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  • Review Article
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Gasotransmitters in cancer: from pathophysiology to experimental therapy

Nature Reviews Drug Discovery volume 15, pages 185–203 (2016)Cite this article

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Key Points

  • Nitric oxide (NO), carbon monoxide (CO) and hydrogen sulfide (H2S) are labile gaseous mediators that have multiple biological functions in tumour cells and in the host tissue. Each of these gases is produced by specific enzyme systems and regulates (among other aspects) cell viability, cell division, mitochondrial activity, angiogenesis and vascular tone.

  • Upregulation of the various gasotransmitter-producing enzymes occurs in many tumours. Most commonly, NO is overproduced by upregulation of inducible NO synthase (iNOS); CO is overproduced by haem oxygenase 1 (HO1); and H2S is overproduced by cystathionine-β-synthase (CBS).

  • Selective genetic silencing or pharmacological inhibition of iNOS, HO1 or CBS has been shown to exert anticancer effects in various in vitro and in vivo models. Many of these approaches also sensitize the tumour to chemotherapy and/or radiotherapy.

  • Because of the bell-shaped pharmacological character of the gasotransmitters, not only inhibition of gasotransmitter biosynthesis, but also elevation of gasotransmitter levels beyond a certain threshold can exert antitumour effects; preclinical data show that tumour-targeted NO donors, CO donors or CO inhalation therapy, and H2S donors of various classes exert antitumour effects.

  • Although the clinical translation of the findings of gasotransmitters in the field of tumour biology has been slow, several compounds can be identified that may be suitable for clinical repurposing and translational research activity.

Abstract

The three endogenous gaseous transmitters — nitric oxide (NO), carbon monoxide (CO) and hydrogen sulfide (H2S) — regulate a number of key biological functions. Emerging data have revealed several new mechanisms for each of these three gasotransmitters in tumour biology. It is now appreciated that they show bimodal pharmacological character in cancer, in that not only the inhibition of their biosynthesis but also elevation of their concentration beyond a certain threshold can exert anticancer effects. This Review discusses the role of each gasotransmitter in cancer and the effects of pharmacological agents — some of which are in early-stage clinical studies — that modulate the levels of each gasotransmitter. A clearer understanding of the pharmacological character of these three gases and the mechanisms underlying their biological effects is expected to guide further clinical translation.

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Figure 1: Effects of the three gasotransmitters on tumour survival and growth.
Figure 2: Chemical structures of selected compounds that affect gasotransmitter levels.
Figure 3: Implications of the bell-shaped pharmacological profile of gasotransmitters for the therapy of cancer.

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Acknowledgements

The author's research in the field of H2S and cancer is supported by a grant from the US National Institutes of Health (NIH; R01CA175803) and the US Cancer Prevention Research Institute of Texas (CPRIT; DP150074).

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  1. Department of Anesthesiology, The University of Texas Medical Branch at Galveston, 601 Harborside Drive, Galveston, 77555, Texas, USA

    Csaba Szabo

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The author is a principal and a shareholder of CBS Therapeutics Inc., a start-up company involved in the research and development of CBS inhibitors for cancer therapy.

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Glossary

Peroxynitrite

A short-lived cytotoxic oxidant species that is the product of the diffusion- controlled reaction between nitric oxide (NO) and a superoxide radical (O2−).

Bacillus Calmette–Guérin

A live attenuated strain of Mycobacterium bovis that is a US-approved therapy for in situ bladder carcinoma.

3-methylcholanthrene

The most common isomer of a highly carcinogenic polycyclic aromatic hydrocarbon — its topical administration in mice is often used as an experimental cancer model.

Secretagogue

A biological substance that induces the secretion of another substance. For example, angiotensin II is a secretagogue for aldosterone.

Glutathione-S-transferase

(GST). A soluble protein with a molecular mass of ~50 kDa. GSTs represent a major group of detoxification enzymes and catalyse the conjugation of the reduced form of glutathione (GSH) to various cellular substrates.

Multi-arm polymeric nanocarriers

Branched, globular, nanoscale materials exhibiting a large surface area. They are commonly used for targeted drug delivery.

Prodrugs

Inactive precursors of active therapeutic agents. The conversion from the inactive to the active form occurs through normal metabolic processes, often involving the hydrolysis of an ester group.

Chorioallantoic membrane model

A common experimental model in which melanoma cells are grown on chick chorioallantoic membranes (CAMs). It is a model with a substantial angiogenesis component.

Epithelial–mesenchymal transition

(EMT). A process by which epithelial cells lose their cell polarity and cell–cell adhesion and assume a migratory and invasive phenotype.

Protoporphyrins

(PPs). Tetrapyrroles containing four methyl side chains, two propionic acid side chains and two vinyl side chains. The iron complex of PPs occurs in a number of proteins, including haemoglobin, myoglobin and several electron transport proteins of the mitochondrial respiratory chain.

Transgenic adenocarcinoma mouse prostate cancer model

(TRAMP cancer model). One of the most well-known prostate cancer mouse models. The expression of both the large and small SV40 tumour antigens is regulated by the prostate-specific rat probasin promoter.

Theranostic approach

Approaches that incorporate the development of molecular diagnostic tests in combination with targeted therapeutics. These approaches are integral to the personalized medicine concept. Also known as 'theranostics'.

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Szabo, C. Gasotransmitters in cancer: from pathophysiology to experimental therapy. Nat Rev Drug Discov 15, 185–203 (2016). https://doi.org/10.1038/nrd.2015.1

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