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Keywords:

  • angiogenesis;
  • cancer;
  • cardiovascular disease;
  • aspirin;
  • β-blocker;
  • statin;
  • ACEI;
  • ARB

Abstract

  1. Top of page
  2. Abstract
  3. Aspirin
  4. β-Blockers
  5. Angiotensin converting enzyme inhibitors and ARBs
  6. Statins
  7. Calcium channel blockers
  8. Others
  9. Perspectives
  10. Acknowledgements
  11. References

Cancer and cardiovascular disease are the leading causes of death worldwide. Cardiovascular medications have recently been found to have favorable effects also for the treatment of noncardiovascular diseases, including cancer. In this review, we use a reverse bedside-to-bench approach to investigate the effects of common cardiovascular medications on tumor angiogenesis and vascular angiogenesis. Aspirin seems to reduce the risk of developing cancer, particularly colon cancer. However, whether the protective influence of aspirin is due to antiangiogenesis effect is still unclear. β-Blockers, which are normally used to reduce heart rate and prolong diastole, trigger an increase in stretch-associated release of proangiogenic growth factors thereby inducing angiogenesis. However, according to other studies β-blockers are able to inhibit angiogenesis via multiplicate mechanisms. Similarly, angiotensin converting enzyme inhibitor and angiotensin II type 1 receptor blocker have controversial effects for the regulation of cell proliferation and angiogenesis. Statins can augment collateral vascular growth in ischemic tissues and restrict the development of cancer. So this topical anti-inflammatory drug seems to be of high value for further therapy. Finally, suggestions on how this pilot experience may guide the conduct of future preclinical investigations, and clinical trials are discussed.

Currently, many widely used cardiovascular medications are being reconsidered due to their versatile properties in the field of cancer therapeutics and prevention. Preclinical evidence and clinical experience indicate that common cardiovascular medications are able to reduce morbidity and mortality of cardiovascular diseases. In addition, these medications can also play a protective role for reducing incidence and mortality of cancer.1–8

The term angiogenesis, as one of the hallmarks of cancer,9 is used to describe all forms of blood vessel growth, both beneficial compensatory blood vessel growths in tissue ischemia as well as detrimental blood vessel growth, as it occurs in cancer.10–14 Bevacizumab, the novel humanized monoclonal antibody designed to inhibit vascular endothelial growth factor-A (VEGF-A), has been approved by the United States Food and Drug Administration (FDA) for the treatment of many advanced tumors. However, a significantly increased risk of cardiac ischemic events has been reported recently.15–17 Angiotensin receptor blockers (ARBs) are widely used drugs for treatment of hypertension and heart failure. Their role for tumor development is under discussion according to a recent meta-analysis,18 possibly due to the proangiogenic effects of these drugs.19

Both of these unexpected phenomena raise the question: Is increased angiogenesis as a reparative process with ischemia often associated with cancer? Although many studies indicate that newly developed strategies, including the administration of common cardiovascular medications, are beneficial for treating ischemic vascular disease and improving the outcome of common malignancies, these findings lead us to the question of whether there is more than meets the eye with these strategies.

With the use of a reverse bedside-to-bench approach, we examine the current knowledge about common cardiovascular medications with relation to cardiovascular disease and tumor therapy by discussing each agent individually below (Tables 1 and 2).

Table 1. Reports on proangiogenic effects of cardiovascular medications in experimental studies
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Table 2. Reports on antiangiogenic effects of cardiovascular medications in experimental studies
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Aspirin

  1. Top of page
  2. Abstract
  3. Aspirin
  4. β-Blockers
  5. Angiotensin converting enzyme inhibitors and ARBs
  6. Statins
  7. Calcium channel blockers
  8. Others
  9. Perspectives
  10. Acknowledgements
  11. References

Several lines of evidence suggested that use of aspirin might reduce the risk of some cancers, particularly gastrointestinal tumors.75, 76 More recently, a large number of randomized trials have showed that daily aspirin reduces the long-term risk of death due to several common cancers.2 The 20-year risk of cancer death remained about 20% lower in the daily aspirin group. The latent period before the effect on death was about 5 years for oesophageal, pancreatic, brain and lung cancer and was more delayed for stomach, colorectal and prostate cancer.

