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ABSTRACT
Department of
Pharmacology, Meharry
Medical College,
Nashville, TN 37208,
USA, *Division of
Developmental Biology,
Vanderbilt University
School of Medicine,
Nashville, TN 37232,
USA, and **Department
of Biochemistry, JIPMER,
Pondicherry - 605 006,
India.
Received: 26.4.2004
Revised: 10.7.2004
Accepted: 15.8.2004
Correspondence to:
B. C. Koner
E-mail:
bckoner@hotmail.com
Hypertension and cancer are two leading diseases in the world. Often they coexist in patients.
They share some common predisposing factors e.g., ageing, obesity, alcohol consumption and
smoking habit. Abnormal angiogenesis (i.e. the formation of new blood vessels from an existing
vasculature) is a common pathological feature, and some pro-angiogenic factors e.g., vascular
endothelial growth factor, basic fibroblast growth factor, tumor necrosis factoralpha and few
interleukins are common mediators in both the conditions. Among these, the most important is
vascular endothelial growth factor, a specific mitogen for vascular endothelium. It increases vascular permeability and induces proteolytic enzymes that are necessary for vascular remodeling. Monocyte/macrophages also have been shown to play a role in angiogenesis by releasing some of the
above mediators. Angiogenesis is essential for the growth and metastasis of solid tumors. The
essence of impaired angiogenesis (despite high level of angiogenic factors), probably due to signaling
defects in the endothelium in hypertension, is not clearly understood. Some anticancer drugs e.g.,
taxanes, vinblastine, temozolomide and doxorubicin have antiangiogenic activity. Nevertheless,
several classes of specific antiangiogenic agents are being evaluated for their anticancer effects
and are emerging as new drugs for cancer treatment. COX-2 inhibitors (e.g., celecoxib and rofecoxib),
neovastat, thalidomide analogues and some cytokine inhibitors also inhibit angiogenesis. Although
certain antihypertensives are found to have antiangiogenic properties, some show pro-angiogenic
activity. Also, a number of epidemiological studies have found an association between the use of
antihypertensive drugs and risk of cancer. However, a better understanding of common cell biology and the relationship between hypertension and malignancy may be helpful in elucidating
more preventive and therapeutic avenues to manage hypertension and cancer.
KEY WORDS: Antihypertensive drugs, macrophages, new blood vessel, tumors
Introduction
Hypertension is the most common cardiovascular disease
and a major public health problem in both developed and developing countries.1 Hypertension is a major risk factor for
stroke, coronary heart disease, cardiac failure and renal failure. Prevention and treatment of hypertension have been shown
to reduce morbidity and mortality substantially.2
Epidemiological evidence from prospective studies points
to the possibility that there may be an association between the
pathogenesis of hypertension and cancer.3 Many epidemiological factors and pathophysiological pathways are quite similar
in two distinct disorders. Phaeochromocytoma, a rare tumor of
the adrenal medulla is associated with hypertension. The incidence of both hypertension and cancer increases with the ageing process and interestingly, some other risk factors are common. Obesity is responsible for hypertension and some forms
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Hypertension and cancer
Table 1
Factors influencing angiogenesis
Pro-angiogenic factors
Antiangiogenic factors
Macrophages are supposed to play a key role in tumor angiogenesis. By release of VEGF, bFGF, transforming growth factor-alpha (TGF-alpha), IL-1, IL-6, IL-8 and TNF, activated
macrophages have the capability to influence each phase of
the angiogenic process, such as alterations of the local extracellular matrix and stimulation of vascular endothelial
cells.40,44,45 The tumor-infiltrating macrophage density correlates significantly and positively with intratumor microvessel
counts and negatively with patients survival.46 Quantification
of microvessel density in the tumor specimen correlates with
either metastasis or recurrence in many malignancies such as
breast and lung cancer.47 Several studies have shown that the
number of infiltrating macrophages were significantly associated with VEGF expression.41,48 On the other hand, VEGF has
also been found to stimulate migration in macrophages. Thus,
VEGF expression may be an important factor in the recruitment of tumor-associated macrophages.49 Further, some recent studies showed an association between the mutation of
p53 protein and VEGF expression.50,51 It appears that VEGF is
a major regulator of angiogenesis and vasculogenesis.
