ArticlePDF AvailableLiterature Review

Is COX-2 a 'collateral' target in cancer prevention?

Authors:
Khosrow Kashfi at City University of New York School of Medicine
Khosrow Kashfi
  • City University of New York School of Medicine
Basil Rigas at Stony Brook University
Basil Rigas
Download full-text PDF
Read full-text
Download citation

Abstract and Figures

NSAIDs (non-steroidal anti-inflammatory drugs) prevent colon and other cancers. The fact that NSAIDs inhibit the eicosanoid pathway prompted mechanistic drug-developmental work focusing on COX (cyclo-oxygenase) and its products. The increased prostaglandin E2 levels and the overexpression of COX-2 in colon and many other cancers provided the rationale for clinical trials with COX-2 inhibitors for cancer prevention or treatment. However, one COX-2 inhibitor has been withdrawn from the market because of cardiovascular side effects, and there are concerns about a class effect. Evidence suggests that COX-2 may not be the only, or the ideal, target for cancer prevention; for example, COX-2 is not expressed in human aberrant crypt foci, the earliest recognizable pre-malignant lesion in the colon; COX-2 is expressed in less than half of the adenomas; in vitro data show that NSAIDs do not require the presence of COX-2 to prevent cancer; in familial adenomatous polyposis, the COX-2 inhibitor, celecoxib, had a modest effect, which was weaker than that of a traditional NSAID; and COX-2-specific inhibitors have several COX-2-independent activities, which may account for part of their cancer-preventive properties. The multiple COX-2-independent targets, and the limitations of COX-2 inhibitors, suggest the need to explore targets other than COX-2.
Figures - uploaded by Khosrow Kashfi
Author content
All figure content in this area was uploaded by Khosrow Kashfi
Content may be subject to copyright.
Content uploaded by Khosrow Kashfi
Author content
All content in this area was uploaded by Khosrow Kashfi
Content may be subject to copyright.
724 Biochemical Society Transactions (2005) Volume 33, part 4
Is COX-2 a ‘collateral’ target in cancer prevention?
K. Kashfi* and B. Rigas†1
*Department of Physiology and Pharmacology, City University of New York Medical School, NY 10031, U.S.A., and †Division of Cancer Prevention,
Department of Medicine, SUNY at Stony Brook, Stony Brook, NY 11794-5200, U.S.A.
Abstract
NSAIDs (non-steroidal anti-inflammatory drugs) prevent colon and other cancers. The fact that NSAIDs
inhibit the eicosanoid pathway prompted mechanistic drug-developmental work focusing on COX (cyclo-
oxygenase) and its products. The increased prostaglandin E2levels and the overexpression of COX-2 in colon
and many other cancers provided the rationale for clinical trials with COX-2 inhibitors for cancer prevention
or treatment. However, one COX-2 inhibitor has been withdrawn from the market because of cardiovascular
side effects, and there are concerns about a class effect. Evidence suggests that COX-2 may not be the
only, or the ideal, target for cancer prevention; for example, COX-2 is not expressed in human aberrant
crypt foci, the earliest recognizable pre-malignant lesion in the colon; COX-2 is expressed in less than half
of the adenomas; in vitro data show that NSAIDs do not require the presence of COX-2 to prevent cancer;
in familial adenomatous polyposis, the COX-2 inhibitor, celecoxib, had a modest effect, which was weaker
than that of a traditional NSAID; and COX-2-specific inhibitors have several COX-2-independent activities,
which may account for part of their cancer-preventive properties. The multiple COX-2-indpendent targets,
and the limitations of COX-2 inhibitors, suggest the need to explore targets other than COX-2.
Introduction
Cancer prevention, at present a better option than cancer
treatment, is entering an era when it appears to be a realistic
possibility. The seminal epidemiological observation that
NSAIDs (non-steroidal anti-inflammatory drugs) prevent
colon, and possibly other, cancers has led to the unambiguous
demonstration that aspirin does prevent colon cancer. Two
randomized interventional studies using polyp recurrence as
a general end point demonstrated the chemopreventive effect
of aspirin [1,2]. The relative risks following administration of
aspirin ranged between 0.59 and 0.96, depending on the speci-
fic end point and aspirin dose. Although specific aspects of
this effect appear unclear at this point, these studies, neverthe-
less, constitute proof-of-principle for pharmacological cancer
prevention. However, NSAIDs are ill-suited for widespread
application as chemopreventive agents. Their two prohibi-
tive limitations concern their safety (among patients using
NSAIDs, up to 4% per year suffer serious gastrointestinal
complications) and efficacy (NSAIDs can prevent at best 50%
of colon cancer) (reviewed in [3]). To these, one should add
the need to have more stringent criteria for safety and efficacy
for chemoprevention, as opposed to chemotherapy, when one
deals with a life-threatening cancer.
Considerations of safety and efficacy have prompted the
search for a ‘better NSAID’, with coxibs, selective inhibitors
of COX-2 (cyclo-oxygenase-2), being the most notable out-
come. Coxibs have been developed based on the notion that
inhibition of COX-2, the induced isoform of COX, will
Key words: apoptosis, carbonic anhydrase, cell cycle, coxib, cytochrome c, NAG-1 (non-steroidal
anti-inflammatory drug-activated gene).
Abbreviations used: COX, cyclo-oxygenase; FAP, familial adenomatous polyposis; LOX,
lipoxygenase; NSAID, non-steroidal anti-inflammatory drug; PG, prostaglandin; PGI2,prostacyclin;
TxA2, thromboxane A2.
1To whom correspondence should be addressed (email basil.rigas@sunysb.edu).
diminish the pro-inflammatory activities of COX, whereas
sparing COX-1, the constitutive isoform of COX, will
diminish the gastrointestinal, and perhaps other, side effects
of NSAIDs [4]. Recent concerns on the safety of coxibs, es-
pecially after their long-term use, justify a re-examination of
the fundamental tenet underlying their use in cancer, namely
that COX-2 is central to the pathogenesis of several cancers,
and that its inhibition would prevent them and regress those
already established.
