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Abstract

  1. Top of page
  2. Abstract
  3. OVERVIEW ON HYPOXIA-INDUCIBLE FACTOR 1 (HIF-1)
  4. THE ROLE OF HIF-1 IN THE PATHOGENESIS AND TREATMENT OF CARDIOVASCULAR DISEASE
  5. THE ROLE OF HIF IN CARCINOGENESIS
  6. ATHEROSCLEROTIC PLAQUE AND MICROMETASTASIS
  7. CONCLUSIONS
  8. Acknowledgements
  9. LITERATURE CITED

Tissue hypoxia occurs where there is an imbalance between oxygen supply and consumption in both, solid tumors as a result of exponential cellular proliferation and in atherosclerotic diseases as a result of inefficient blood supply. Hypoxia-inducible factor 1 (HIF-1) is central in normal angiogenesis and cancer angiogenesis. HIF-1 is a transcriptional activator composed of an O2- and growth factor-regulated HIF-1α subunit and a constitutively expressed HIF-1β subunit. Upon activation, HIF-1 drives the expression of genes controlling cell survival and governing the formation of new blood vessels. A better understanding of the regulation of HIF-1α levels by the receptor tyrosine kinases/phosphatidylinositol 3-kinase signaling pathway and by the HIF prolyl hydoxylases has provided new insights into the development of anticancer and revascularization therapeutics. We will focus on the potential of a new pharmacology for regulating HIF pathways in both, cancer and ischemic cardiac diseases. The consequences of the switch of HIF activation in these two disease states and the signaling pathway overlap that atherosclerosis and cancer angiogenesis share are discussed. © 2004 Wiley-Liss, Inc.


OVERVIEW ON HYPOXIA-INDUCIBLE FACTOR 1 (HIF-1)

  1. Top of page
  2. Abstract
  3. OVERVIEW ON HYPOXIA-INDUCIBLE FACTOR 1 (HIF-1)
  4. THE ROLE OF HIF-1 IN THE PATHOGENESIS AND TREATMENT OF CARDIOVASCULAR DISEASE
  5. THE ROLE OF HIF IN CARCINOGENESIS
  6. ATHEROSCLEROTIC PLAQUE AND MICROMETASTASIS
  7. CONCLUSIONS
  8. Acknowledgements
  9. LITERATURE CITED

HIF-1 is a transcription factor and is critical to survival in hypoxic conditions, both in cancer and cardiac cells. HIF-1 is composed of the O2- and growth factor-regulated subunit HIF-1α, and the constitutively expressed HIF-1β subunit (arylhydrocarbon receptor nuclear translocator, ARNT), both of which belong to the basic helix-loop-helix (bHLH)–PAS (PER, ARNT, SIM) protein family (Brahimi-Horn et al., 2001; Semenza, 2001; Harris, 2002). So far in the human genome 3 isoforms of the α subunit of the transcription factor HIF have been identified: HIF-1α, HIF-2α (also referred to as EPAS-1, MOP2, HLF, and HRF), and HIF-3α (of which HIF-3α2 also referred to as IPAS, inhibitory PAS domain) (Maynard et al., 2003). HIF-1α is the best-characterized isoform and upon activation heterodimerizes with the HIF-1β subunit. Two transactivation domains—N-terminal (N-TAD) and C-terminal (C-TAD), both located in the C-terminal half of the HIF-1α protein—have been identified. C-TAD has been found to interact with coactivators to activate transcription. Transactivation, involves dimerization of the two HIF subunits, which bind to an enhancer element called the hypoxia-response element (HRE) in target genes. The bHLH and PAS motifs are required for dimerization, but the downstream basic region affords specific binding to the HRE DNA core recognition sequence (5′-T/A/G-CGTG-3′). The presence of a HIF-1-binding site is necessary, but not sufficient to direct gene expression in response to hypoxia, suggesting that HIF-1 must interact with other transcription factors bound at adjacent sites. HIF-1α also interacts with coactivators such as CBP, p300, SRC-1, and TIF2 (for complete list see (Semenza, 2001) and this association is regulated by both oxygen concentration and redox state. In addition to DNA-binding proteins and coactivators HIF-1α also interacts with proteins that regulate its half-life such as Hippel–Lindau tumor suppressor protein (pVHL) and p53 (Semenza, 2001). Under normoxic conditions, HIF-1α is targeted to ubiquitinylation by pVHL and is rapidly degraded by the proteasome (Fig. 1). This is triggered through posttranslational HIF-α hydroxylation on specific proline residues (proline 402 and 564 in human HIF-1α protein) within the oxygen dependent degradation domain (ODDD) (Epstein et al., 2001a; Ivan et al., 2001), by specific HIF-prolyl hydroxylases (HPH1-3 also referred to as PHD1-3) (Bruick and McKnight, 2001; Epstein et al., 2001a; Metzen et al., 2003) in the presence of iron, oxygen, and 2-oxoglutarate. The hydroxylated protein is then recognized by pVHL, which functions as an E3 ubiquitin ligase. The interaction between HIF-1α and pVHL is further accelerated by acetylation of lysine residue 532 through an N-acetyltransferase (ARD1) (Jeong et al., 2002). Concurrently, hydroxylation of the asparagine residue 803 within the C-TAD also occurs by an asparaginyl hydroxylase (also referred to as FIH-1 (Mahon et al., 2001), which by its turn does not allow the coactivator p300/CBP to bind to HIF-1α subunit. In hypoxia HIF-1α remains not hydroxylated and stays away from interaction with pVHL and CBP/p300 (Fig. 1). Following hypoxic stabilization HIF-1α translocates to the nucleus where it heterodimerizes with HIF-1β. The resulting activated HIF-1 drives the transcription of over 60 genes important for adaptation and survival under hypoxia including glycolytic enzymes, glucose transporters Glut-1 and Glut-3, endothelin-1 (ET-1), VEGF (vascular endothelial growth factor), tyrosine hydroxylase, transferrin, and erythropoietin (Brahimi-Horn et al., 2001; Beasley et al., 2002; Fukuda et al., 2002; Maxwell and Ratcliffe, 2002).