The mechanisms involved are complex, but accumulating evidence suggests that cyclooxygenase-2 (COX-2) overexpression promotes tumorigenesis, and most nonsteroidal anti-inflammatory drugs, such as aspirin, act as nonselective inhibitors of the enzyme COX, which in turn suppress tumorigenesis.77–81 In a study involving angiogenesis in rats, it was observed that corneal blood vessel formation was suppressed by celecoxib but not by a COX-1 inhibitor.82 Williams et al. found that tumor growth was markedly attenuated in COX-2(−/−), but not COX-1(−/−) or wild-type mice. Treatment of wild-type C57BL/6 mice bearing Lewis lung carcinoma tumor using a selective COX-2 inhibitor also reduced tumor growth. A decrease in vascular density was observed in tumor grown in COX-2(−/−) mice when compared with those in wild-type mice.83 Uefuji et al. showed that COX-2 protein was over-expressed in 31 of 42 (74%) gastric cancers based on an immunoblot analysis. The COX-2 overexpressed cases showed significantly elevated levels of prostaglandin E2 in cancer tissues and significantly higher microvessel density.84 These data indicated that COX-2 and COX-2 derived prostaglandin may play a major role in cancer development through the mechanism of stimulating tumor cell growth and angiogenesis.

At present, the effect of aspirin on vascular angiogenesis or arteriogenesis remains unclear. Hoefer tested the potential of aspirin and clopidogrel to influence collateral artery growth in 54 New Zealand white rabbits.55 In contrast to the neutral effect on natural arteriogenesis of clopidogrel, aspirin significantly inhibited collateral artery growth, probably due to its anti-inflammatory effects through inhibition of COX activity. But the results of this study were based on doses (10 mg/kg) of aspirin and clopidogrel higher than those given in clinical practice for ischemic vascular disease. But Borthwick et al. concluded with similar results in vitro that aspirin directly inhibits angiogenesis via a COX-independent mechanism.56 In a prospective clinical study, VEGF had lower titer levels in patients who received 100 mg aspirin daily during undergoing coronary artery bypass graft operation, and this effect was independent of the ischemic burden.57 However, some patients remained on aspirin even during the perioperative period because of interfering with other agents containing aspirin or an urgent operation, which might represent a possible limitation. Only one study reported that low-dose aspirin promotes migration and adhesion and delayed the onset of senescence of circulating endothelial progenitor cells (EPCs), which plays a key role in restoring endothelial function and enhancing angiogenesis.20

β-Blockers

  1. Top of page
  2. Abstract
  3. Aspirin
  4. β-Blockers
  5. Angiotensin converting enzyme inhibitors and ARBs
  6. Statins
  7. Calcium channel blockers
  8. Others
  9. Perspectives
  10. Acknowledgements
  11. References

In 2004, a cohort study including 839 patients with cardiovascular disease, followed up prospectively for an average period of 10 years, had shown a reduced cancer risk for patients taking β -blockers.3 Recently, a population-based study provided the evidence to support preclinical observations suggesting that inhibiting the β(2)-adrenergic signaling pathway could reduce breast cancer progression and mortality.7

Animal experiments have shown that carvedilol reduces the expression of hypoxia-inducible factor-1α (HIF-1α). This molecular switch activates transcription by binding to hypoxia-response elements, which in turn act as key regulators for tumor angiogenesis.70 The expression of matrix metalloproteinases (MMPs), particularly MMP-9, is significantly increased during tumor progression and is thought to play a major role for angiogenesis.85 Propranolol, also a nonselective β-antagonist like carvedilol, can inhibit MMP-9 secretion and tubulogenesis of endothelial cells.71

In 2008, propranolol was shown to inhibit the growth of hemangiomas, the most common vascular tumor of infancy.86 Infantile hemangiomas are composed of a complex mixture of clonal endothelial cells. Two major proangiogenic factors are involved during the capillary growth: basic fibroblast growth factor (bFGF) and VEGF.87 Léauté-Labrèze hypothesized that downregulated expression of VEGF and bFGF genes through the down-regulation of the Raf-mitogen-activated protein kinase pathway may cause the triggering of apoptosis of capillary endothelial cells, and this might be the mechanisms for the inhibition of angiogenesis by propranolol. Lamy et al. showed that in vitro propranolol inhibits the proliferation of human umbilical vein endothelial cells based on multiple molecular targeting of critical steps in the angiogenic cascade. These data provided further justification for the investigation of the use of β-blockers for other angiogenesis-dependent human diseases.72

