Generation of gaseous sulfur-containing compounds in tumour tissue and suppression of gas diffusion as an antitumour treatment

Yamagishi, Kazue; Onuma, Kazuo; Chiba, Yota; Yagi, Shunsuke; Aoki, Shigenobu; Sato, Tomoyuki; Sugawara, Yasuhiko; Hosoya, Noriyasu; Saeki, Yasutake; Takahashi, Minoru; Fuji, Masayoshi; Ohsaka, Takeo; Okajima, Takaharu; Akita, Kenji; Suzuki, Takashi; Senawongse, Pisol; Urushiyama, Akio; Kawai, Kiyoshi; Shoun, Hirofumi; Ishii, Yoshimasa; Ishikawa, Hiroya; Sugiyama, Shigeru; Nakajima, Madoka; Tsuboi, Masaru; Yamanaka, Tateo

doi:10.1136/gutjnl-2011-300721

Cited by 40 publications

(38 citation statements)

References 43 publications

(25 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Lower levels were found for several (CH x ) x S x compounds, whereas increased levels of other sulfur-containing compounds, like carbon disulfide and 2,4-dithiapentane, were seen in patients with CD and UC compared with HC. Sulfur compounds have been implicated in the onset32 47 and relapse of UC48 but also in the initiation of carcinogenesis 47 49 50. Previously, we showed that mucosal sulfide detoxification mechanisms are decreased in CD and UC 51…”

Section: Discussionmentioning

confidence: 94%

Faecal metabolite profiling identifies medium-chain fatty acids as discriminating compounds in IBD

Preter

Machiels

Joossens

et al. 2014

Gut

193

137

View full text Add to dashboard Cite

show abstract

Section: Discussionmentioning

confidence: 94%

Faecal metabolite profiling identifies medium-chain fatty acids as discriminating compounds in IBD

Preter

Machiels

Joossens

et al. 2014

Gut

193

137

View full text Add to dashboard Cite

show abstract

“…There are several lines of prior studies demonstrating that volatile sulfur compounds, including H 2 S, are increased in patients with certain forms of cancer (31,32), although its sources or biological functions remained unexplored. In addition, several prior studies demonstrated an increase in CBS expression in various forms of human cancer (33)(34)(35), although the functional consequence of these observations remained unclear.…”

Section: Discussionmentioning

confidence: 99%

Tumor-derived hydrogen sulfide, produced by cystathionine-β-synthase, stimulates bioenergetics, cell proliferation, and angiogenesis in colon cancer

Szabó¹,

Coletta²,

Chao³

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

640

693

View full text Add to dashboard Cite

The physiological functions of hydrogen sulfide (H 2 S) include vasorelaxation, stimulation of cellular bioenergetics, and promotion of angiogenesis. Analysis of human colon cancer biopsies and patient-matched normal margin mucosa revealed the selective upregulation of the H 2 S-producing enzyme cystathionine-β-synthase (CBS) in colon cancer, resulting in an increased rate of H 2 S production. Similarly, colon cancer-derived epithelial cell lines (HCT116, HT-29, LoVo) exhibited selective CBS up-regulation and increased H 2 S production, compared with the nonmalignant colonic mucosa cells, NCM356. CBS localized to the cytosol, as well as the mitochondrial outer membrane. ShRNA-mediated silencing of CBS or its pharmacological inhibition with aminooxyacetic acid reduced HCT116 cell proliferation, migration, and invasion; reduced endothelial cell migration in tumor/endothelial cell cocultures; and suppressed mitochondrial function (oxygen consumption, ATP turnover, and respiratory reserve capacity), as well as glycolysis. Treatment of nude mice with aminooxyacetic acid attenuated the growth of patientderived colon cancer xenografts and reduced tumor blood flow. Similarly, CBS silencing of the tumor cells decreased xenograft growth and suppressed neovessel density, suggesting a role for endogenous H 2 S in tumor angiogenesis. In contrast to CBS, silencing of cystathionine-γ-lyase (the expression of which was unchanged in colon cancer) did not affect tumor growth or bioenergetics. In conclusion, H 2 S produced from CBS serves to (i) maintain colon cancer cellular bioenergetics, thereby supporting tumor growth and proliferation, and (ii) promote angiogenesis and vasorelaxation, consequently providing the tumor with blood and nutritients. The current findings identify CBS-derived H 2 S as a tumor growth factor and anticancer drug target.

