TheRoleofStatinsinCancerTherapy.docx

1、TheRoleofStatinsinCancerTherapyThe Role of Statins in Cancer Therapy【关键词】 HMG-CoA，reductase，inhibitor，•，Tumor，•，Chemotherapy，•，Inflammation，•，PreventionLEARNING OBJECTIVES After completing this course， the reader will be able to: Explain how statins， used in the treatment of

2、hypercholesterolemia， may be applicable to cancer prevention. Discuss how statins potentially interfere with biologic processes relevant to cancer etiology. Outline the gaps in our understanding in this area of theoretical versus applied medicine. ABSTRACT Administration of 3-hydroxy-3-methylglutary

3、l coenzyme A reductase inhibitors， or statins， to ambulatory patients is associated with a lower incidence of long-term adverse cardiovascular events， including death， myocardial infarction， stroke， atrial fibrillation， and renal dysfunction. However， increasing clinical evidence suggests that stati

4、ns， independent of their effects on serum cholesterol levels， may also play a potential role in the prevention and treatment of cancer. Specifically， statins have been shown to exert several beneficial antineo-plastic properties， including decreased tumor growth， angiogenesis， and metastasis. The fe

5、asibility and efficacy of statins for the prevention and treatment of cancer is reviewed. INTRODUCTION 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors， or statins， are commonly-used drugs for the treatment of hypercholesterolemia1， 2. Statins decrease low-density lipoprotein (LD

6、L) cholesterol levels by inhibiting HMG-CoA reductase. HMG-CoA reductase in turn catalyzes the conversion of HMG-CoA into mevalonate and is the rate-limiting step in hepatic cholesterol biosynthesis 3. Clinically， statin treatment is associated with a reduction in atherosclerotic plaque formation an

7、d a stabilization of pre-existing vulnerable atherosclerotic plaques 4. Moreover， statins have been shown to decrease the incidence of adverse cardiovascular outcomes， including death， myocardial infarction， stroke， atrial fibrillation， and renal dysfunction in ambulatory patient populations 2， 513.

8、 Statin administration is also associated with a lower incidence of adverse cardiovascular outcomes after invasive procedures such as percutaneous transluminal coronary angioplasty 9 and cardiac 14， 15， vascular 1618， and noncardiovascular 19 surgery. However， the beneficial effects of statin therap

9、y are not limited to patients with hypercholesterolemia. Several randomized clinical trials have shown that， even in patients with normal total and LDL cholesterol levels， statin administration is associated with less cardiovascular morbidity and mortality 7， 8. Statins thus exert pleiotropic effect

10、s independent of their effects on cholesterol 20. Although the exact mechanisms by which statins reduce the likelihood of cardiovascular events have yet to be fully elucidated， the metabolite of HMG-CoA reductase， mevalonic acid， is a precursor of cholesterol and the isoprenoid intermediates farnesy

11、l and geranyl-geranyl pyrophosphate. These intermediates are essential for the post-translational modification of intracellular G-proteins， such as Rho， Rac， and Ras， that regulate endothelial， platelet， and leukocyte function 2123. Statins have also been shown to modulate vascular remodeling by inh

12、ibiting cellular matrix metalloproteinases and transcription factors， such as nuclear factor-B 23. In patients with acute coronary syndromes or idiopathic dilated cardiomyopathy， statin therapy has been shown to reduce untoward inflammatory activity， including changes in C-reactive protein (CRP)， se

13、rum amyloid A， tumor necrosis factor alpha (TNF-)， interleukin-6， and brain natriuretic peptide levels 21， 24， 25. Moreover， statins have been reported to decrease serum levels of the inflammatory marker CRP within 14 days of administration， suggesting an acute protective role for these drugs 26. St

14、atins have also been shown to reduce tissue injury in models of ischemia and reperfusion in several organs， including the heart， lung， brain， kidney， and gut 19， 2730. Further， statins have been shown to attenuate vasoconstriction by increasing endothelial nitric oxide (NO) activity， a benefit seen

15、within 6 weeks of the start of treatment 31. Statins thus exert pleiotropic effects， independent of cholesterol reduction， that have direct antiatherosclerotic， antithrombotic， and anti-inflammatory impacts 23， 3234. Increasing evidence suggests that statins might be useful for cancer prevention and

16、/or treatment through their interactions with essential cellular functions， such as cell proliferation and differentiation 35， 36. For example， both in vitro and in vivo studies have demonstrated that statins inhibit tumor growth and induce apoptosis in a variety of tumor cells， including melanoma 3

17、7， glioma 38， neuroblastoma 39， and leukemia cell lines 40. Additionally， several clinical trials have also assessed the antitumor activity of statins 4146. The potential role of statins in both cancer prevention and treatment is reviewed. ANTITUMOR EFFECTS OF STATINS Inhibition of Tumor Cell Growth