The negative correlation between heart rate (HR) and capillary to myocyte ratio supports that bradycardia is one of the stimulators of the increased angiogenic response.41, 88, 89 The reduced HR prolongs diastole, which aggravates the degree of stretch in concert with the remodeling-associated dilation of chamber and triggers an increase in stretch-associated release of angiogenic growth factors. Zheng et al. showed that stretch of cardiac myocytes upregulated VEGF and tumor growth factor-β (TGF-β) signaling may regulate VEGF expression.90 Alinidine, a bradycardic agent, also showed the upregulation effect of VEGF, VEGF receptor 1 (FLT-1) and bFGF proteins in the postmyocardial infarction (post-MI) rat hearts.41 Dedkov et al. demonstrated that the largest portion of the increase in arteriolar length density detected in post-MI hearts is due to the formation of the smallest “terminal” arterioles.40 Similar observations were reported by Lei,41, 91 suggesting the concept that new arterioles most likely emerge from pre-existing capillaries via arteriogenesis.

Angiotensin converting enzyme inhibitors and ARBs

  1. Top of page
  2. Abstract
  3. Aspirin
  4. β-Blockers
  5. Angiotensin converting enzyme inhibitors and ARBs
  6. Statins
  7. Calcium channel blockers
  8. Others
  9. Perspectives
  10. Acknowledgements
  11. References

In 1998, Lever et al. investigated the risk of cancer in patients receiving ACE inhibitors in a retrospective cohort study. Compared with the controls, the relative risk of cancer incidence was 0.72 (95% confidence interval (95% CI) 0.55–0.92).8 In 2003, the Candesartan in Heart failure Assessment of Reduction in Mortality and Morbidity programme, which assessed candesartan in heart failure, reported an unexpected finding of slightly more cancer deaths in the treatment group than with the placebo (86 [2.3%] vs. 59 [1.6%], p = 0.038).92 This led us to examine the effects of ARB on occurrence of new cancers. More recently, a meta-analysis of randomized controlled trials on the correlation between ARB and the risk of cancer was published. Patients randomly assigned to receive ARB had a significantly increased risk of new cancer occurrence compared with patients in control groups (7.2% vs. 6.0%, risk ratio [RR] 1.08, 95% CI 1.01–1.15; p = 0.016). When analysis was limited to trials where cancer was a prespecified endpoint, the RR was 1.11 (95% CI 1.04–1.18, p = 0.001).18 Later, the debate has been fuelled by conflicting data.93, 94 Another unexpected relationship of ARBs with MI risk was first described in 200495 and confirmed the existence of ARB-MI paradox by the meta-analyses, which including 11 key ARB trials, nine of them extended an excess rates of MI.96 Such nonconcordances indicated that the underlying mechanism between ARB and angiogenesis certainly requires further investigation.

Currently, a number of studies demonstrated the antiangiogenic effects of ARBs in cancer models.65, 66, 97 But a recent study challenged this initial hypothesis and revealed that candesartan treatment increased tumor size.98 Walther et al. applied the alginate implant angiogenesis model in mice and showed that losartan administration increased vascular density.31 This revealed that the effects of ARBs on tumor angiogenesis are somewhat controversial.

Angiotensin II (AngII), the biologically active peptide of renin–angiotensin system (RAS), is a key regulator of blood pressure and body fluid homeostasis and is also recognized as a potent mitogen on endothelial cells. Several in vivo and in vitro models investigated the effects of AngII on vascular angiogenesis through the upregulation of VEGF99 and VEGF-induced EPC proliferation.100 But Fabre et al. showed that treatment with the angiotensin converting enzyme inhibitor (ACEI) quinaprilat, which decreased circulating levels of AngII, promotes angiogenesis in a rabbit model of hindlimb ischemia,25 leaving an argument of AngII-mediated angiogenesis.

