Statins as Anticancer Drugs

Author: Gianpiero Pescarmona
Date: 15/05/2008


Potentiating the effects of radiotherapy in rectal cancer: the role of aspirin, statins and metformin as adjuncts to therapy, 2017

Biochim Biophys Acta. 2010 Jan 4. [Epub ahead of print]
Statin-triggered cell death in primary human lung mesenchymal cells involves p53-PUMA and release of Smac and Omi but not cytochrome c.

Ghavami S, Mutawe MM, Hauff K, Stelmack GL, Schaafsma D, Sharma P, McNeill KD, Hynes T, Kung SK, Unruh H, Klonisch T, Hatch GM, Los M, Halayko AJ.

Department of Physiology, University of Manitoba, Winnipeg, MB, Canada; National Training Program in Allergy and Asthma, University of Manitoba, Winnipeg, MB, Canada; Biology of Breathing Group, Manitoba Institute of Child Health, Winnipeg, MB, Canada.

Statins inhibit 3-hydroxy-3-methyl-glutarylcoenzyme CoA (HMG-CoA) reductase, the proximal enzyme for cholesterol biosynthesis. They exhibit pleiotropic effects and are linked to health benefits for diseases including cancer and lung disease. Understanding their mechanism of action could point to new therapies, thus we investigated the response of primary cultured human airway mesenchymal cells, which play an effector role in asthma and chronic obstructive lung disease (COPD), to simvastatin exposure. Simvastatin induced apoptosis involving caspase-9, -3 and -7, but not caspase-8 in airway smooth muscle cells and fibroblasts. HMG-CoA inhibition did not alter cellular cholesterol content but did abrogate de novo cholesterol synthesis. Pro-apoptotic effects were prevented by exogenous mevalonate, geranylgeranyl pyrophosphate and farnesyl pyrophosphate, downstream products of HMG-CoA. Simvastatin increased expression of Bax, oligomerization of Bax and Bak, and expression of BH3-only p53-dependent genes, PUMA and NOXA. Inhibition of p53 and silencing of p53 unregulated modulator of apoptosis (PUMA) expression partly counteracted simvastatin-induced cell death, suggesting a role for p53-independent mechanisms. Simvastatin did not induce mitochondrial release of cytochrome c, but did promote release of inhibitor of apoptosis (IAP) proteins, Smac and Omi. Simvastatin also inhibited mitochondrial fission with the loss of mitochondrial Drp1, an essential component of mitochondrial fission machinery. Thus, simvastatin activates novel apoptosis pathways in lung mesenchymal cells involving p53, IAP inhibitor release, and disruption of mitochondrial fission. Copyright © 2009 Elsevier B.V. All rights reserved.

Statins Reduce the Risk of Lung Cancer in Humans. A Large Case-Control Study of US Veterans
Vikas Khurana, MD; Hanmanth R. Bejjanki, MD; Gloria Caldito, PhD; and
Michael W. Owens, MD
Background: Statins are commonly used cholesterol-lowering agents that are noted to suppress
tumor cell growth in several in vitro and animal models.
Methods: We studied the association of lung cancer and the use of statins in patients enrolled in the Veterans Affairs (VA) Health Care System. A retrospective case-control study nested in a
cohort study was conducted using prospectively collected data from the Veterans Integrated
Service Networks 16 VA database from 1998 to 2004. We analyzed data on 483,733 patients from eight states located in south central United States. The primary variables of interest were lung cancer and the use of statins prior to the diagnosis of lung cancer. Multiple logistic regression analysis was done to adjust for covariates including age, sex, body mass index, smoking, diabetes, and race. Statistical software was used for statistical computing.
Results: Of the 483,733 patients in the study, 163,662 patients (33.8%) were receiving statins and 7,280 patients (1.5%) had a primary diagnosis of lung cancer. Statin use > 6 months was
associated with a risk reduction of lung cancer of 55% (adjusted odds ratio, 0.45; 95% confidence interval, 0.42 to 0.48; p < 0.01). Furthermore, the protective effect of statin was seen across different age and racial groups and was irrespective of the presence of diabetes, smoking, or alcohol use.
Conclusions: Statins appear to be protective against the development of lung cancer, and further studies need to be done to define the clinical utility of statins as chemo protective agents.
(Chest. 2007; 131: 1282-8)

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