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Figure 1. The hypoxia-inducible factor 1 (HIF-1) pathway under normoxia and hypoxia and its possible interfering agents. Under normoxia HIF-1α is subject to oxygen-dependent hydroxylation on specific proline residues in the oxygen dependent degradation domain (ODDD) and following ubiquitination and proteasomal degradation that is mediated by the von Hippel–Lindau protein. This mechanism is furthermore triggered through posttranslational HIF-α acetylation of lysine residues in the ODDD and hydroxylation of asparagine residue within the C-TAD. These events do not occur under hypoxia and so HIF-1alpha is stabilized, translocates to the nucleus, interacts with hypoxia responsive elements (HRE), and promotes the activation of target genes. Abbreviations: PI3K, phosphatidylinositol 3-kinase; AKT, protein kinase B; mTOR, mammalian target of rapamycin; HIF-1α/β, hypoxia inducible factor α/β; PHD, prolyl hydroxylase; FIH-1, factor inhibiting HIF-1; ARD-1, N-acetyltransferase; ODDD, oxygen dependent degradation domain; C-TAD, C-terminal-transactivation domain; pVHL, protein Von Hippel–Lindau; MAPK, mitogen-activated protein kinase; HRE, hypoxia-response element; VEGF, vascular endothelial growth factor; ET-1, endothelin-1; Glut-1, glucose transporter 1.

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In addition to hypoxia, multiple oncogenic pathways including growth factor signaling or genetic loss of tumor suppressor genes, like VHL and PTEN, upregulate HIF activity (Semenza, 2002). Studies from our and others' laboratory have shown that HIF-1 regulation stabilization is dependent on the phosphatidylinositol 3-kinase (PI3K), AKT (protein kinase B), and its effector FKBP-rapamycin-associated protein (FRAP or mTOR; mammalian target of rapamycin) (Minet et al., 2000; Zhong et al., 2000; Zundel et al., 2000; Jiang et al., 2001; Laughner et al., 2001; Sodhi et al., 2001; Tacchini et al., 2001; Stiehl et al., 2002). Dysregulated signal transduction from receptor tyrosine kinases to PI3K/AKT/mTOR occurs via autocrine stimulation or inactivation of the tumor suppressor PTEN in many cancers. Basic fibroblast growth factor, insulin, interleukin-1, hepatocyte growth factor and heregulin induce the expression of HIF-1α (Zhong et al., 2000; Jiang et al., 2001; Laughner et al., 2001; Sodhi et al., 2001; Tacchini et al., 2001; Stiehl et al., 2002). HIF-1-dependent gene transcription is also blocked by dominant-negative AKT or PI3K and by wild-type PTEN, whereas transcription is stimulated by constitutively active AKT or dominant-negative PTEN (Zhong et al., 2000; Zundel et al., 2000; Jiang et al., 2001; Sodhi et al., 2001; Stiehl et al., 2002). However, the exact regulatory mechanisms of HIF-1α by PI3K pathway remain unknown.

Regulation of HIF-1 by phosphorylation through the mitogen-activated protein kinase (MAPK) signaling pathway has also been demonstrated. Indeed, several studies showed that phosphorylation through the ERK/MAPK is needed for activation of the transcriptional activity, but not for the HIF-1α stabilization in hypoxia (Salceda et al., 1997; Minet et al., 2000; Hur et al., 2001). Particularly, ERK1/2 (also known as p44/p42), two kinases of the MAPK signaling pathway, have been implicated in HIF activation (Minet et al., 2001). ERK1/2 are activated by extracellular proliferative signaling triggered by membrane-tyrosine kinases and transduced through the Ras-Raf-MEK pathway by a cascade of phosphorylation events that can be repressed by specific kinase inhibitors. In the meantime, it is unclear whether phosphorylation of the HIF-1α subunit itself or other downstream effect of the phosphorylation by MAPK signaling has the activation effect on HIF-1. Recently, a study showed that MAPK signaling may affect HIF activity not by directly affecting the activation of HIF-1α but rather by promoting the formation of the HIF-p300/CBP complex and by modulating the transactivation activity of p300/CBP itself (Sang et al., 2003).

However, in addition to the now well-established mechanism of oxygen sensing, models involving the role of reactive oxygen species (ROS) on HIF have recently received particular attention. Conflicting results emerged from several studies that showed decreased or increased ROS production in hypoxia; however, in each case HIF-1 activation was directly correlated with changes in ROS. The collective data suggest that ROS seem to be key players: either they inhibit the HIF-1 activation pathway (NADPH oxidase hypothesis) (Jones et al., 2000) or they activate it (mitochondria model) (Chandel et al., 1997). In either case, the effector whose activity is regulated by ROS and that transduces the signal directly or indirectly to HIF-1 remains unknown. Further investigation is required not only to identify these intermediates, if they exist, but also to determine whether one or both of these models modulate the prolyl or asparginyl hydroxylase systems.