The rationale for COX-2 as a molecular
target for cancer prevention
The initial response of many investigators, including our-
selves, to the epidemiological data showing that NSAIDs
are associated with a decreased incidence of cancer, was that
NSAIDs act by inhibiting COX, an important enzyme in
the eicosanoid cascade that ultimately leads to PGs (prosta-
glandins) and related compounds [4]. Thus we demonstrated
that, in human colon cancers, PGE2levels were strikingly
increased compared with uninvolved mucosa [5]. Subsequen-
tly, Tunni and DuBois [6] demonstrated overexpression of
COX-2 in 45% of colon adenomas and 85% of colon
carcinomas. COX-2 is overexpressed to varying degrees in
several more human cancers, including gastric, breast, lung,
oesophagealandhepatocellularcarcinomas.Additionalmech-
anistic studies showed that PGE2increases colon cancer
cell proliferation [7] and suppresses apoptosis [8]. The role
of eicosanoids in carcinogenesis has been expanded further
by studies demonstrating that, in certain cases, LOX (lipoxy-
genase) products may also play a role in carcinogenesis [9]
(Figure 1). The conclusion that inhibition of COX-2 would
arrest carcinogenesis has been supported by a constellation
of cell culture, animal and human studies, culminating in
C
2005 Biochemical Society
The Molecular Biology of Colorectal Cancer 725
Figure 1 Overview of the arachidonic acid metabolic pathway
Arachidonic acid, derived from diet, is released from membrane phospholipids through the action of PLA2(phospholipase
A2) or is synthesized from linolenic acid. The COX pathway produces various PGs and TxA2, and the LOX pathways produce
LTs (leukotrienes) and HETEs (hydroxyeicosatetraenoic acids). Some 5-LOX and 12-LOX metabolites, such as LTB4and
12-HETE, appear to enhance tumorigenesis, whereas 13-HODE [13(S)-hydroxyoctadecadienoic acid], a product of 15-LOX-1,
is anticarcinogenic.
celecoxib receiving FDA (U.S. Food and Drug Adminstra-
tion) approval for cancer prevention in patients with FAP
(familial adenomatous polyposis).
Studies using genetically modified animals have indicated
that COX-2 may be required for tumorigenesis. Deletion of
COX-2, and, importantly, of COX-1 as well, decreased signi-
ficantly the number of intestinal tumours in Apc716 mice [10].
Overexpression of the human COX-2 gene in the mammary
glands of female mice led to focal-mammary-gland hyper-
plasia, dysplasia, and transformation into metastatic tumours
[11]. Overexpression of COX-2 in basal epidermal cells of
transgenic mice was either insufficient for tumour induc-
tion (although it sensitized the tissue to carcinogens) [12] or,
rather surprisingly, protected them from developing tumours
that were induced by an initiation/promotion protocol [13].
Alternatively, numerous animal studies have shown that
coxibs prevent tumours arising from a variety of tissues [6].
The limitations of current coxibs
The APPROVe (Adenomatous Polyp Prevention on Vioxx)
study was designed to evaluate the efficacy of rofecoxib in
preventing colon cancer. During the trial, which involved
2600 subjects with a history of colorectal polyps, 3.5% of
rofecoxib recipients and 1.9% of placebo recipients suffered
myocardial infarctions or strokes. This led to the termination
of this and all related trials and the permanent withdrawal of
rofecoxib. It is still controversial whether other coxibs share
this side effect, but concerns for a ‘class (side) effect’ have
been voiced [14].
To explain this side effect, it was suggested that inhibition
by coxibs of COX-2, the principal enzyme involved in the
production of PGI2(prostacyclin), tips the balance towards
platelet aggregation and vasoconstriction [14]. As discussed
below, this may constitute a limiting side effect of coxibs for
their required long-term application in cancer prevention.
Is COX-2 overexpression central to
carcinogenesis?
Several observations suggest that it may be worth reassessing
the notion that COX-2 is central to the pathogenesis of sev-
eral cancers, and therefore its inhibition should be the prime
target of cancer chemoprevention. Below, we outline data that
are at variance with this notion.
The pattern of COX-2 expression
Taking colon carcinogenesis as an example, it is apparent that
the pattern of COX-2 expression is not entirely consistent
with the idea that COX-2 is central to carcinogenesis. COX-2
expression is absent in aberrant crypt foci, the earliest recog-
nizable pre-malignant lesion in the colon [15], and com-
mences only at the adenoma stage (45% of them), increasing
in frequency (85%) in carcinomas [6]. An unconventional
look at the data may suggest that COX-2 expression is the re-
sult of, and not a dominant contributor to, carcinogenesis.
In support of this idea is the finding that targeted overex-
pression of human microsomal PGE synthase-1 (mPGES) in
the alveolar type II cells of transgenic mice, accompanied by
highly elevated PGE2production (12.2-fold over control),
failed to induce lung tumours [16].
NSAIDs and COX-2 in cancer prevention
NSAIDs do not require the presence of COX-2 to prevent
cancer [17]. This was based on our finding that in vitro
C
2005 Biochemical Society
726 Biochemical Society Transactions (2005) Volume 33, part 4
Figure 2 Selected COX-2-independent effects of coxibs relevant
to cancer
Coxibs modulate a large array of molecular targets, some of which are
shown here. NAG-1, NSAID-activated gene.
NSAIDs display effects compatible with cancer prevention,
such as inhibition of cell proliferation, induction of apoptosis,
inhibition of angiogenesis and many others, in the absence
of COX-1 or -2. Our initial observation is now firmly
established by the work of many investigators.
Coxibs have only limited clinical efficacy in
cancer prevention
In FAP patients, celecoxib reduced the mean number of colo-
rectal polyps by 28% and the polyp burden by 30.7% (the
respective placebo reductions were 4.5% and 4.9%) [18].
Rofecoxib had a statistically significant, but marginal, effect
on the number of polyps in FAP patients (6.8% reduction
from baseline values) [19]. In contrast, the NSAID sulindac
had a more pronounced effect on colorectal polyps in FAP
patients, being around twice as effective as celecoxib and far
more effective than rofecoxib [20].
Coxibs have several COX-2-independent
activities
This may account, at least in part, for coxibs’ cancer-pre-
ventive properties (Figure 2). For example, celecoxib inhibits
the growth of various cancer cell lines [21], including haem-
atopoietic cell lines that are COX-2-deficient. Interestingly,
celecoxib also inhibited the growth of COX-2-deficient colon
cancer xenografts in nude mice [22]. Moreover, a selective
COX-2 inhibitor reduced tumour growth and angiogenesis
in COX-2-positive pancreatic cancer, but in COX-2-negative
pancreatic cancer, it increased angiogenesis and tumour
growth [23]. Thus the chemopreventive effect of COX-2-
specific inhibitors may be due to their effect on these targets
and not on COX-2.
The expression of COX-2 is not restricted to
tumour cells
While COX-2 is undetectable in most tissues in the absence of
stimulation, it is induced in cells such as monocytes, macro-
phages, neutrophils and endothelial cells [4]. A study in
healthy humans suggests that COX-2 is a major source of sys-
temic PGI2biosynthesis [24]. Importantly, atheromatous le-
sions contain both COX-1 and COX-2, co-localizing mainly
with macrophages of the shoulder region and lipid core
periphery, whereas smooth-muscle cells show lower levels
[25]. Inhibition of vascular COX-2 may shift the delicate
balance between TxA2(thromboxane A2)andPGI
2,which
have opposite effects on platelets and vascular tone. Shifting
this balance in the wrong direction (reduction of PGI2) could
have catastrophic effects. Indeed, this may account for the
cardiovascular side effects of coxibs. If such a mechanism is
proven, it may be of great importance to chemoprevention,
in which a chemopreventive agent against cancer will be ad-
ministered on a long-term basis to older subjects, i.e. those
likely to have atheromatous lesions.