AngII mediates its biological effects through binding to two subtypes of receptors, AT1R and AT2R. The effects of candesartan, an AT1R blocker, have been analyzed in experimental rat model of coronary capillary growth and angiogenesis. Candesartan strongly inhibited vascular expressions of VEGF, HIF-1α and advanced glycation end products (AGEs) and ameliorated the morphometric changes, suggesting that AT1R has a major role in these processes.63 Valsartan, another AT1R antagonist, has adverse effects on survival rate concomitant with the progression of cardiac remodeling owing to impaired VEGF-mediated angiogenesis.62 However, de Boer et al. reported that microvessel density after MI is decreased, when the AT1R is overexpressed and the increase in microvessel density after the AT receptor blockade was not accompanied by increased myocardial VEGF levels.101 Other studies provided the evidence that the AT2R mediates a stimulation of in vivo angiogenesis and indicated that AngII is a humoral regulator of peripheral angiogenesis involving two receptor subtypes.31

Another important factor is bradykinin (BK), a 9-amino acid peptide that is degraded by ACE. Perenti et al. demonstrated that BK receptor 1 induced angiogenesis by coupling to nitric oxide synthase (NOS) activation and upregulation FGF-2.102 Afterward Silvestre et al. showed the proangiogenic effect of ACEI is mediated by BK receptor 2 signaling and was associated with upregulation of endothelial NOS (eNOS) content, independent of VEGF expression.21 There is now a general consensus that both B1 and B2 receptors contribute to angiogenesis.

Statins

  1. Top of page
  2. Abstract
  3. Aspirin
  4. β-Blockers
  5. Angiotensin converting enzyme inhibitors and ARBs
  6. Statins
  7. Calcium channel blockers
  8. Others
  9. Perspectives
  10. Acknowledgements
  11. References

Statins are a class of drug used to lower cholesterol levels by inhibiting the enzyme 3-hydroxy-3-methylglutaryl-coenzyme A reductase, which plays a central role in the production of cholesterol in the liver. As randomized controlled trials have shown that they are most effective in those already suffering from cardiovascular disease (secondary prevention), they are also advocated and used extensively in those without previous cardiovascular disease but with elevated cholesterol levels and other risk factors.103, 104

As angiogenic factors are also involved in the growth of solid tumors, targeting the formation of blood vessels is consequently regarded as a promising strategy in cancer therapy. The role of statins in cancer prevention and treatment through their multitargeted effects is puzzled. Two groups reported on the immunosuppression effect of statins, with an unexpected sign they may contribute to the development of malignant diseases.105, 106 Concerns about the long-term safety of statins were originally raised by a review of the carcinogenicity of lipid-lowering drugs in rodent studies.107 The meta-analysis published in 2001 demonstrated no association between statin use over a 5-year period and the risk of fatal and nonfatal cancers.4 This conclusion was limited by the relatively short follow-up of the studies analyzed, but this led to concern for the potential carcinogenicity of statins in the long term. However, an analysis from the PHARMO database of 3,129 statins users and 16,976 matched controls revealed that statin use was associated with a 20% reduction of cancer and suggested that statins are protective when used longer than 4 years.5 The latest survey to determine whether statin treatment is effective and safe in very elderly (80 years and older) acute MI patients also showed that statin treatment is associated with lower cardiovascular mortality without increasing the risk of the development of cancer.6

Although some studies showed statins to have antiangiogenic effects,108 many datasets have also showed statins to have angiogenic effects.43, 45, 46 But the most accepted theory is that there is a biphasic dose-dependent effect of statins on angiogenesis. Weis et al. investigated the effect of the statins cerivastatin and atorvastatin on angiogenesis at low concentrations (0.005–0.01 μmol/L) and high concentrations (0.05–1 μmol/L). Statins have proangiogenic effects at low therapeutic concentrations but antiangiogenic effects at high concentrations that are reversed by geranylgeranyl pyrophosphate.109 Dulak and Urbich confirmed the dual effect of atorvastatin on angiogenic activity of endothelial cells, being stimulatory at low (nanomolar) concentrations and inhibitory at higher (micromolar) doses.110, 111