THE ROLE OF HIF-1 IN THE PATHOGENESIS AND TREATMENT OF CARDIOVASCULAR DISEASE

  1. Top of page
  2. Abstract
  3. OVERVIEW ON HYPOXIA-INDUCIBLE FACTOR 1 (HIF-1)
  4. THE ROLE OF HIF-1 IN THE PATHOGENESIS AND TREATMENT OF CARDIOVASCULAR DISEASE
  5. THE ROLE OF HIF IN CARCINOGENESIS
  6. ATHEROSCLEROTIC PLAQUE AND MICROMETASTASIS
  7. CONCLUSIONS
  8. Acknowledgements
  9. LITERATURE CITED

Does HIF-1 play an important role in the pathogenesis of cardiovascular diseases, starting from the formation and progression of atherosclerotic plaques causing ischemia and in its treatment modalities including restenosis after percutaneous transluminal coronary angioplasty (PTCA) or stent implantation (Fig. 2)?

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Figure 2. Vicious circle in the ischemic heart and its possible points of application. HIF and its downstream genes trigger atherosclerotic plaque-formation, its consecutively occurring ischemia and hypoxia in the myocardium, what leads again to an increasing HIF-production. To break through this development, the HIF-triggered arising of atherosclerotic plaques would have to be determined by HIF-inhibitors. After plaque formation another option would be to place a stent in the narrowed vessel to overcome ischemia. But this treatment entails an increased production of HIF, what leads by proceeding restenosis to ischemia again. A possible starting point would be to inhibit restenosis by preventing HIF-increase via coated stents. On the other side HIF and its downstream genes are driving angiogenesis that might be, supported by HIF-inducers, a promising way to get over ischemia. HIF, hypoxia-inducible factor.

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A significant controversy currently exists about the role of HIF in the pathogenesis of atherosclerotic plaques. This is a central question for improved molecular techniques of interrogation. Preclinical studies showed that the formation and progression of atherosclerotic plaques are attributed to the VEGF-mediated increase of angiogenesis and the recruitment and activation of monocytes (Inoue et al., 1998; Celletti et al., 2001a,b; Zhao et al., 2002). How VEGF accelerates or inhibits plaque formation and to what extent HIF is involved in this process are open questions (Isner, 2001; Inoue et al., 2001). Furthermore, a recent study using conditional knockouts of HIF-1α demonstrated the essential role of HIF-1α in the direct regulation of survival and function in the inflammatory response (Cramer et al., 2003). An approach is blockade of the VEGF effect of the enhanced rate and degree of plaque formation locally either with nonspecific anti-angiogenic agents such as paclitaxel or with specific anti-angiogenic agents such as angiostatin or TNP-470 (Moulton et al., 1999; Celletti et al., 2002). The role of HIF in the formation and progression of human coronary atherosclerosis has to be further investigated and the downregulation of HIF-1, as a strong inducer of VEGF, must be considered as a possible target of preventing plaque formation. Atherosclerotic lesions lead to heart ischemia caused by the imbalance between the supply and the demands of the heart muscle of oxygen and glucose, delivered via blood flowing through the coronary arteries. Although coronary blood flow may be enough to meet myocardial needs at rest, sometimes the circulation is not able to abide a sufficient supply during exercise, what also run into the condition of “ischemic myocardium.” HIF-1 plays a crucial role in the response of the myocardium to the hypoxic conditions by initiating early cellular changes to this situation. One of the first responses of the human myocardium to ischemia is the increase of HIF activation (Lee et al., 2000; Wurzel and Goldman, 2000). This leads to a detectable increase of nuclear HIF-1α protein in myocytes and consequently of HIF-regulated genes, that help in adaptation to the ischemic episode. Among these genes is VEGF, which is believed to play an important role in the neoangiogenic process within the ischemic myocardium (Lee et al., 2000). Angiogenesis itself is a multistep process. Once, tissue is hypoxic or injured the angiogenic growth factors are released and diffused to nearby preexisting blood vessels to induce the capillary formation of new blood vessels. Further stabilization of the new-formed blood vessels requires the recruitment of pericytes and smooth muscle cells, which is regulated by platelet-derived growth factor (PDGF). PDGF by itself also induces the expression of HIF-1α protein and HIF-regulated genes (Gorlach et al., 2001).

Upregulation of HIF is not restricted to the ischemic stimulus only but there are also HIF-mediated changes in response to mechanical stress. Kim et al. (2002) found increased HIF-1α protein accumulation and elevated VEGF levels in cardiac myocytes after expanding an intraventricular balloon and by producing haemodynamic overload using an aortocaval shunt (Kim et al., 2002). HIF appears to play an important role in the adaptation of the myocardium to the different stresses besides ischemia.

Based on these findings it is to assume that HIF-1α is an essential mediator in the response of myocardial disease associated with ischemia and infarction contributing to the limitation of the infarct size by providing angiogenesis (Li et al., 2000; Khan et al., 2003). Therefore it is to discuss, whether HIF-1 stimulants may be helpful in the prevention and the treatment of the ischemic heart disease.

Currently, there are some potent inducers of HIF pathway/angiogenesis already under investigation (Table 1).

Table 1. Agents that induce HIF-1α expression or function
Agent, Ref.MechanismComment
  1. HIF-1, hypoxia-inducible factor 1; Ref., reference; PHDs, prolyl hydroxylases; NF-κB, nuclear factor-kappaB; VEGF, vascular endothelial growth factor; IGF-1, insulin like growth factor-1; MAPK, mitogen-activated protein kinase; ROS, reactive oxygen species; ODDD, oxygen dependent degradation domain; pVHL, Von Hippel–Lindau Protein; CoCl2, cobalt chloride.

