOS for anti-cancer therapy.

Results

The available experimental evidences highlight contrasting pro- and anti-tumour effects of iNOS expression, which appear to be reconciled by consideration of the concentrations of NO involved, the temporo-spatial mode of NO action, intracellular targets, cellular redox state and the timing of an apoptotic stimulus. Several clinical and experimental studies indicate that the presence of NO in tumour microenvironment is detrimental to tumour cell survival and metastasis. In contrast, numerous reports suggest that NO can have tumour-promoting effects. NO is a ‘double-edged sword’ in cancer, and this review offers insight into the dichotomous nature of NO and discuss the therapeutic gain that can be achieved by manipulating tumour NO.

Conclusions

NO may exert a biphasic response, such that when NO levels go beyond a critical concentration that would be suitable for tumour growth and survival, growth arrest and/or apoptotic pathways are initiated. These characteristics of NO have been exploited therapeutically with impressive effects in pre-clinical models of cancer to slow tumour growth and to enhance the efficacy of both chemotherapy and radiotherapy.

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Abbreviations

NO:

Nitric oxide

NOS:

Nitric oxide synthase

TNF-α:

Tumour necrosis factor-α

IFN-γ:

Interferon-γ

NF-κB:

Nuclear factor-κB

HIF-1:

Hypoxia inducible factor-1

HMGB1:

High-mobility group box 1

MAPK:

Mitogen-activated protein kinase

JNK:

c-Jun N-terminal kinase

VEGF:

Vascular endothelial growth factor

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Acknowledgments

The authors acknowledge the support received from the Department of Biotechnology at Sharda University. We apologise to researchers whose findings that form the basis for our current knowledge in this field could not be cited due to space limitations.

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  1. Department of Biotechnology, School of Engineering and Technology, Sharda University, Greater Noida, Gautam Budha Nagar, 201306, India

    Simendra Singh

  2. Institute of Integrative Biology, Swiss Federal Institute of Technology (ETH), Zurich, Switzerland

    Alok K. Gupta

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  1. Simendra Singh
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Correspondence to Simendra Singh.

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Singh, S., Gupta, A.K. Nitric oxide: role in tumour biology and iNOS/NO-based anticancer therapies. Cancer Chemother Pharmacol 67, 1211–1224 (2011). https://doi.org/10.1007/s00280-011-1654-4

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