The cholesterol biosynthesis enzyme oxidosqualene cyclase is a new target to impair tumour angiogenesis and metastasis dissemination

Maione, Federica; Oliaro‐Bosso, Simonetta; Meda, Claudia; Nicolantonio, Federica Di; Bussolino, Federico; Balliano, Gianni; Viola, Franca; Giraudo, Enrico

doi:10.1038/srep09054

Cited by 61 publications

(54 citation statements)

References 63 publications

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“…This was particularly true for RB model 3, wherein, the model had higher flux through 'nadph' utilizing reactions, including the fatty acid elongation, alpha and omega oxidation, cortisol, testosterone, leukotriene synthesis, and peroxisomal beta oxidation pathways, as compared to the healthy model. In line with this, enzymes of cholesterol metabolism have been suggested as potential targets for different tumors [57,58].…”

Section: Significant Differences Between Healthy and Cancer Modelsmentioning

confidence: 85%

“…The model building algorithm, iMAT, was used to integrate the data and derive the metabolic models from the human metabolic network, Recon 2 [17] (1B). In line with this, enzymes of cholesterol metabolism have been suggested as potential targets for different tumors [57,58]. The developed models were then used to explain the RB-specific metabolism (3A).…”

Section: Significant Differences Between Healthy and Cancer Modelsmentioning

confidence: 96%

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Metabolite systems profiling identifies exploitable weaknesses in retinoblastoma

et al. 2018

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Retinoblastoma (RB) is a childhood eye cancer. Currently, chemotherapy, local therapy, and enucleation are the main ways in which these tumors are managed. The present work is the first study that uses constraint‐based reconstruction and analysis approaches to identify and explain RB‐specific survival strategies, which are RB tumor specific. Importantly, our model‐specific secretion profile is also found in RB1‐depleted human retinal cells in vitro and suggests that novel biomarkers involved in lipid metabolism may be important. Finally, RB‐specific synthetic lethals have been predicted as lipid and nucleoside transport proteins that can aid in novel drug target development.

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Section: Significant Differences Between Healthy and Cancer Modelsmentioning

confidence: 85%

Section: Significant Differences Between Healthy and Cancer Modelsmentioning

confidence: 96%

Metabolite systems profiling identifies exploitable weaknesses in retinoblastoma

et al. 2018

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“…High doses of statins were required for growth inhibition in cancer cells strongly expressing ORP5, while only low doses were required in cells with moderate expression (62). In addition, a growing body of research has identified that targeting mediators of mevalonate/cholesterol synthesis and lipid metabolism other than HMG-CoA reductase with statins or alternative inhibitors modulates chemotherapy and radiation resistance in pancreatic cancer, and suppresses pancreatic cancer growth and metastasis (63)(64)(65)(66)(67).…”

Section: Mechanisms Of Action and Evidence Of Antitumor Effects Of Stmentioning

confidence: 99%

Statins and pancreatic cancer

et al. 2017

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Abstract. Pancreatic cancer remains among the most lethal cancers, despite ongoing advances in treatment for all stages of the disease. Disease prevention represents another opportunity to improve patient outcome, with metabolic syndrome and its components, such as diabetes, obesity and dyslipidemia, having been recognized as modifiable risk factors for pancreatic cancer. In addition, statins have been shown to potentially reduce pancreatic cancer risk and to improve survival in patients with a combination of metabolic syndrome and pancreatic cancer. Furthermore, preclinical studies have demonstrated that statins exhibit antitumor effects in pancreatic cancer cell lines in vitro and animal models in vivo, in addition to delaying the progression of pancreatic intraepithelial neoplasia to pancreatic ductal adenocarcinoma (PDAC) and inhibiting PDAC formation in conditional K-Ras mutant mice. The mechanisms by which statins produce anticancer effects remain poorly understood, although appear to involve inhibition of the mevalonate/cholesterol synthesis pathway, thus blocking the synthesis of intermediates important for prenylation and activation of the Ras/mitogen-activated protein kinase 1 signaling pathway. Furthermore, statins have been identified to modulate the phosphoinositide 3-kinase/Akt serine/threonine kinase 1 and inflammation signaling pathways, and to alter the expression of genes involved in lipid metabolism, which are important for PDAC growth and proliferation. In addition, statins have been demonstrated to exhibit further antitumor mechanisms in a number of other cancer types, which are beyond the scope of the present review. In the present review, current evidence highlighting the potential of statins as chemopreventive agents in pancreatic cancer is presented, and the antitumor mechanisms of statins elucidated thus far in this disease are discussed.

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“…Experimental data has shown that terbinafine can decrease the proliferation in various cultured human malignant cells with a dose‐dependent effect . Furthermore, mouse model studies have suggested that terbinafine might play a crucial role in the regulation of cancer progression and tumor angiogenesis . In our study, we aimed to explore whether post‐diagnostic use of terbinafine might be associated with an improved prognosis in patients with prostate cancer.…”

Section: Introductionmentioning

confidence: 99%

“…15 Furthermore, mouse model studies have suggested that terbinafine might play a crucial role in the regulation of cancer progression and tumor angiogenesis. 16 In our study, we aimed to explore whether post-diagnostic use of terbinafine might be associated with an improved prognosis in patients with prostate cancer. By combining data from several national Swedish registers, we could study the mortality rate among patients that received terbinafine, and compared them with patients that did not use terbinafine.…”

Section: Introductionmentioning

confidence: 99%

Use of terbinafine and risk of death in patients with prostate cancer: A population‐based cohort study

Sundquist

2018

Intl Journal of Cancer

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Terbinafine is used for the treatment of several superficial fungal infections. In silico analyses and animal models suggest that terbinafine might have an anti‐tumor effect. We aimed to explore whether subsequent administration of terbinafine might be associated with a lower mortality rate in patients with prostate cancer. We identified patients diagnosed with prostate cancer between July 2005 and December 2014 from the Swedish Cancer Registry, and linked them to the Swedish Prescribed Drug Register to ascertain subsequent use of terbinafine. A total of 799 patients received oral treatment of terbinafine during the study period with a mortality rate of 18.6 per 1,000 person‐years. Compared to patients who did not use terbinafine and adjusting for a range of confounding factors, patients that received oral treatment of terbinafine had a decreased risk of death from prostate cancer (HR, 0.53; 95% CI, 0.38–0.73) and a decreased risk of death overall (HR, 0.64; 95% CI, 0.52–0.77). To account for indication bias, we further identified 907 patients who received topical use of terbinafine. However, the risk of death from prostate cancer in patients with topical use of terbinafine was 0.92 (95% CI 0.74–1.12) and the risk of death overall was 1.03 (95% CI 0.91–1.17) as compared to the controls, which suggests that there was no association between risk of death in patients with prostate cancer with topical use of terbinafine. These findings suggest that this drug's potential anti‐tumor effect needs to be explored further.

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The cholesterol biosynthesis enzyme oxidosqualene cyclase is a new target to impair tumour angiogenesis and metastasis dissemination

Cited by 61 publications

References 63 publications

Metabolite systems profiling identifies exploitable weaknesses in retinoblastoma

Metabolite systems profiling identifies exploitable weaknesses in retinoblastoma

Statins and pancreatic cancer

Use of terbinafine and risk of death in patients with prostate cancer: A population‐based cohort study

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