PHDs inhibitors (Jaakkola et al., 2001; Ivan et al., 2002)These compounds lead to the accumulation of transcriptionally active HIF-1 by inhibiting PHDsFG-0041 is an interesting oxoglutarate analog particularly since it has been shown earlier to preserve left ventricular function in a rodent model of myocardial infarction (Nwogu et al., 2001)
Capsaicin (8-methyl-N-vanillyl-6-nonenamide) (Patel et al., 2002)Enhances constitutive and induced HIF-1α expression and binding activity under normoxic conditions, most likely by inhibiting NF-κB activation which may trigger stress-signaling pathwaysA natural dietary chemopreventive agent that inhibit melanoma cell proliferation
DBM (dibenzoylmethane) (Mabjeesh et al., 2003b)Inhibition of HIF-1α protein degradation, mainly under normoxic conditionsA natural dietary compound and iron chelator
  Studied in rat cultured cardiomyocytes and prostate cancer cells
  Low toxicity
  Oral bioavailable
CPX (ciclopirox olamine) (Linden et al., 2003)Stabilizes HIF-1α and induces HIF-1 target gene expression including VEGF, probably by inhibiting HIF-1α hydroxylation under normoxiaAnti-mycotic, and iron chelator active in vitro and in vivo
  Rapidly inactivated in the organism by glucuronidation (Bohn and Kraemer, 2000)
Deferoxamine (Wang and Semenza, 1993)Induces HIF-1 activity by inhibiting HIF-1α hydroxylationIron chelator
  The effect on erythropoietin was studied in Hep3B cells and in mice
Mersalyl [o-[(3-hydroxymercuri-2-methoxypropyl)carbamoyl]phenoxyacetic acid] (Agani and Semenza, 1998)Reacts with free thiol groups of proteins and induces HIF-1α through IGF-1/MAPK dependent pathwayOrgan mercurial compound
  Studied in cultured Hep3B cells
Chromium (VI) (Gao et al., 2002)Induces the expression of HIF-1α and VEGF proteins by production of ROS, especially H2O2, through p38 signaling pathwayCarcinogen
  Potent inducer of tumors in animals
  The effect on ROS/HIF/VEGF was studied in DU145 human prostate cancer cells
CoCl2 (Semenza et al., 1994, Yuan et al., 2003)Cobalt binds to the ODDD and inhibits the pVHL-binding to HIF-α subunitCobalt is a transition metal
  A carcinogen to humans and experimental animals

Some promising preclinical trials using a gene therapy approach with HIF-1α/VP-16 hybrid transcription showed a significant improvement in perfusion, a reduced infarct size and enhanced neovascularisation in an acute ischemic myocardium in rats (Vincent et al., 2000; Shyu et al., 2002). Compared to the findings from the clinical trials, using VEGF-1 and FGF-4 as gene therapy agents, both inducible by HIF-1, only a modest evidence of clinical benefit in myocardial ischemia in patients was provided (Grines et al., 2002; Makinen et al., 2002), and therefore it seems that the idea of interfering HIF transcriptome affecting HIF-1 in different ways may be auspicious and the right target because of its wide downstream effect rather than part of the whole transcriptome. Of course, results of adequately powered, randomized, double blind, and placebo-controlled studies are currently not available.

A fine balance between therapeutic benefit and harmful side effects must be cautiously analyzed before introducing the concept of encouraging angiogenesis after acute ischemia especially there is a study reporting an association of increased coronary flow within the collaterals with poorer prognosis after myocardial infarction (Nicolau et al., 1999). In addition, recent studies showed that harmful effects might accompany angiogenesis therapeutics, especially by a systemic application in patients who have known or yet unrecognized coexistent diseases such as hemangioma formation, retinopathies, arthritis, induction of occult tumor growth or atherosclerotic plaque progression (Celletti et al., 2001b; Epstein et al., 2001b; Su et al., 2002).

After reopening of the coronary arteries it is an important goal to maintain the vessels patent and prevent the reduction of the luminal size (restenosis) due to loss of gain in lumen size after intravascular interventional procedure. Coronary stents reduce the restenosis rate compared to PTCA and have become the standard procedure in coronary revascularization for atherosclerotic disease (Tebbe et al., 1990; Fischman et al., 1994). However, in-stent restenosis remains a significant clinical problem with rising incidence of coronary stenting. Besides the already known factors for restenosis like small diameter reference coronary arteries, longer lesion length, and longer stent length (Kereiakes et al., 2000; Goldberg et al., 2001; Hsieh et al., 2001), new important parameters were found, including extent of medial injury, inflammation and degree of neoangiogenesis (Farb et al., 2002). Ongoing studies now focus on the local anti-angiogenesis treatment, trying to target any of several angiogenic ligands or their signaling pathways, to prevent the excessive neointimal expansion after angioplasty (Fuchs et al., 2001). Since the so-called drug eluting stents are in use, many studies showed a dramatic decrease in restenosis rate, but cost-effectiveness and long-term reliability remain to be defined (Degertekin et al., 2003; Fattori and Piva, 2003; Schwertz and Vaitkus, 2003; Sousa et al., 2003a,b). At least in cancer cells the effectivity of rapamycin (sirolimus) against tumor growth is mediated, in part, by the inhibition of cellular responses to hypoxic stress, namely by inhibiting mTOR and its downstream effects on HIF-1 activation (Hudson et al., 2002; Mayerhofer et al., 2002; Treins et al., 2002). Moreover, this PI3K/AKT/mTOR signaling pathway, which induces HIF-1α, seems to play an important role in the adaptation of intracoronary endothelial cells and the neointimal inflammatory process leading to restenosis. Stents coated with sirolimus, a natural macrocyclic lactone and mTOR inhibitor, have been proven efficient in preventing restenosis rates in multiple independent clinical trials (RAVEL, SIRIUS (Presbitero and Asioli, 2002). In addition, Taxol which also inhibits HIF-1 through disrupting microtubules (Mabjeesh et al., 2003a) has been proven to show profound inhibition of neointimal thickening depending on delivery duration and drug dosage in several studies (TAXUS I-VI, ELUTES, ASPECT, DELIVER (Grube and Bullesfeld, 2002; Hong et al., 2003). Based on these results we anticipate that other compounds dysregulating HIF and eluted by coated stents may show a similar outcome.