Inhibition of COX may shift its substrate fatty
acid to a non-COX pathway and generate a
pro-carcinogenic end product
For example, inhibition of COX-2 could shift arachidonic
acid to the LOX pathway, some of whose products have pro-
tumorigenic activities. Although this possibility has not been
systematically explored, a recent study suggests that it may
not be that unlikely; in humans, under physiological condi-
tions, oral celecoxib increased leukotriene B4production in
the lung micro-environment [26].
Time to search for targets beyond COX-2
It is apparent that the central concept of a dominant role of
COX-2 in cancer prevention may have significant limitations
that make necessary its re-examination. If the cardiovascular
toxicity of coxibs is in fact due to their COX-2 effects,
then it may be difficult to envision their practical long-term
administration to individuals who, in the context of arthero-
sclerosis, may have endothelial COX-2 overexpression.
Thus alternative approaches should focus on targets beyond
COX-2.
The two main reasons justifying the search for targets other
than COX-2 are the following: first, NSAIDs prevent colon
and other cancers and do this sub-optimally, probably by
modulating several molecular targets in addition to COX-2.
NSAIDs are not reasonable candidates for chemoprevention,
owing to their safety and efficacy limitations. Secondly, coxibs
have limited clinical efficacy; it is likely that they achieve their
clinical effect by modulating targets other than COX-2, and
they may have limiting side effects.
At this time, strategies incorporating these considerations
may lead to the next, and, one hopes, final, stage in our ef-
forts to prevent cancer. Such an approach appears to be both
rational and promising.
This work was supported by the NIH (National Institutes of Health)
Grants CA92423 and CA34527, and PSC-CUNY (Professional Staff
Congress-City University of New York) Grant 65201-00 34.
References
1 Baron, J.A., Cole, B.F., Sandler, R.S., Haile, R.W., Ahnen, D., Bresalier, R.,
McKeown-Eyssen, G., Summers, R.W., Rothstein, R., Burke, C.A. et al.
(2003) N. Engl. J. Med. 348, 891–899
C
2005 Biochemical Society
The Molecular Biology of Colorectal Cancer 727
2 Sandler, R.S., Halabi, S., Baron, J.A., Budinger, S., Paskett, E.,
Keresztes, R., Petrelli, N., Pipas, J.M., Karp, D.D., Loprinzi, C.L. et al.
(2003) N. Engl. J. Med. 348, 883–890
3 Rayyan, Y., Williams, J. and Rigas, B. (2002) Cancer Invest. 20,
1002–1011
4 Simmons, D.L., Botting, R.M. and Hla, T. (2004) Pharmacol. Rev. 56,
387–437
5 Rigas, B., Goldman, I.S. and Levine, L. (1993) J. Lab. Clin. Med. 122,
518–523
6 Turini, M.E. and DuBois, R.N. (2002) Annu. Rev. Med. 53, 35–57
7 Qiao, L., Kozoni, V., Tsioulias, G.J., Koutsos, M.I., Hanif, R., Shiff, S.J. and
Rigas, B. (1995) Biochim. Biophys. Acta 1258, 215–223
8 Sheng, H.M., Shao, J.Y., Morrow, J.D., Beauchamp, R.D. and Dubois, R.N.
(1998) Cancer Res. 58, 362–366
9 Shureiqi, I. and Lippman, S.M. (2001) Cancer Res. 61, 6307–6312
10 Chulada, P.C., Thompson, M.B., Mahler, J.F., Doyle, C.M., Gaul, B.W.,
Lee, C., Tiano, H.F., Morham, S.G., Smithies, O. and Langenbach, R.
(2000) Cancer Res. 60, 4705–4708
11 Liu, C.H., Chang, S.H., Narko, K., Trifan, O.C., Wu, M.T., Smith, E.,
Haudenschild, C., Lane, T.F. and Hla, T. (2001) J. Biol. Chem. 276,
18563–18569
12 Muller-Decker, K., Neufang, G., Berger, I., Neumann, M., Marks, F. and
Furstenberger, G. (2002) Proc. Natl. Acad. Sci. U.S.A 99, 12483–12488
13 Bol, D.K., Rowley, R.B., Ho, C.P., Pilz, B., Dell, J., Swerdel, M., Kiguchi, K.,
Muga, S., Klein, R. and Fischer, S.M. (2002) Cancer Res. 62, 2516–2521
14 Fitzgerald, G.A. (2004) N. Engl. J. Med. 351, 1709–1711
15 Nobuoka, A., Takayama, T., Miyanishi, K., Sato, T., Takanashi, K.,
Hayashi, T., Kukitsu, T., Sato, Y., Takahashi, M., Okamoto, T. et al. (2004)
Gastroenterology 127, 428–443
16 Blaine, S.A., Meyer, A.M., Hurteau, G., Wick, M., Hankin, J.A., Murphy,
R.C., Subbaramaiah, K., Dannenberg, A.J., Geraci, M.W. and Nemenoff,
R.A. (2005) Carcinogenesis 26, 209–217
17 Hanif, R., Pittas, A., Feng, Y., Koutsos, M.I., Qiao, L., Staiano-Coico, L.,
Shiff, S.I. and Rigas, B. (1996) Biochem. Pharmacol. 52, 237–245
18 Steinbach, G., Lynch, P.M., Phillips, R.K., Wallace, M.H., Hawk, E., Gordon,
G.B., Wakabayashi, N., Saunders, B., Shen, Y., Fujimura, T. et al. (2000)
N. Engl. J. Med. 342, 1946–1952
19 Higuchi, T., Iwama, T., Yoshinaga, K., Toyooka, M., Taketo, M.M. and
Sugihara, K. (2003) Clin. Cancer Res. 9, 4756–4760
20 Giardiello, F.M., Hamilton, S.R., Krush, A.J., Piantadosi, S., Hylind, L.M.,
Celano, P., Booker, S.V., Robinson, C.R. and Offerhaus, G.J. (1993) N. Engl.
J. Med. 328, 1313–1316
21 Maier, T.J., Schilling, K., Schmidt, R., Geisslinger, G. and Grosch, S. (2004)
Biochem. Pharmacol. 67, 1469–1478
22 Grosch, S., Tegeder, I., Niederberger, E., Brautigam, L. and Geisslinger, G.
(2001) FASEB J. 15, 2742–2744
23 Eibl, G., Takata, Y., Boros, L.G., Liu, J., Okada, Y., Reber, H.A. and Hines,
O.J. (2005) Cancer Res. 65, 982–990
24 McAdam, B.F., Catella-Lawson, F., Mardini, I.A., Kapoor, S., Lawson,
J.A. and FitzGerald, G.A. (1999) Proc. Natl. Acad. Sci. U.S.A. 96,
272–277
25 Schonbeck, U., Sukhova, G.K., Graber, P., Coulter, S. and Libby, P. (1999)
Am. J. Pathol. 155, 1281–1291
26 Mao, J.T., Tsu, I.H., Dubinett, S.M., Adams, B., Sarafian, T., Baratelli, F.,
Roth, M.D. and Serio, K.J. (2004) Clin. Cancer Res. 10, 6872–6878
Received 22 March 2005
C
2005 Biochemical Society
... Administration of COX-2 inhibitors for organs like lung, breast, colon, and prostate has been attested to cause a reduction of cancer risk by about 68% (Brizzolara et al., 2017). Interestingly, although it has been estimated that about half of the adenomatic cancers do not express COX-2 (Kashfi & Rigas, 2005;Noda et al., 2002), administration of COX-2 inhibitors has shown promising results for suppression of adenoma F I G U R E 6 Cancers known to overexpress cyclooxygenase-2 (COX-2). HNSCC: head and neck squamous cell carcinoma; LSCC: laryngeal squamous cell carcinoma; NSCLC: non-small-cell lung cancer; OSCC: oral squamous cell carcinoma F I G U R E 7 Agents identified for their chemopreventive roles against tumors working through cyclooxygenase-2 (COX-2) blockade in cancer cells. ...