show abstract

“…Moreover, in one prior study, CBS expression has been associated with increased cell proliferation (MacLean et al ., ) (even though none of these prior investigations raised the potential involvement of H 2 S). In addition, several studies demonstrated increased H 2 S production in the exhaled air and flatus of cancer patients (Kumar et al ., ; Yamagishi et al ., ; Altomare et al ., ) and increased urinary excretion of thiosulfate, the stable breakdown product of H2S (Chwatko et al ., ) (even though these investigations have not identified the enzymatic source). Finally, several recent studies noted the inhibitory effect of AOAA on cancer cell proliferation in vitro and/or in vivo (Thornburg et al ., ; Weinberg et al ., ; Anso et al ., ; Son et al ., ) (even though these investigators attributed the effects of AOAA to pharmacological actions other than CBS inhibition).…”

Section: H2s As Endogenously Produced Metabolic ‘Fuel’ In Cancer Cellsmentioning

confidence: 98%

Regulation of mitochondrial bioenergetic function by hydrogen sulfide. Part II. Pathophysiological and therapeutic aspects

Módis

Bos

Calzia

et al. 2014

British J Pharmacology

134

112

View full text Add to dashboard Cite

Emerging work demonstrates the dual regulation of mitochondrial function by hydrogen sulfide (H2S), including, at lower concentrations, a stimulatory effect as an electron donor, and, at higher concentrations, an inhibitory effect on cytochrome C oxidase. In the current article, we overview the pathophysiological and therapeutic aspects of these processes. During cellular hypoxia/acidosis, the inhibitory effect of H2S on complex IV is enhanced, which may shift the balance of H2S from protective to deleterious. Several pathophysiological conditions are associated with an overproduction of H2S (e.g. sepsis), while in other disease states H2S levels and H2S bioavailability are reduced and its therapeutic replacement is warranted (e.g. diabetic vascular complications). Moreover, recent studies demonstrate that colorectal cancer cells up-regulate the H2S-producing enzyme cystathionine β-synthase (CBS), and utilize its product, H2S, as a metabolic fuel and tumour-cell survival factor; pharmacological CBS inhibition or genetic CBS silencing suppresses cancer cell bioenergetics and suppresses cell proliferation and cell chemotaxis. In the last chapter of the current article, we overview the field of H2S-induced therapeutic 'suspended animation', a concept in which a temporary pharmacological reduction in cell metabolism is achieved, producing a decreased oxygen demand for the experimental therapy of critical illness and/or organ transplantation. LINKED ARTICLESThis article is part of a themed issue on Mitochondrial Pharmacology: Energy, Injury & Beyond. To view the other articles in this issue visit http://dx.doi. org/10.1111/bph.2014.171.issue-8 Abbreviations 3-MST, 3-mercaptopyruvate sulfurtransferase; AOAA, aminooxyacetic acid; CBS, cystathionine β-synthase; CSE, cystathionine γ-lyase; H2S, hydrogen sulfide; KATP, ATP-sensitive potassium channel; PAG, propargylglycine; SOU, sulfide-oxidizing unit Introduction H2S, a colourless, flammable, water-soluble gas, is gaining increased attention as an endogenous biological mediator. The distribution and regulation of the three H2S-producing enzymes [cystathionine β-synthase (CBS), cystathionine γ-lyase (CSE) and 3-mercaptopyruvate sulfurtransferase (3-MST)], and the wide range of biological effects of H2S are discussed in separate reviews Szabo, 2007 Snyder, 2010;Kimura, 2010;2013;Predmore and Lefer, 2010;Whiteman and Winyard, 2011;Kimura et al., 2012;Wang, 2012). In a recent article, we have overviewed the dual mitochondrial effects of H2S, which range from stimulatory effects, occurring at lower concentrations, to the suppression of mitochondrial function, which occurs at higher concentrations . The purpose of the current article is to outline the physiological, pathophysiological and therapeutic aspects of this regulation. Similar to our approach in the companion article , in the current article we use the terms 'sulfide' and H2S interchangeably to collectively refer to H2S gas as well as its two ionized forms in solution: HS -and S 2-. H 2 S as a potential inducer of ...

show abstract

Generation of gaseous sulfur-containing compounds in tumour tissue and suppression of gas diffusion as an antitumour treatment

Abstract: Gaseous sulfur-containing compounds are the main products in tumours and preventing the diffusion of these compounds reduces the tumour proliferation rate, which suggests the possibility of a new approach to cancer treatment.

Cited by 40 publications

References 43 publications

Faecal metabolite profiling identifies medium-chain fatty acids as discriminating compounds in IBD

Faecal metabolite profiling identifies medium-chain fatty acids as discriminating compounds in IBD

Tumor-derived hydrogen sulfide, produced by cystathionine-β-synthase, stimulates bioenergetics, cell proliferation, and angiogenesis in colon cancer

Regulation of mitochondrial bioenergetic function by hydrogen sulfide. Part II. Pathophysiological and therapeutic aspects

Contact Info

Product

Resources

About