THE ROLE OF HIF IN CARCINOGENESIS

  1. Top of page
  2. Abstract
  3. OVERVIEW ON HYPOXIA-INDUCIBLE FACTOR 1 (HIF-1)
  4. THE ROLE OF HIF-1 IN THE PATHOGENESIS AND TREATMENT OF CARDIOVASCULAR DISEASE
  5. THE ROLE OF HIF IN CARCINOGENESIS
  6. ATHEROSCLEROTIC PLAQUE AND MICROMETASTASIS
  7. CONCLUSIONS
  8. Acknowledgements
  9. LITERATURE CITED

In tumors the rapid cell proliferation is associated with areas of hypoxia. Hypoxia appears to promote tumor growth by promoting cell survival through its induction of angiogenesis and its activation of anaerobic metabolism. Tumor hypoxia has direct consequences on clinical and prognostic parameters and creates a therapeutic challenge. The hypoxic response depends critically on HIF-1. HIF-1α was found overexpressed in more than 70% of human cancers and their metastases compared to their adjacent normal tissue, including breast, prostate, brain, lung and head and neck cancers (Zhong et al., 1999; Birner et al., 2000; Blancher et al., 2000; Achilles et al., 2001; Aebersold et al., 2001; Birner et al., 2001; Giatromanolaki et al., 2001; Beasley et al., 2002; Hui et al., 2002; Katschinski et al., 2002; Schindl et al., 2002; Sivridis et al., 2002; Sondergaard et al., 2002; Bos et al., 2003). The effect of HIF-1 on tumor growth is complex and involves the activation of several adaptive pathways. Different genetic studies using embryonic stem (ES) cells or mouse embryonic fibroblasts (mEF) have indicated that loss of HIF-1α or disruption of HIF-1 function causes tumor growth retardation. However, the precise role of HIF in tumor development remains highly controversial because recent work by one group has indicated that HIF-1α acts as a tumor suppressor, or negative factor, in ES cell-derived tumors (Carmeliet et al., 1998). An additional study provided indirect evidence in support that HIF is not necessarily a positive regulator of tumor growth where ES cells lacking VHL and constitutively expressing HIF-α subunits, did not promote teratocarcinoma growth (Mack et al., 2003). On the other hand, another recent study showed that teratocarcinoma tumors derived from mixed HIF-1α(+/+) with HIF-1α(−/−) ES cells at a ratio of 1:100, respectively, were able to rescue the growth of mixed tumors although these tumors are not significantly different phenotypically or genotypically from the original HIF-1α(−/−) tumors. The same results also were confirmed with mixtures of Hepa1/Hepa1C4 cells (where HIF-1β is mutated). These data demonstrate that the HIF-1α-dependent response of a few cells is capable of sustaining the growth of the whole tumor, probably through the secretion of factors unregulated under low oxygen conditions. The situation is similar to tumors growing from a small number of cancer cells (Hopfl et al., 2002).

With the growing knowledge of the molecular mechanisms in HIF field, novel strategies to prevent tumor growth and angiogenesis can be developed, and from these, new anticancer therapies may arise (Choi et al., 2003). Herein, we describe a number of the approaches targeting HIF pathway, which we believe could be utilized and applicable in future cancer therapeutics (Table 2).

Table 2. Signaling inhibitors that also block HIF-1
Agent, Ref.MechanismComment
  1. HIF-1, hypoxia-inducible factor; Ref., reference; PI3K, phosphatidylinositol 3-kinase; AKT, protein kinase B; mTOR, mammalian target of rapamycin; MAPK, mitogen-activated protein kinase; PGE2, prostaglandin E2; IL-1, interleukin 1; ERK, extracellular signal-regulated kinase; ODDD,oxygen dependent degradation domain; VHL, Von Hippel–Lindau; COX-2, cyclooxygenase 2; Flt-1, vascular endothelial growth factor receptor-1; Hsp90, heat-shock protein 90.