Cyclooxygenase-2 in cancer: A review
Article
  • Oct 2018
Cyclooxygenase‐2 (COX‐2) is frequently expressed in many types of cancers exerting a pleiotropic and multifaceted role in genesis or promotion of carcinogenesis and cancer cell resistance to chemo‐ and radiotherapy. COX‐2 is released by cancer‐associated fibroblasts (CAFs), macrophage type 2 (M2) cells, and cancer cells to the tumor microenvironment (TME). COX‐2 induces cancer stem cell (CSC)‐like activity, and promotes apoptotic resistance, proliferation, angiogenesis, inflammation, invasion, and metastasis of cancer cells. COX‐2 mediated hypoxia within the TME along with its positive interactions with YAP1 and antiapoptotic mediators are all in favor of cancer cell resistance to chemotherapeutic drugs. COX‐2 exerts most of the functions through its metabolite prostaglandin E2. In some and limited situations, COX‐2 may act as an antitumor enzyme. Multiple signals are contributed to the functions of COX‐2 on cancer cells or its regulation. Members of mitogen‐activated protein kinase (MAPK) family, epidermal growth factor receptor (EGFR), and nuclear factor‐κβ are main upstream modulators for COX‐2 in cancer cells. COX‐2 also has interactions with a number of hormones within the body. Inhibition of COX‐2 provides a high possibility to exert therapeutic outcomes in cancer. Administration of COX‐2 inhibitors in a preoperative setting could reduce the risk of metastasis in cancer patients. COX‐2 inhibition also sensitizes cancer cells to treatments like radio‐ and chemotherapy. Chemotherapeutic agents adversely induce COX‐2 activity. Therefore, choosing an appropriate chemotherapy drugs along with adjustment of the type and does for COX‐2 inhibitors based on the type of cancer would be an effective adjuvant strategy for targeting cancer.
View
... Recently some COX-independent targets have been identified as being involved in the anticancer effects of NSAIDs [3,[7][8][9][10]. Moreover, both cAMP and cyclic guanosine monophosphate (cGMP) phosphodiesterases (PDEs) have gained particular interest in relation to CRN [3,11,12]. ...
Phosphodiesterases in non-neoplastic appearing colonic mucosa from patients with colorectal neoplasia
Article
Full-text available
  • Dec 2016
  • BMC CANCER
Background Intracellular signaling through cyclic nucleotides, both cyclic AMP and cyclic GMP, is altered in colorectal cancer. Accordingly, it is hypothesized that an underlying mechanism for colorectal neoplasia involves altered function of phosphodiesterases (PDEs), which affects cyclic nucleotide degradation. Here we present an approach to evaluate the function of selected cyclic nucleotide-PDEs in colonic endoscopic biopsies from non-neoplastic appearing mucosa. Methods Biopsies were obtained from patients with and without colorectal neoplasia. Activities of PDEs were characterized functionally by measurements of transepithelial ion transport and their expression and localization by employing real-time qPCR and immunohistochemistry. ResultsIn functional studies PDE subtype-4 displayed lower activity in colorectal neoplasia patients (p = 0.006). Furthermore, real-time qPCR analysis showed overexpression of subtype PDE4B (p = 0.002) and subtype PDE5A (p = 0.02) in colorectal neoplasia patients. Finally, immunohistochemistry for 7 PDE isozymes demonstrated the presence of all 7 isozymes, albeit with weak reactions, and with no differences in localization between colorectal neoplasia and control patients. Of note, quantification of PDE subtype immunostaining revealed a lower amount of PDE3A (p = 0.04) and a higher amount of PDE4B (p = 0.02) in samples from colorectal neoplasia patients. Conclusion In conclusion, functional data indicated lower activity of PDE4 subtypes while expressional and abundance data indicated a higher expression of PDE4B in patients with colorectal neoplasia. We suggest that cyclic nucleotide-PDE4B is overexpressed as a malfunctioning protein in non-neoplastic appearing colonic mucosa from patients with colorectal neoplasia. If a predisposition of reduced PDE4B activity in colonic mucosa from colorectal neoplasia patients is substantiated further, this subtype could be a potential novel early diagnostic risk marker and may even be a target for future medical preventive treatment of colorectal cancer.
View
... 48,49 Downregulation of COX-2 expression by PSP, in the context of persistent chronic inflammation, is also worth noting as playing an important role in carcinogenesis. 50 In our previous studies we found that HL-60 cells treated with PSP inhibited COX-2 expression accompanied by decreases in cellular proliferation, increases in apoptosis, and the modulation of genes involved in cell cycle regulation. 46 Some of the observed modulation of gene expression by PSP may involve its ability to control signaling pathways, resulting in growth control. ...
Recent Advances and Challenges in Studies of Control of Cancer Stem Cells and the Gut Microbiome by the Trametes-Derived Polysaccharopeptide PSP (Review)
Article
Full-text available
  • Jan 2016
  • INT J MED MUSHROOMS
The medicinal mushroom Trametes versicolor has been well recognized for its activity in maintaining the general health of the population and in managing and treating human diseases in various cultures. Its use has been recently gaining acceptance and popularity in Western countries. The reported health benefits of T. versicolor led to a search for the identity of its bioactive ingredients. These efforts have resulted in the isolation of the polysaccharopeptide PSP from cultured mycelia of strain Cov-1, which expresses large amounts of PSP. The availability of highly purified PSP was followed by studies of its biological activities using tissue culture models and limited human clinical trials. In this review we summarize recent advances in the antitumorigenic and immunomodulatory effects of PSP, elimination of prostate cancer stem cells and control of the intestinal microbiome, and its interplay with host cells as a prebiotic. These findings may have implications for widening and repurposing the use of PSP.
View
... Celecoxib have been shown to cause tumor cell specific increases in cell death, and that are also associated with a lower rate of growth (Koehne and Dubois, 2004; Cui et al, 2005; Kang et al, 2006; Klenke et al, 2006). Prolonged treatment with COX2 inhibitors can reduce the incidence of developing cancer, which, in addition, argues that COX2 inhibitors have cancer preventative effects (Kashfi and Rigas, 2005; Narayanan et al, 2006). Expression levels of COX2 do not simplistically correlate with tumor cell sensitivity to COX2 inhibitors (Patel et al, 2005; Kulp et al, 2004 ). ...