Antiangiogenic drugs
Angiogenesis begins with local degradation of the basement membrane-surrounding stroma by the endothelial cells
in the direction of the angiogenic stimulus (Figure 1). It has
already been mentioned that endothelial invasion is regulated
by different autocrine and paracrine factors. Malignant invasion and physiological invasion share some common gene products and signaling cascades. Understanding the difference in
gene expression in the development of the pro-angiogenic and
invasive phenotype is an important step towards therapeutic
targeting. Nevertheless, certain chemotherapeutic agents have
potent antiangiogenic properties, which may be a part of their
antitumor activity. Among taxanes, paclitaxel (taxol) and
docetaxel (taxotere) have antiangiogenic activity.52 However,
docetaxel appears to be more potent at inhibiting angiogenesis. 53 Similarly, anticancer drugs such as vinblastine 54
temozolomide55 and doxorubicin56 are capable of inhibiting
angiogenesis. On the other hand, antiangiogenic therapy using angiogenesis inhibitors is a relatively new and promising
area of cancer treatment that specifically inhibits new blood
vessel formation within the tumor. Physiologically, angiogenesis occurs during embryogenesis, wound healing and repro-
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hibiting matrix breakdown, the matrix metalloproteinase inhibitors, such as matrimastat, prinomastat and neovastat. (2)
Drugs that block endothelial cell signaling via VEGF and its
receptor like antiVEGF antibodies. (3) Drugs that are similar
to endogenous inhibitors of angiogenesis including endostatin,
angiostatin, interferons and IL-12. (4) Thalidomide and its
analogs have been shown to inhibit growth factor-induced
neovessel formation. Moreover, (5) drugs such as celecoxib,
rofecoxib, squalamine, fumagillin analog, and those targeting
the integrins are also being evaluated as angiogenesis inhibitors.
Non-steroidal antiinflammatory drugs (NSAIDs), particularly selective cyclooxygenase-2 (COX-2) inhibitors such as
celecoxib or rofecoxib have been shown to inhibit angiogenesis.60,61 COX-2 catalyzes the synthesis of prostaglandins from
arachidonic acid and there is evidence that it may promote
tumor angiogenesis.60 COX-2 is upregulated in cancer cells,
adjacent stromal cells and angiogenic endothelial cells during
tumor progression.62 There is enough preclinical evidence that
strongly supports the potential role of COX-2 inhibitors for the
prevention and treatment of cancer.60 On the other hand,
neovastat is another promising antiangiogenic drug purified
from shark cartilage.63 The drug is effective after oral administration and induces endothelial cell apoptosis, inhibits matrix metalloproteinase activities and VEGF-mediated signaling
pathways.64 Recently, it has been observed that a number of
thalidomide analogs act as antimalignant drugs due to their Tcell co-stimulatory, antiangiogenic and antiinflammatory effects. These thalidomide analogs are known as
immunomodulatory drugs and include revimid and actimid.
Further, the other class of analogs termed as selective cytokine
inhibitory drugs (SelCIDs) are phosphodiesterase 4 inhibitors.
They do not stimulate T-cells. These analogs have been evaluated for their ability to inhibit tumor angiogenesis, vascularity
and growth.65,66
Antihypertensive agents and angiogenesis
Interestingly, bradykinin facilitates growth in many cancers by increasing tissue permeability and stimulating angiogenesis. Certain peptide and non-peptide bradykinin antagonists show potential anticancer properties by inhibiting angiogenesis (VEGF-mediated) and membrane metalloproteinase
activity (MMP-2 and 9).67 It is well known that bradykinin is an
important component of physiological blood pressure lowering system. Several antihypertensive drugs have effects on
the process of angiogenesis. 68 In general, drugs such as
atenolol, diltiazem and enalapril do not affect in vitro angiogenesis in humans within therapeutic ranges.69 On the other
hand, drugs like mibefradil70 (calcium channel blocker) and
terazosin71 (1-blocker) show direct antiangiogenic activity.
Similarly, angiotensin-converting enzyme (ACE) inhibitors such
as captopril and perindopril have been shown to inhibit angiogenesis.72,73 Perindopril, which was shown to be a potent inhibitor of the growth of hepatocellular carcinoma and angiogenesis, also suppresses VEGF at clinically relevant doses.73
On the contrary, it has been observed that the very low dose
combination of perindopril and indapamide (a non-thiazide
sulfonamide diuretic) induces neovascularization.74 Similarly,
ACE inhibitor quinaprilat, an active metabolite of quinapril,
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Hypertension and cancer
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Conclusions
12.
A substantial number of cancer patients have cardiovascular co-morbidity, particularly hypertension. These two distinct diseases, i.e., cancer and hypertension, can share some
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experimental cancer therapy, inhibition of angiogenesis has
become a major goal to block the tumor growth. This therapeutic approach requires a precise knowledge of angiogenesis. In this context, more studies at the basic biological level
may improve our understanding about the relationship between
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