LY 294002 Wortmannin (Zhong et al., 2000; Stiehl et al., 2002)Suppressed HIF-1 activationStudied in human hepatoma and prostate cancer cell cultures
 Highly potent in normoxia, less potent in hypoxiaAlthough toxicity is associated with LY294002 there is a therapeutic window for clinical use
 Reduces HIF-1α translation through PI3K/Akt/mTOR pathway 
Rapamycin, cell cycle inhibitor-779 (CCI-779), RAD-001 (Yu et al., 2001; Huang and Houghton, 2002; Hudson et al., 2002)Inhibits both the accumulation of HIF-1alpha and HIF-1-dependent transcription under hypoxia by inhibiting the mTOR-dependent phosphorylation of p70S6K; a central role in protein synthesis pathwaymTOR inhibitor, in clinical use
  The effect on HIF-1α has been studied in breast cancer cell lines and PC-3 prostate cancer cells
PD98059 (Liu et al., 2002; Stiehl et al., 2002)Blocks HIF-1 activation by inhibiting MAPK KinasesPotential negative effects of the kinase inhibitors on cell viability
  Inhibits PGE2 effects on HIF-1α
  Decreases the hypoxic response and the stimulatory effects of insulin and IL-1 on HIF-1α in HepG2 cells
GL331 (Chang et al., 2003)Decreases the binding of cellular components to the promoter of HIF1A geneSemi synthetic compound derived from a plant toxin podophyllotoxin
 Downregulates HIF-1α expression and function by inhibiting ERK pathwayStudied in human lung adenocarcinoma CL1-5 (in vivo animal angiogenesis model)
Cyclosporin A (CsA) (D'Angelo et al., 2003)CsA increases VHL-ODDD interaction during hypoxia by stimulating the proline 564 hydroxylationStudied in C6 glioma cells
2-Methoxyestradiol (2ME2) (Mabjeesh et al., 2003a)Depolymerizes microtubules and inhibits HIF-1α protein synthesis and HIF-regulated genes including VEGF under both normoxia and hypoxiaAnti-angiogenic/antitumoral, orally active and well-tolerable (Lakhani et al., 2003)
  The effects on HIF-1 have been studied in prostate and breast cancer cells
COX-2 inhibitors (meloxicam, NS398) (Jones et al., 2002; Liu et al., 2002)Decreases PGE2-Levels which promotes nuclear translocation of HIF-1α under normoxic and hypoxic conditions (Liu et al., 2002)Anti-inflammatory, in clinical use
 Inhibit hypoxia-induced angiogenesis in endothelial cells by inhibiting VEGF and Flt-1 expression through increased VHL expression and the resulting ubiquitination and degradation of HIF-1α protein (Jones et al., 2002)Studied in human prostate and colonic cancer cells
HSP90-inhibitors geldanamycin, 17-allyl aminogeldanamycin (17-AAG), radicicol, KF58333 (Kurebayashi et al., 2001; Hur et al., 2002; Isaacs et al., 2002; Mabjeesh et al., 2002)Reduction of HIF-1α levels and its downstream transcriptional activity by accelerating protein degradation through the proteasome under normoxia and hypoxia17-AAG currently in clinical trials
  The effects on HIF-1α have been studied in wide spectrum of common cancer cells
FK228 (Mie Lee et al., 2003)Inhibits HIF-1α and the expression of VEGF especially under hypoxiaA specific histone deacetylase inhibitor
 Deacetylation and acetylation of histones have regulatory effects on gene transcriptionSignificant inhibition of angiogenesis in Lewis lung carcinoma model

PI3K pathway inhibitors

The expression HIF-1α protein, HIF-1-dependent gene transcription, and HIF-1-regulated gene products like VEGF can be blocked efficiently by different agents, interfering in the above mentioned PI3K/AKT/FRAP-pathway on different levels (Fig. 1). LY294002, wortmannin, and rapamycin represent tested agents that block not only basal HIF-1α protein level but also growth factor induced HIF-1α nuclear accumulation, and further impair the HIF-1 activation (Zhong et al., 2000; Blancher et al., 2001; Jiang et al., 2001; Laughner et al., 2001). Therefore, the inhibitors/antagonists of PI3K upstream signals are potential anti-HIF-1 agents.

A possible example is trastuzumab (herceptin), a humanized monoclonal antibody that targets the human EGF receptor-2 (HER2). HER2 overexpression or HER2 ligand heregulin stimulation induces VEGF expression in cancer cells (Yen et al., 2000). HER2 signaling stimulations by HER2 over expression or heregulin in human breast cancer cells results in increased HIF-1α protein and VEGF expression that is dependent upon activity of PI3K/AKT/FRAP (Laughner et al., 2001). Treatment of breast cancer cells with a neutralizing antibody against HER2 results in a dose-dependent inhibition of VEGF expression possibly via a HIF-1α down regulation (Petit et al., 1997).

MAPK pathway inhibitors

Specific inhibitors of MAPK such as PD98059 do not change either the stabilization or DNA binding ability of HIF-1α, but it inhibits the transactivation ability of HIF-1α (Hur et al., 2001). Recently anticancer mechanism of GL331, a semi synthetic compound derived from a plant toxin podophyllotoxin, was investigated in a human lung adenocarcinoma cell line (Chang et al., 2003). The results show a promising new way of anticancer activity. GL331 was shown to down regulates the expression of HIF-1α mRNA, through the inhibition of the ERK-pathway, without decreasing its stability and that GL331 inhibited the binding of cellular components to the promoter of HIF-1α gene (Chang et al., 2003). On the other hand, the MAPK kinases inhibitors, PD98059 and U0126 were as effective as PI3K inhibitors when studied in the hepatoma cell line HepG2 (Stiehl et al., 2002). Therefore, the clinical applicability of MAPK kinases inhibitors is yet to be further investigated.

PHDs activators

Cyclosporin A (CsA) is a well known immunosuppressive drug that binds to cyclophilins, a family of ubiquitous and conserved proteins with peptidyl-prolyl cis-trans isomerase and molecular chaperone activities. Recent studies in C6 glioma cells showed that CsA act as an inhibitor of HRE-mediated hypoxic response by activation of PHD activity. However, CsA has to be considered as a potent drug against the adaptative response to hypoxia in tumor cells (D'Angelo et al., 2003).