OSU-03012 and Viagra Treatment Inhibits the Activity of Multiple Chaperone Proteins and Disrupts the Blood-Brain Barrier: Implications for Anti-Cancer Therapies: AR-12 AND VIAGRA
Article
Full-text available
  • Mar 2015
  • J CELL PHYSIOL
We examined the interaction between OSU-03012 (also called AR-12) with phosphodiesterase 5 (PDE5) inhibitors to determine the role of the chaperone GRP78/BiP/HSPA5 in the cellular response. Sildenafil (Viagra) interacted in a greater than additive fashion with OSU-03012 to kill stem-like GBM cells. Treatment of cells with OSU-03012/sildenafil: abolished the expression of multiple oncogenic growth factor receptors and plasma membrane drug efflux pumps and caused a rapid degradation of GRP78 and other HSP70 and HSP90 family chaperone proteins. Decreased expression of plasma membrane receptors and drug efflux pumps was dependent upon enhanced PERK-eIF2α-ATF4-CHOP signaling and was blocked by GRP78 over-expression. In vivo OSU-03012/sildenafil was more efficacious than treatment with celecoxib and sildenafil at killing tumor cells without damaging normal tissues and in parallel reduced expression of ABCB1 and ABCG2 in the normal brain. The combination of OSU-03012/sildenafil synergized with low concentrations of sorafenib to kill tumor cells, and with lapatinib to kill ERBB1 over-expressing tumor cells. In multiplex assays on plasma and human tumor tissue from an OSU-03012/sildenafil treated mouse we noted a profound reduction in uPA signaling and identified FGF and JAK1/2 as response biomarkers for potentially suppressing the killing response. Inhibition of FGFR signaling and to a lesser extent JAK1/2 signaling profoundly enhanced OSU-03012/sildenafil lethality. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
View
... Mechanism of Action of NSAIDs. The effect of NSAIDs in cancer prevention is pleiotropic (Shiff and Rigas, 1999a,b;Kashfi and Rigas, 2005;Schror, 2011;Stolfi et al., 2013). There are at least three major classes of effects: those mediated through COX inhibition, COX-independent effects, and effects on colon stem cells. ...
The Evolving Role of Nonsteroidal Anti-Inflammatory Drugs in Colon Cancer Prevention: A Cause for Optimism
Article
  • Jan 2015
  • J PHARMACOL EXP THER
Colorectal cancer (CRC) is a serious yet preventable disease. The low acceptance and the cost of colonoscopy as a screening method for CRC make its chemoprevention an important option. Nonsteroidal anti-inflammatory drugs (NSAIDs), not currently recommended for CRC prevention, have the potential to evolve into the agents of choice for this indication. Here, we discuss the promise and challenge of NSAIDs for this chemoprevention application. Multiple epidemiological studies, randomized clinical trials (RCTs) of sporadic colorectal polyp recurrence, RCTs in patients with hereditary colorectal cancer syndromes, and pooled analyses of cardiovascular-prevention RCTs linked to cancer outcomes have firmly established the ability of conventional NSAIDs to prevent CRC. NSAIDs are, however, seriously limited by their toxicity, which can become cumulative with their long-term administration for chemoprevention, whereas drug interactions in vulnerable elderly patients compound their safety. Newer, chemically modified NSAIDs offer the hope of enhanced efficacy and safety. Recent work also indicates that targeting earlier stages of colorectal carcinogenesis such as the lower-complexity aberrant crypt foci, is a promising approach that may only require relatively short use of chemopreventive agents. Drug combination approaches exemplified by sulindac plus difluoromethylornithine, appear very efficacious. Identification of those at risk or most likely to benefit from a given intervention using predictive biomarkers may usher in personalized chemoprevention. Agents that offer simultaneous chemoprevention of diseases in addition to CRC, e.g. cardiovascular and/or neurodegenerative diseases may have a much greater potential for a broad clinical application. The American Society for Pharmacology and Experimental Therapeutics.
View
... Nontransformed cells such as primary hepatocytes are significantly less sensitive to the drug. Prolonged treatment with COX2 inhibitors can reduce the incidence of developing cancer, which, in addition, argues that COX2 inhibitors have cancer preventative effects (Kashfi and Rigas, 2005; Narayanan et al, 2006). Expression levels of COX2 do not simplistically correlate with tumor cell sensitivity to COX2 inhibitors (Patel et al, 2005; Kulp et al, 2004). ...
GRP78 / BiP / HSPA5 / Dna K is a universal therapeutic target for human disease
Article
Full-text available
  • Dec 2014
  • J CELL PHYSIOL
The chaperone GRP78 / Dna K is conserved throughout evolution down to prokaryotes. The GRP78 inhibitor OSU-03012 (AR-12) interacted with sildenafil (Viagra) or tadalafil (Cialis) to rapidly reduce GRP78 levels in eukaryotes and as a single agent reduce Dna K levels in prokaryotes. Similar data with the drug combination were obtained for: HSP70, HSP90, GRP94, GRP58, HSP27, HSP40 and HSP60. OSU-03012/sildenafil treatment killed brain cancer stem cells and decreased the expression of: NPC1 and TIM1; LAMP1; and NTCP1, receptors for Ebola / Marburg / Hepatitis A, Lassa fever, and Hepatitis B viruses, respectively. Pre-treatment with OSU-03012/sildenafil reduced expression of the coxsakie and adenovirus receptor in parallel with it also reducing the ability of a serotype 5 adenovirus or coxsakie virus B4 to infect and to reproduce. Similar data were obtained using Chikungunya, Mumps, Measles, Rubella, RSV, CMV and Influenza viruses. OSU-03012 as a single agent at clinically relevant concentrations killed laboratory generated antibiotic resistant E. coli and clinical isolate multi-drug resistant N. gonorrhoeae and MRSE which was in bacteria associated with reduced Dna K and Rec A expression. The PDE5 inhibitors sildenafil or tadalafil enhanced OSU-03012 killing in N. gonorrhoeae and MRSE and low marginally toxic doses of OSU-03012 could restore bacterial sensitivity in N. gonorrhoeae to multiple antibiotics. Thus Dna K and bacterial phosphodiesterases are novel antibiotic targets, and inhibition of GRP78 is of therapeutic utility for cancer and also for bacterial and viral infections. This article is protected by copyright. All rights reserved
View
... Celecoxib TM (Celebrex TM ) could suppress tumor cell growth in vitro and when grown as xenografts in animals (Klenke et al., 2006;Koehne et al., 2004;Cui et al, 2005;Kang et al., 2006). Studies in patients demonstrated that individuals with prolonged exposure to COX2 inhibitors as part of an anti-inflammatory therapeutic regimen also had a lower incidence of developing cancer, suggestive that COX2 inhibitors were cancer preventative (Kashfi and Rigas, 2005;Narayanan et al., 2006). However, as the sensitivity of tumor cells to COX2 inhibitors was investigated in greater detail, it became apparent that expression of COX2 did not per se correlate with tumor cell sensitivity to COX2 inhibitor treatment (Patel et al, 2005;Kulp et al., 2004). ...