The angiogenic mechanism of statin at low concentrations concerns the PI3K–Akt pathway.112 The constitutive activation of Akt signaling protects cardiomyocytes from apoptosis, actives endothelial cell nitric oxide (NO) production in response to VEGF113, 114 and augments mobilization of bone marrow-derived EPCs.115, 116 Landmesser et al. suggested endothelial NO bioavailability likely represents an important therapeutic target and mediates beneficial effects for statin-induced improvement of EPCs mobilization, myocardial neovascularization, left ventricular dysfunction, interstitial fibrosis and survival after MI.117 Siddiqui et al. showed simvastatin enhanced VEGF expression in hearts of apo-E knockout mice and its receptor VEGFR-2 mRNAs as well as increased production of eNOS.118 Matsumura et al. showed that atorvastatin strongly induced angiogenesis with increases of VEGF, IL-8, Ang-1, Ang-2, eNOS and heme oxygenase-1 proteins in ischemic hindlimbs.42 Chen indicated two prominent factors; VEGF and brain-derived neurotrophic factor (BDNF) mediate angiogenesis, brain plasticity and enhance functional recovery after stroke.43 Another study demonstrated that fluvastatin increased the expression of Id1 protein, which is involved in the control of cell cycle progression and thereby could delay cellular differentiation and senescence.119

Evidence available so far demonstrates the diverse effects of statins on angiogenesis and tumor growth.120 The study performed by Sata et al. suggests that statins may not promote the development of cancer and atherosclerosis at the doses that augment collateral flow growth in ischemic tissues.44 They induced hind limb ischemia in wild-type mice by resecting the right femoral artery and subsequently inoculated cancer cells in the same animal. Cerivastatin enhanced blood flow recovery in the ischemic hind limb as determined by laser Doppler imaging, whereas tumor growth was significantly retarded. Cerivastatin did not affect capillary density in tumors. Cerivastatin, pitavastatin and fluvastatin inhibited atherosclerotic lesion progression in apoE-deficient mice, whereas they augmented blood flow recovery and capillary formation in ischemic hind limb. They suggested that proangiogenic or antiangiogenic effects of statins might also depend on the model and the milieu.

Calcium channel blockers

  1. Top of page
  2. Abstract
  3. Aspirin
  4. β-Blockers
  5. Angiotensin converting enzyme inhibitors and ARBs
  6. Statins
  7. Calcium channel blockers
  8. Others
  9. Perspectives
  10. Acknowledgements
  11. References

Calcium channel blockers (CCBs), widely used for the treatment of hypertension and angina pectoris, could prevent cardiovascular complications, because these drugs induce an effective vasodilatation. In 2001, a comprehensive review of CCB specific effects on cancer, bleeding and suicide showed highly variable results.121 Nonetheless, both biologically and epidemiologically, the evidence of a link to cancer is inconclusive. Recent analysis from randomized clinical trials on the correlation between CCBs and cancer showed an increased risk of cancer with CCBs (1.06, 1.01–1.12; p = 0.02).94 Thus, the relation between CCBs and risk of cancer cannot be ruled out.

Several bodies of evidence supported the putative role of CCB in the modulation of angiogenesis. Nishizawa et al. observed that benidipine induced an increase in the capillary-to-cardiomyocyte ratio (40% increase compared with the control group), resulting in complete restoration of capillary density, but nitrendipine had no such effects.36 Alternatively, coronary capillaries were significantly smaller in the benidipine group. These observations suggested that the decreased capillary ratio and density present in the untreated and nitrendipine-treated groups may dilate fully to maximize blood flow, whereas the coronary reserve is sufficient in the benidipine group. Nifedipine induces upregulation of superoxide dismutase expression in vascular smooth muscle cell via NO production from endothelial cell.122 Increased NO production in endothelial cell is important for angiogenesis that is confirmed by a study in eNOS knockout mice in which impaired angiogenesis was restored by adenoviral eNOS administration.123 In addition, nifedipine improved angiogenesis-related functions of EPCs (differentiation, migration and resistance to oxidative stress) in vitro.37

The effect of CCB on inhibition of angiogenesis has also been studied. Nimodipine significantly inhibited the growth of new vessels in rats with significant decreases of platelet-derived growth factor, VEGF and TGF-β2 in retinal and vitreous tissues.68 Benidipine suppresses expression of angiogenic growth factors, such as VEGF, bFGF and TGF-β1 on cardiac remodeling in Otsuka-Long–Evans-Tokushima-Fatty rats, a Type II (noninsulin-dependent) diabetes mellitus model.67