Microtubule-disrupting agents (MDA's)

Pribluda et al. (2000) showed in their investigations that 2-methoxyestradiol (2ME2), a naturally occurring derivative of estradiol, is an orally active, well-tolerated small molecule that possess antitumor and anti-angiogenic activity (Pribluda et al., 2000). We recently showed that 2ME2 depolymerizes microtubules (MTs), down regulates HIF-1α protein levels and inhibits HIF transcriptional activity in an oxygen- and proteasome-independent manner (Mabjeesh et al., 2003a). Interestingly, at concentrations of 2ME2 that inhibit tumor growth and vascularization in vivo, 2ME2 did not cause any serious drug-related adverse effects even when administered at doses of 1,000–1,200 mg/day (Lakhani et al., 2003). This makes 2ME2 attractive to be used as an orally available anti-HIF drug for tumor treatment. Furthermore, we demonstrated that other MDA such as taxol and vincristine also inhibited HIF-1α levels and HIF-1 transcriptional activity. Interestingly a recent study by Jung et al. (2003) showed opposite effects of certain MDAs on HIF-1. MDAs like colchicine, vinblastine or nocodazole led to an increase in HIF-1activation through pathway dependent on the nuclear factor kappa B (NF-κB) (Jung et al., 2003).

Cyclooxygenase-2 (COX-2) inhibitors

Nonsteroidal anti-inflammatory drugs (NSAIDs) block prostaglandin synthesis and impair growth of colonic tumors, in part, by inhibiting angiogenesis. Jones et al. (2002) have demonstrated that both nonselective (indomethacin) and COX-2-selective (meloxicam, NS-398) NSAIDs reduce HIF-1α accumulation and the expression of downstream VEGF, and the VEGF specific receptor Flt-1 under normoxic and hypoxic conditions (Jones et al., 2002). This effect might be caused by an increased VHL expression leading to the ubiquitination and degradation of HIF-1α (Jones et al., 2002). Another study showed that PGE(2), through MAPK pathway, was able to increase HIF-1α nuclear accumulation while the two selective COX-2 inhibitors, meloxicam and NS398, decreased HIF-1α nuclear localization, in prostate cancer cells under both normoxic and hypoxic conditions (Liu et al., 2002). From both studies, it is clear that HIF is a downstream target of COX-2 inhibitors.

Heat shock protein 90 (Hsp90) inhibitors

Hsp90 is an ATP dependent molecular chaperone involved in the folding and activation of a number of substrate proteins. Substrate proteins include steroid-hormone receptors, protein kinases, and transcription factors such as bHLH proteins (Richter and Buchner, 2001). ATP dependent conformational changes of Hsp90 occur during the hydrolysis reaction and these changes are thought to drive the chaperone cycle. Inhibitors of the ATPase activity, like geldanamycin and radicicol, block the processing of Hsp90 substrate proteins. Gradin et al. (1996) found a stable interaction between de novo-synthesized HIF-1α and Hsp90. Hsp90 activity is essential for HIF-1 activity under hypoxia, and geldanamycin, inhibits HIF-1 function (Minet et al., 1999).

More recent discoveries have been added to support that Hsp90 chaperone activity is necessary for HIF-1 transcriptional activation and HIF-1α nuclear accumulation induced by hypoxia or heat (Suzuki et al., 2001; Isaacs et al., 2002; Katschinski et al., 2002; Mabjeesh et al., 2002). For instance, radicicol and the radicicol derivative, KF58333, inhibit the expression of HIF-1α, VEGF, and angiogenesis in human cancer cells, at least partially mediated by the inhibition of Hsp90 activity (Kurebayashi et al., 2001; Hur et al., 2002). These compounds and their derivates might be useful in treatment for HIF-1α overexpressing cancers, via their inhibition of Hsp90 chaperone functions.

Anti-sense therapy

Sun et al. (2001) showed that intratumoural gene transfer of an anti-sense HIF-1α plasmid leads to downregulation of HIF-1α levels, VEGF, and decreased tumor microvessel density. Anti-sense HIF-1α monotherapy resulted in the complete and permanent rejection of small EL-4 lymphoma cell tumors but larger EL-4 tumors were refractory to monotherapies. However, the effect of HIF-1α anti-sense therapy was synergized with B7-1-mediated immunotherapy. This could be explained either by anti-HIF-1 therapy rendering tumors more susceptible to an attack by NK cells, or alternately HIF-1 may play an important role in switching small “nonangiogenic” tumors to “angiogenic” tumors (Achilles et al., 2001). In a more recent study by Dai et al. (2003) showed that the anti-sense HIF-1α phosphorothioate oligodeoxynucleotide (AS-HIF ODN) suppresses HIF-1α expression and HIF-1 activation in U-87 malignant glioma cells under both normoxic and hypoxic conditions (Dai et al., 2003). In conclusion this proceeding might be a promising strategy in tumor therapy in combination with the well-established chemotherapies.

Others

The benzylindazole derivative YC-1 is a newly developed agent that inhibits platelet aggregation and vascular contraction and stimulates soluble guanylate cyclase, which increases intracellular cGMP concentration. It was proven to inhibit the DNA-binding activity of HIF-1 and thus to block the induction of EPO and VEGF mRNAs. Furthermore YC-1 suppressed the hypoxic-, cobalt- and the desferrioxamine-induced accumulation of HIF-1α. This study presents another new possible strategy to inhibit HIF-regulated genes by tumor cells (Chun et al., 2003).

Another attracting drug is bucillamine, an anti-rheumatic drug, which has been used clinically primarily for patients with rheumatoid arthritis. Bucillamine was shown to inhibit the hypoxic induction of VEGF through inhibition of HIF-1 induction and binding activity in bovine retinal micro capillary endothelial cells (Koyama et al., 2002). It would be interesting to test whether similar effects on HIF could be obtained in cancer cells as well.