View
Serum metabolite signatures in normal individuals and patients with colorectal adenoma or colorectal cancer using UPLC-MS/MS method
Article
  • Sep 2022
Colorectal cancer (CRC) is one of the main causes of cancer-related deaths worldwide. Sporadic CRC develops from normal mucosa via adenoma to adenocarcinoma, which provides a long screening window for clinical detection. However, early diagnosis of sporadic colorectal adenoma (CRA) and CRC using serum metabolic screening remains unclear. The purpose of this study was to identify some promising signatures for distinguishing the different pathological metabolites of colorectal mucosal malignant transformation. A total of 238 endogenous metabolites were elected. We found that CRA and CRC patients had 72 and 73 different metabolites compared with healthy controls, respectively. There were 20 different metabolites between CRA and CRC patients. The potential metabolites of tumor growth (including patients with CRA and CRC) were found, such as A-d-glucose, D-mannose, N-acetyl-D-glucosamine, L-cystine, Sarcosine, TXB 2, 12-Hete, and chenodeoxycholic acid. Compared with CRA, 3,4,5-trimethoxybenzoic acid was significantly higher in CRC patients. There results prompt us to use the potential serum signatures to screen CRC as the novel strategy. Serum metabolite screening is useful for early detection of mucosal intestinal malignancy. We will further investigate the roles of these promising biomarkers during intestinal tumorigenesis in future. Significance CRC is one of the main causes of cancer-related deaths worldwide. Sporadic CRC develops from normal mucosa via adenomas to adenocarcinoma, which provides a long screening window for about 5–10 years. We adopt the metabolic analysis of extensive targeted metabolic technology. The main purpose of the metabolic group analysis is to detect and screen the different metabolites, thereby performing related functional prediction and analysis of the differential metabolites. In our study, 30 samples are selected, divided into 3 groups for metabolic analysis, and 238 metabolites are elected. In 238 metabolites, we find that CRA patients have 72 different metabolites compared with health control. Compared with health control, CRC have 73 different metabolites. Compared with CRA and CRC patients, there are 20 different metabolites. The annotation results of the significantly different metabolites are classified according to the KEGG pathway type. The potential metabolites of tumor growth stage (including patients with CRA and CRC) are found, such as A-d-glucose, D-mannose, N-acetyl-D-glucosamine, L-cystine, sarcosine, TXB 2, 12-Hete and chenodeoxycholic acid. Compared with CRA patients, CRC patients had significantly higher 3,4,5-trimethoxybenzoic acid level. It is prompted to use serum different metabolites to screen CRC to provide new possibilities.
View
Beyond Cox-Inhibition: ‘Side-Effects’ of Ibuprofen on Neoplastic Development and Progression
Article
  • May 2015
  • CURR PHARM DESIGN
Ibuprofen is a non-steroidal anti-inflammatory drug of generalized use with over-the-counter availability. Population-based studies have provided evidence that its long-term use is associated with a 30-60% decrease in the risk of developing major types of cancer. Initially, the underlying molecular mechanism was thought to be exclusively dependent on its inhibitory effect on cyclooxygenase activity, which is involved in the inflammatory response. However, numerous studies have now shown that the cancer chemopreventive properties of ibuprofen are much more complex and likely involve multiple COX-2-independent effects. Here we review the current knowledge on COX-independent effects of ibuprofen, which affect changes in gene expression or alternative splicing and act through various cell cycle- and apoptosis-regulating pathways, including β-catenin, NF-κB, PPARγ and p53.
View
GRP78/Dna K Is a Target for Nexavar/Stivarga/Votrient in the Treatment of Human Malignancies, Viral Infections and Bacterial Diseases
Article
Full-text available
  • Apr 2015
  • J CELL PHYSIOL
Prior tumor cell studies have shown that the drugs sorafenib (Nexavar) and regorafenib (Stivarga) reduce expression of the chaperone GRP78. Sorafenib/regorafenib and the multi-kinase inhibitor pazopanib (Votrient) interacted with sildenafil (Viagra) to further rapidly reduce GRP78 levels in eukaryotes and as single agents to reduce Dna K levels in prokaryotes. Similar data were obtained in tumor cells in vitro and in drug-treated mice for: HSP70, mitochondrial HSP70, HSP60, HSP56, HSP40, HSP10 and cyclophilin A. Prolonged 'rafenib / sildenafil treatment killed tumor cells and also rapidly decreased the expression of: the drug efflux pumps ABCB1 and ABCG2; and NPC1 and NTCP, receptors for Ebola / Hepatitis A and B viruses, respectively. Pre-treatment with the 'Rafenib/sildenafil combination reduced expression of the Coxsackie and Adenovirus receptor in parallel with it also reducing the ability of a serotype 5 Adenovirus or Coxsackie virus B4 to infect and to reproduce. Sorafenib / pazopanib and sildenafil was much more potent than sorafenib / pazopanib as single agents at preventing Adenovirus, Mumps, Chikungunya, Dengue, Rabies, West Nile, Yellow Fever and Enterovirus 71 infection and reproduction. 'Rafenib drugs / pazopanib as single agents killed laboratory generated antibiotic resistant E. coli which was associated with reduced Dna K and Rec A expression. Marginally toxic doses of 'Rafenib drugs / pazopanib restored antibiotic sensitivity in pan-antibiotic resistant bacteria including multiple strains of blakpc Klebsiella pneumoniae. Thus Dna K is an antibiotic target for sorafenib, and inhibition of GRP78/Dna K has therapeutic utility for cancer and for bacterial and viral infections. This article is protected by copyright. All rights reserved. © 2015 The Authors. Journal of Cellular Physiology Published by Wiley Periodicals, Inc.
View
The Effect of Celecoxib, a Cyclooxygenase-2 Inhibitor, in Familial Adenomatous Polyposis
Article
Full-text available
  • Jul 2000
Patients with familial adenomatous polyposis have a nearly 100 percent risk of colorectal cancer. In this disease, the chemopreventive effects of nonsteroidal antiinflammatory drugs may be related to their inhibition of cyclooxygenase-2. We studied the effect of celecoxib, a selective cyclooxygenase-2 inhibitor, on colorectal polyps in patients with familial adenomatous polyposis. In a double-blind, placebo-controlled study, we randomly assigned 77 patients to treatment with celecoxib (100 or 400 mg twice daily) or placebo for six months. Patients underwent endoscopy at the beginning and end of the study. We determined the number and size of polyps from photographs and videotapes; the response to treatment was expressed as the mean percent change from base line. At base line, the mean (+/-SD) number of polyps in focal areas where polyps were counted was 15.5+/-13.4 in the 15 patients assigned to placebo, 11.5+/-8.5 in the 32 patients assigned to 100 mg of celecoxib twice a day, and 12.3+/-8.2 in the 30 patients assigned to 400 mg of celecoxib twice a day (P=0.66 for the comparison among groups). After six months, the patients receiving 400 mg of celecoxib twice a day had a 28.0 percent reduction in the mean number of colorectal polyps (P=0.003 for the comparison with placebo) and a 30.7 percent reduction in the polyp burden (the sum of polyp diameters) (P=0.001), as compared with reductions of 4.5 and 4.9 percent, respectively, in the placebo group. The improvement in the extent of colorectal polyposis in the group receiving 400 mg twice a day was confirmed by a panel of endoscopists who reviewed the videotapes. The reductions in the group receiving 100 mg of celecoxib twice a day were 11.9 percent (P=0.33 for the comparison with placebo) and 14.6 percent (P=0.09), respectively. The incidence of adverse events was similar among the groups. In patients with familial adenomatous polyposis, six months of twice-daily treatment with 400 mg of celecoxib, a cyclooxygenase-2 inhibitor, leads to a significant reduction in the number of colorectal polyps.