However, CCBs are believed to increase coronary blood flow by inhibiting the entry of Ca2+ into smooth muscle cells through specific L-type calcium channel-blocking effects38; CCB also exerts a direct effect on endothelial cell permeability that is independent of calcium channels.124 Orth et al. demonstrated that CCB inhibited the proliferation of mesangial cells, which have no L-type calcium channels.125 Miura et al. suggested that nifedipine-induced VEGF secretion might be dependent of L-type calcium channels in human coronary smooth muscle cell (HCSMCs) and cellular interaction between human coronary artery endothelial cells and HCSMCs seems very important for nifedipine-induced angiogenesis.38 The research of Nishizawa et al. demonstrated that benidipine (a blocker of T-type and L-type Ca2+ channels), but not nitrendipine (a blocker of L-type Ca2+ channels), promotes ischemia-induced angiogenic response by enhancing HIF-1α -mediated VEGF and eNOS expressions.36 Nebe et al. also demonstrated that mibefradil, the T-type Ca2+ channel blocker, but not the L-type Ca2+ channel blockers amlodipine and verapamil, attenuated leukocyte adhesion in vitro.126

Others

  1. Top of page
  2. Abstract
  3. Aspirin
  4. β-Blockers
  5. Angiotensin converting enzyme inhibitors and ARBs
  6. Statins
  7. Calcium channel blockers
  8. Others
  9. Perspectives
  10. Acknowledgements
  11. References

Nitroglycerin (NTG) is one of the oldest and most useful drugs as a vasodilator for treating heart disease by shortening or even preventing attacks of angina pectoris. These effects arise, because NTG is converted to NO in the body by mitochondrial aldehyde dehydrogenase.127

Several studies emphasized the essential role of NO to stimulate angiogenesis, and it appears feasible that soon an NO-releasing chemical will be available for clinical testing.51, 128, 129 But DiFabio et al. indicated that continuous NTG therapy might do all of the following: impair EPC-mediated processes, increase the percentage of circulating cells expressing the EPC marker CD34, increase the susceptibility of expanded EPCs to apoptosis in vivo, increase apoptosis while decreasing phenotypic differentiation, migration and mitochondrial dehydrogenase activity of EPCs ex vivo, all of which could be detrimental in the setting of an ischemic cardiovascular disease.73 A dose of 0.4 mg/kg NTG was reported to reduce tumor blood flow by 32% compared with the control group in female severe combined immunodeficient mice.130 The effect of nitrate on an increase in angiogenesis has been conflicting.

Niacin, also known as vitamin B3, nicotinic acid and vitamin pellagra-preventing-faktor, one of the 40–80 essential human nutrients, is an effective medication in the clinical use for increasing high-density lipoprotein cholesterol.

The study of Chen et al. showed that Niaspan (a prolonged release formulation of niacin) increases tumor necrosis factor-α-converting enzyme (TACE) expression and Notch signaling activity and promotes arteriogenesis after stroke.53 Inhibition of TACE or Notch1 and knockdown of TACE or Notch1 gene expression by siRNA significantly decreased niacin-induced cerebral arterial smooth muscle cells migration and arterial sprouting in vitro. His previous studies have found that niacin upregulates angiogenesis after stroke by the Ang1/Tie2, PI3K/Akt and eNOS pathways.52

Ivabradine is a new therapeutic agent that is reported to reduce HR at the level of the If current in sinus node, obtaining a similar findings like β-blockers treatment on cardiac angiogenesis.39 The underlying mechanism is related not only to the HR reduction but also to prevent the endothelial dysfunction. Both in apoE-deficient and dyslipidemic mice, the protective pathways may involve an improvement of the shear stress-dependent endothelial stimulation or a reduction in mechanical fatigue of the arterial wall.131, 132