Rapisarda et al. (2002) have genetically engineered U251 human glioma cells to consistently express luciferase under the control of HREs in a hypoxia- and HIF-1-dependent fashion. They screened a collection of approximately 2,000 compounds and found three compounds, which relate to camptothecin analogues and topoisomerase (Topo)-I inhibitors (Rapisarda et al., 2002). Collectively, these screening systems may eventually lead to the discovery of a number of different compounds, whether specifically inhibiting HIF-1α or indirectly affecting HIF pathway, which will add more to our knowledge and applicability of HIF-directed therapeutics.

ATHEROSCLEROTIC PLAQUE AND MICROMETASTASIS

  1. Top of page
  2. Abstract
  3. OVERVIEW ON HYPOXIA-INDUCIBLE FACTOR 1 (HIF-1)
  4. THE ROLE OF HIF-1 IN THE PATHOGENESIS AND TREATMENT OF CARDIOVASCULAR DISEASE
  5. THE ROLE OF HIF IN CARCINOGENESIS
  6. ATHEROSCLEROTIC PLAQUE AND MICROMETASTASIS
  7. CONCLUSIONS
  8. Acknowledgements
  9. LITERATURE CITED

Focusing on similarities and differences of the role of HIF-1 in formation of atherosclerotic plaques and micrometastasis, we propose the assumption that from the HIF point of view it is about a similar process but a different result. The HIF-mediated increase of downstream agents lead to an enhanced proliferation and invasion of local cells in environmental tissue. While intimal vascular smooth muscle cells (vSMC) migrate into the near surrounding, the detached cancer cells are carried via bloodstream to a distant target tissue, where it forms a micrometastasis. The aborning plaque is among other things a local result of inflammation triggered proliferation of vSMC in the intima of the vessel. The micrometastasis on the other side establishes in another tissue somewhere in the body and grows by cell division to a local metastasis. The appearance of these tumors varies depending on their origin as a host in a foreign tissue whereas the atherosclerotic plaque has a quite stable appearance caused by similar cells attracted by inflammation and higher blood vessel permeability. A number of important questions remain for future research such as: (1) What are the advantages of HIF-treatment instead of treating downstream agents (e.g., VEGF)? (2) What is the role of HIF in plaque formation and progression? (3) What is the best way to deliver pro- or anti-angiogenic factors? (4) How can you treat a patient with a preexisting tumor? (5) Which role play different subtypes of VEGF and its receptors? (6) How severe are side and late effects of local drug delivery? (7) If we increase VEGF, are there enough receptors or can we stimulate these receptors? (8) Which group of patients (in which stadium of disease) has real benefit (advantages vs. disadvantages) (9) How big is the bad influence on normal antegrade blood flow if we increase collateral blood flow?

CONCLUSIONS

  1. Top of page
  2. Abstract
  3. OVERVIEW ON HYPOXIA-INDUCIBLE FACTOR 1 (HIF-1)
  4. THE ROLE OF HIF-1 IN THE PATHOGENESIS AND TREATMENT OF CARDIOVASCULAR DISEASE
  5. THE ROLE OF HIF IN CARCINOGENESIS
  6. ATHEROSCLEROTIC PLAQUE AND MICROMETASTASIS
  7. CONCLUSIONS
  8. Acknowledgements
  9. LITERATURE CITED

Only now, 80 years after Warburg's Nobel prize winning discoveries, we are beginning to understand the causes of the well known metabolic phenotype of tumor cells. With the discovery of HIF-1, which is widely overexpressed across a broad range of cancers, and strictly involved in the inflammatory response, modern molecular tools have allowed us to better comprehend part of the events that might explain the metabolic differences between precancerous, cancer, and normal cells. As outlined in this review, the role of HIF-1 appears to be a key in the various molecular and cellular components of the hypoxic/angiogenic microenvironments. Because the pathways affecting HIF and their single importance stay unclear it is our challenge to find out about different pathways and to discover novel HIF affecting drugs via high-throughput screens of compounds that have the ability to block or increase HIF activation. We are sure that in the near future we will be witnessing new discoveries on HIF and HIF-regulated pathways that will enhance and facilitate strategies for both, angiogenesis-directed therapeutics whether in preventing the formation of atherosclerotic plaques or reducing the degree of in-stent restenosis as well as new cancer therapeutics.

Acknowledgements

  1. Top of page
  2. Abstract
  3. OVERVIEW ON HYPOXIA-INDUCIBLE FACTOR 1 (HIF-1)
  4. THE ROLE OF HIF-1 IN THE PATHOGENESIS AND TREATMENT OF CARDIOVASCULAR DISEASE
  5. THE ROLE OF HIF IN CARCINOGENESIS
  6. ATHEROSCLEROTIC PLAQUE AND MICROMETASTASIS
  7. CONCLUSIONS
  8. Acknowledgements
  9. LITERATURE CITED

This work was supported by the Avon Foundation with funds raised through the Avon Breast Cancer Crusade (to J.W.S.), NIH Prostate Cancer SPORE Grant CA-58236 (to J.W.S.), CaP CURE Foundation (to J.W.S. and N.J.M.), M.K. Humanitarian Association (to N.J.M.) and Parisian (to J.W.S.).

LITERATURE CITED

  1. Top of page
  2. Abstract
  3. OVERVIEW ON HYPOXIA-INDUCIBLE FACTOR 1 (HIF-1)
  4. THE ROLE OF HIF-1 IN THE PATHOGENESIS AND TREATMENT OF CARDIOVASCULAR DISEASE
  5. THE ROLE OF HIF IN CARCINOGENESIS
  6. ATHEROSCLEROTIC PLAQUE AND MICROMETASTASIS
  7. CONCLUSIONS
  8. Acknowledgements
  9. LITERATURE CITED
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