View
Overexpression of Cyclooxygenase-2 Is Sufficient to Induce Tumorigenesis in Transgenic Mice
Article
Full-text available
  • Jun 2001
The cyclooxygenase (COX)-2 gene encodes an inducible prostaglandin synthase enzyme that is overexpressed in adenocarcinomas and other tumors. Deletion of the murine Cox-2 gene in Min mice reduced the incidence of intestinal tumors, suggesting that it is required for tumorigenesis. However, it is not known if overexpression of Cox-2 is sufficient to induce tumorigenic transformation. We have derived transgenic mice that overexpress the human COX-2 gene in the mammary glands using the murine mammary tumor virus promoter. The human Cox-2 mRNA and protein are expressed in mammary glands of female transgenic mice and were strongly induced during pregnancy and lactation. Female virgin Cox-2 transgenic mice showed precocious lobuloalveolar differentiation and enhanced expression of the beta-casein gene, which was inhibited by the Cox inhibitor indomethacin. Mammary gland involution was delayed in Cox-2 transgenic mice with a decrease in apoptotic index of mammary epithelial cells. Multiparous but not virgin females exhibited a greatly exaggerated incidence of focal mammary gland hyperplasia, dysplasia, and transformation into metastatic tumors. Cox-2-induced tumor tissue expressed reduced levels of the proapoptotic proteins Bax and Bcl-x(L) and an increase in the anti-apoptotic protein Bcl-2, suggesting that decreased apoptosis of mammary epithelial cells contributes to tumorigenesis. These data indicate that enhanced Cox-2 expression is sufficient to induce mammary gland tumorigenesis. Therefore, inhibition of Cox-2 may represent a mechanism-based chemopreventive approach for carcinogenesis.
View
Hanif R, Pittas A, Feng Y, Koutos MI, Qiao L, Staiano-Coico L, Shiff SI, Rigas BEffects of nonsteroidal anti-inflammatory drugs on proliferation and on induction of apoptosis in colon cancer cells by a prostaglandin-independent pathway. Biochem Pharmacol 52: 237-245
Article
  • Aug 1996
  • BIOCHEM PHARMACOL
Nonsteroidal anti-inflammatory drugs (NSAIDs) decrease the incidence of and mortality from colon cancer. We observed that NSAIDs inhibit the proliferation rate, alter the cell cycle distribution, and induce apoptosis in colon cancer cell lines. We evaluated whether the inhibition by NSAIDs of prostaglandin (PG) synthesis is required for their effects on colon cancer cells by studying two human colon cancer cell lines: HCT-15 and HT-29. HCT-15, which lacks cyclooxygenase transcripts, does not produce PGs even when exogenously stimulated, whereas HT-29 produces PGE2, PGF2α, and PGI2. HCT-15 and HT-29 cells, when treated for up to 72 hr with 200 μM sulindac sulfide (an active metabolite of sulindac) or 900 μM piroxicam, showed changes in proliferation, cell cycle phase distribution, and apoptosis. Treatment with PGE2, PGF2α, and PGI2, following a variety of protocols, and at concentrations between 10−6 and 10−11 M, failed to reverse the effects of NSAIDs on these three parameters of cell growth. We concluded that NSAIDs inhibit the proliferation rate of the two colon cancer cell lines independent of their ability to inhibit PG synthesis. Thus, alternative mechanisms for their activity on tumor cell growth must be entertained. These observations may be relevant to the mechanism of colon tumor inhibition by NSAIDs.
View
Qiao L, Kozoni V, Tsioulias GJ, Koutsos MI, Hanif R, Shiff SJ, Rigas BSelected eicosanoids increase the proliferation rate of human colon carcinoma cell lines and mouse colonocytes in vivo. Biochim Biophys Acta 1258: 215-223
Article
  • Oct 1995
  • Biochim Biophys Acta
Eicosanoids have been implicated in colon carcinogenesis, but their role remains unclear. The levels of PGE2 are elevated in colon cancer tissues and in blood draining colon tumors. The effect of eicosanoids on the proliferation of colonic cells is unknown. We studied the effect of several prostaglandins (PGs) and leukotriene (LT)B4 on the proliferation rate of the human colon adenocarcinoma cell lines SW1116 and HT-29 and of 16,16-dimethyl PGE2 (dmPGE2) on the colon of BALB/c mine. PGs E2, F2α, I2, the methyl ester of, PGE2, dmPGE2, and LTB4 (10−10, 10−8, 10−6 M), administered for up to 72 h, stimulated cell proliferation in SW1116 cells and all t but PGF2α and PGI2 stimulated proliferation in HT-29 cells. The proliferative effect was time- and concentration-dependent. However, in SW1116 cells the response to PGs was ‘bell-shaped’, being maximal at 10−8 M, with the 10−10 and 10−6 M concentrations being less effective. In HT-29 cells, the addition of methyl groups to the PGE2 molecule increased the proliferative affect. None of these eicosanoids affected the distribution of these cells in the cell cycle or their rate of programmed cell death (apoptosis). dmPGE2 stimulated 3.6-fold the proliferation of colonocytes in normal BALB/c mice. This was determined by bivariate flow cytometric analysis of the expression of proliferating cell nuclear antigen (PCNA) in virtually pure populations of mouse colonocytes. dmPGE2 did not alter the cell cycle distribution of these cells. We conclude that several PGs as well as LTB4 stimulate the proliferation of human colon carcinoma cells in vitro, while dmPGE2 has a similar effect on mouse colonocytes in vivo. These findings raise the possibility that eicosanoids may contribute to colonic carcinogenesis by stimulating the proliferation rate of tumor cells in the colon.