18、Cholesterol is a major structural component of cell membranes， and the cholesterol biosynthetic pathway is closely related to cell-growth processes. Statins reduce not only serum cholesterol levels but also mevalonate synthesis by inhibiting HMG-CoA reductase. Mevalonate is a precursor of several ma

19、jor products regulating the cell cycle， including dolichol， geranylpyrophosphate (GPP) and farnesyl-pyrophosphate (FPP) 3. Dolichol has a stimulatory effect on DNA synthesis and is linked to several tumor cell proteins 47. GPP and FPP cause isoprenylation of the intra-cellular G-proteins Ras and Rho

20、， which in turn regulate the signal transduction of several membrane receptors crucial for the transcription of genes involved in cell proliferation， differentiation， and apoptosis. Ras and Rho gene mutations are found in a variety of pancreas (90%)， colon (50%)， lung (30%)， thyroid (50%)， and myelo

21、id leukemia (30%) tumor types 36. Statins inhibit dolichol， GPP and FPP production， and block tumor cell growth in vitro and in vivo 48. For example， lovastatin has been shown to stabilize the cell cycle kinase inhibitors p21 and p27， and to arrest breast cancer cell lines in the G1 phase of the cel

22、l cycle 49. Similarly， cerivastatin has been demonstrated to inhibit Ras- and Rho-mediated cell proliferation 50. These observations have led several investigators to hypothesize that statins might inhibit the growth of a variety of tumor cell types， including prostate， gastric， and pancreatic carci

23、noma， as well as colon adenocarcinoma， neuroblastoma， glioblastoma， mesothelioma， melanoma， and acute myeloid leukemia cells 42， 5156. Interestingly， statins also modify normal endothelial， fibroblast， and smooth muscle cell growth 57， 58. However， normal cells appear to be more resistant to the ant

24、iproliferative effects of statins relative to tumor cells， which are much more likely to proliferate 59， 60. Inhibition of AngiogenesisAngiogenesis plays an important role in primary tumor growth and metastasis 61. Statins have been reported to both stimulate 6264 and inhibit 65， 66 blood vessel for

25、mation depending upon the tumor cell type 67. For example， high-dose cerivastatin decreased tumor vascularization by 51% in a murine Lewis lung cancer model 68. Statins have been shown to decrease vascular endothelial growth factor production 69 and to inhibit capillary tube formation66，70. In contr

26、ast， statins have also been shown to stimulate protein kinase B， which in turn activates endothelial nitric oxide synthase (eNOS) and increases proangiogenic activity 64. This NO-mediated effect depends on caveolin， a protein that downregulates eNOS activity 71. Endothelial cells with low caveolin e

27、xpression seem to be extremely sensitive for statin-induced angiogenesis. Finally， there is growing evidence that the effects of statins on angiogenesis are concentration dependent. Weis et al. showed that low concentrations (0.5 mg/kg per day) of cerivastatin and atorvastatin enhanced endothelial c

28、ell proliferation， whereas high concentrations (2.5 mg/kg per day) significantly inhibited angiogenesis 68. Induction of ApoptosisSeveral experimental cancer models have shown that statins exert proapoptotic properties in a variety of tumor cells. For example， lovastatin induces a profound apoptotic

29、 response in cells derived from juvenile monomyelocytic leukemia， pediatric solid malignancies (e.g.， rhabdomyosarcoma and medulloblastoma)， malignant mesothelioma， astrocytoma， and squamous cell carcinoma of the cervix， head， and neck 53， 59， 72， 73. Further， this statin-mediated apoptotic effect i

30、s also seen in cell lines treated with cerivastatin 74， 75. In fact， Wong et al. found that cerivastatin is 10 times more potent in inducing apoptosis in acute myeloblastic leukemia (AML) cell lines than other statins 75. Additionally， tumor cells themselves differ significantly in their sensitivity

31、 to statin-induced cell death. AML cells 76 and neuroblastoma cells 77 seem to be particularly sensitive to statin-induced apoptosis， whereas acute lymphoblastic leukemia cells are relatively insensitive. Proposed mechanisms for statin-mediated apoptosis include an upregulation of proapoptotic prote

32、in expression (e.g.， Bax， Bim) 78， combined with decreased anti-apoptotic protein expression (e.g.， Bcl-2) 40. For example， lovastatin increases Bim protein levels and induces cell death in human glioblastoma cell lines 79. These effects have been seen in both solid tumor and hematologic malignancies. Statins have also been shown to activate caspase proteases involved in programmed cell death. Cafforio et al. showed that cerivastatin caused cell death in human myeloma tumor cells by activating caspase-3