Fenofibrate, like other fibrates, reduces low-density lipoprotein and very low density lipoprotein levels, as well as increasing high-density lipoprotein levels and reducing triglycerides level. Although Katayama et al. showed fenofibrate stimulated in vitro angiogenesis, this effect was abolished by coincubation with L-NAME, the antagonist of eNOS, whose effects on fenofibrate-causing angiogenesis have suggested conflicting results.54, 74

As an agonistic ligand of peroxisome proliferator-activated receptor alpha (PPAR-α), fenofibrate is also found to be critical in cases of inflammation.133 PPAR-α ligands can inhibit endothelial cell proliferation besides migration and induce endothelial cell apoptosis in vitro.134, 135 Recent studies have revealed the expression of PPAR-α in tumor cells136 and PPAR-α ligands decrease tumor development in murine colon carcinogenesis.137 In addition, fenofibrate reduces adventitial angiogenesis and inflammation in a porcine model.138 Also, the anti-inflammatory effect of PPAR-α ligands is mediated notably through inhibition of inducible NOS, COX-2 and tumor necrosis factor-alpha.139

Perspectives

  1. Top of page
  2. Abstract
  3. Aspirin
  4. β-Blockers
  5. Angiotensin converting enzyme inhibitors and ARBs
  6. Statins
  7. Calcium channel blockers
  8. Others
  9. Perspectives
  10. Acknowledgements
  11. References

Conventional cardiovascular medications are associated with significant effects on tumor angiogenesis in addition to their primary functions on vascular angiogenesis. Although insights from many studies over the last decade have taught us that there is a large gap in knowledge between the clinical and experimental setting, it is now easy to scan clinical trials using the concept that some cardiovascular medications could be used for the treatment for cancer patients140–142 (Fig. 1).

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Figure 1. Frequency of reports on “cancer” and “cardiovascular medication” as listed in ClinicalTrials.gov (http://clinicaltrials.gov/) until 2010.

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In consideration of the widely prescription of cardiovascular drugs in the world, there are still two challenges that must be overcome before translating them into successful use within the hospital.

The first challenge are related with the differences between the effects of such medications on in vitro laboratory models and on patients enrolled in clinical trials. The challenge encountered during trial design is not unique to this field, and sporadic progression from preclinical, proof-of-concept studies to clinical use is the rule rather than the exception during therapeutic development.143 Bedside-to-bench approaches are appealing approaches, because it means that patients' unexpected responses become a kind of valuable human experiment, and failed trials can lead to the development of new hypotheses that may help refine the experimental setting in its next iteration.144 The well-known reverse translational example, gefitinib, has provided an example that the application of genomic science to drug selection may be helpful and possibly reduce the odds of adverse drug reactions. Recently, many cardiovascular medications are listed in the FDA's Table of Pharmacogenomic Biomarkers in Drug Labels (www.fda.gov/Drugs/ScienceResearch/ResearchAreas/Pharmacogenetics/ucm083378.htm). Such studies that are based on a rapid scan of markers across the genome of drug–response phenotype deserve further implementation.145–148

The second challenge is the risk–benefit analysis of this kind of novel, possibly double edged therapeutic interventions. In actuality, potent therapeutic interventions are rarely free of harmful side effects.149 As our understanding of complex interactions and crosstalk between mechanisms involved in tumor angiogenesis and vascular angiogenesis becomes more refined, we are optimistic that these strategies can be developed to deliver agents to target tissues with enough selectivity. Preceding future clinical trials about cardiovascular medication in cancer therapy, an open dialogue between both cardiologists and oncologists will be required for optimal patient care.

Acknowledgements

  1. Top of page
  2. Abstract
  3. Aspirin
  4. β-Blockers
  5. Angiotensin converting enzyme inhibitors and ARBs
  6. Statins
  7. Calcium channel blockers
  8. Others
  9. Perspectives
  10. Acknowledgements
  11. References

The authors thank Dr. Marion Anders (Universitätsklinikum Hamburg-Eppendorf) for fruitful discussions during the preparation of the manuscript and John Chang (NY, USA) for valuable comments and suggestions on the manuscript.

References

  1. Top of page
  2. Abstract
  3. Aspirin
  4. β-Blockers
  5. Angiotensin converting enzyme inhibitors and ARBs
  6. Statins
  7. Calcium channel blockers
  8. Others
  9. Perspectives
  10. Acknowledgements
  11. References