View
Altered eicosanoid levels in human colon cancer
Article
  • Dec 1993
  • J Lab Clin Med
Eicosanoids may participate in colon carcinogenesis, as evidenced from work in animal tumor models showing prevention of colon cancer by inhibitors of their synthesis and epidemiologic studies demonstrating reduced risk of colon cancer in long-term users of aspirin and other nonsteroidal antiinflammatory drugs (NSAIDs). The levels of prostaglandin E2 (PGE2), PGF2 alpha, PGI2, thromboxane A2 (TXA2), and leukotriene B4 (LTB4), which represent the cyclooxygenase and 5-lipoxygenase pathways, were determined in 21 pairs of surgically excised human colon cancer and histologically normal mucosa samples 5 to 10 cm away from the tumor. The levels of PGE2 were elevated in colon cancer samples as compared with histologically normal mucosa samples distant from the cancer (p < 0.01), whereas levels of prostacyclin (PGI2) were decreased (p < 0.05). The differences in the levels of PGF2 alpha, TXA2, and LTB4 between normal and malignant tissue were not statistically significant. No statistically significant association was found between the level of each of the eicosanoids assayed and Dukes' stage of colon cancer. These findings, confirming and extending earlier work from tumors and cell culture, suggest that the protective effect of aspirin and other NSAIDs in the development of human colon cancer may be mediated, at least in part, through their inhibition of arachidonic acid metabolism by cyclooxygenase.
View
Treatment of Colonic and Rectal Adenomas with Sulindac in Familial Adenomatous Polyposis
Article
  • May 1993
Familial adenomatous polyposis is an autosomal dominant disorder characterized by the formation of hundreds of colorectal adenomas and eventual colorectal cancer. Administration of the nonsteroidal antiinflammatory drug sulindac has been followed by regression of polyps in patients with this disorder, but no controlled trial of this drug in patients who have not had surgery has been reported. We conducted a randomized, double-blind, placebo-controlled study of 22 patients with familial adenomatous polyposis, including 18 who had not undergone colectomy. The patients received sulindac at a dose of 150 mg orally twice a day for nine months or identical-appearing placebo tablets. The number and size of the polyps were evaluated every three months for one year. A statistically significant decrease in the mean number of polyps and their mean diameter occurred in patients treated with sulindac, as compared with those given placebo. When treatment was stopped at nine months, the number of polyps had decreased to 44 percent of base-line values and the diameter of the polyps to 35 percent of base-line values (P = 0.014 and P < 0.001, respectively, for the comparison with the changes in the group given placebo). No patient had complete resolution of polyps. Three months after treatment with sulindac was stopped, both the number and the size of the polyps increased in sulindac-treated patients but remained significantly lower than the values at base line. No side effects from sulindac were noted. Sulindac reduces the number and size of colorectal adenomas in patients with familial adenomatous polyposis, but its effect is incomplete, and it is unlikely to replace colectomy as primary therapy.
View
Systemic Biosynthesis of Prostacyclin by Cyclooxygenase (COX)-2: The Human Pharmacology of a Selective Inhibitor of COX2
Article
  • Feb 1999
Prostaglandins (PG) are synthesized by two isoforms of the enzyme PG G/H synthase [cyclooxygenase (COX)]. To examine selectivity of tolerated doses of an inhibitor of the inducible COX-2 in humans, we examined the effects of celecoxib on indices of COX-1-dependent platelet thromboxane (Tx) A2 and on systemic biosynthesis of prostacyclin in vivo. Volunteers received doses of 100, 400, or 800 mg of celecoxib or 800 mg of a nonselective inhibitor, ibuprofen. Ibuprofen, but not celecoxib, significantly inhibited TxA2-dependent aggregation, induced ex vivo by arachidonic acid (83 +/- 11% vs. 11. 9 +/- 2.2%; P < 0.005) and by collagen. Neither agent altered aggregation induced by thromboxane mimetic, U46619. Ibuprofen reduced serum TxB2 (-95 +/- 2% vs. -6.9 +/- 4.2%; P < 0.001) and urinary excretion of the major Tx metabolite, 11-dehydro TxB2 (-70 +/- 9.9% vs. -20.3 +/- 5.3%; P < 0.05) when compared with placebo. Despite a failure to suppress TxA2-dependant platelet aggregation, celecoxib had a modest but significant inhibitory effect on serum TxB2 4 hr after dosing. By contrast, both ibuprofen and celecoxib suppressed a biochemical index of COX-2 activity (endotoxin induced PGE2 in whole blood ex vivo) to a comparable degree (-93.3 +/- 2% vs. -83 +/- 6.1%). There was no significant difference between the doses of celecoxib on COX-2 inhibition. Celecoxib and ibuprofen suppressed urinary excretion of the prostacyclin metabolite 2,3 dinor 6-keto PGF1alpha. These data suggest that (i) platelet COX-1-dependent aggregation is not inhibited by up to 800 mg of celecoxib; (ii) comparable COX-2 inhibition is attained by celecoxib (100-800 mg) and ibuprofen (800 mg) after acute dosing; and (iii) COX-2 is a major source of systemic prostacyclin biosynthesis in healthy humans.
View
Schonbeck U., Sukhova G.K., Graber P., Coulter S., Libby P. 1999. Augmented expression of cyclooxygenase-2 in human atherosclerotic lesions. Am. J. Pathol
Article
  • Nov 1999
Cyclooxygenase-1 (Cox-1) and Cox-2 convert arachidonic acid to prostaglandin H(2), the precursor of other prostaglandins and thromboxanes, eicosanoids important in vascular pathophysiology. However, knowledge of the expression of cyclooxygenases within atherosclerotic lesions is scant. This study tested the hypothesis that human atheroma and nonatherosclerotic arteries express the two Cox isoforms differentially. Cox-1 mRNA and protein localized on endothelial and medial smooth muscle cells of normal arteries (n = 5), whereas Cox-2 expression was not detectable. In contrast, atheromatous (n = 7) lesions contained both Cox-1 and Cox-2, colocalizing mainly with macrophages of the shoulder region and lipid core periphery, whereas smooth muscle cells showed lower levels, as demonstrated by immunohistochemical and in situ hybridization analysis. Furthermore, microvascular endothelium in plaques showed notable staining for both isoforms. In accord with immunohistochemical studies, Western blot analysis of protein extracts from normal arteries revealed constitutive Cox-1, but not Cox-2, expression. Extracts of atheromatous lesions, however, contained both Cox-1 and Cox-2 protein, detected as two immunoreactive proteins of approximately 70 and 50 kd. Macrophages expressed the short form of Cox-1/-2 constitutively after several days of in vitro culture, rather than the 70-kd protein. These results shed new light on the inflammatory pathways that operate in human atheroma. In particular, the expression of Cox-2 in atheromatous, but not in unaffected, arteries has therapeutic implications, given the advent of selective Cox-2 inhibitors.
View
Genetic disruption of Ptgs-1, as well as of Ptgs-2, reduces intestinal tumorigenesis in Min mice
Article
  • Oct 2000
Two isoforms of cyclooxygenase (COX) are known, and to date most studies have implicated COX-2, rather than COX-1, as the isoform involved in colon carcinogenesis. In the present study, we show that homologous disruption of either Ptgs-1 or Ptgs-2 (genes coding for COX-1 or COX-2, respectively) reduced polyp formation in Min/+ mice by approximately 80%. Only COX-1 protein was immunohistochemically detected in normal intestinal tissue, whereas both COX-1 and variable levels of COX-2 protein were detected in polyps. Prostaglandin E2 was increased in polyps compared with normal tissue, and both COX-1 and COX-2 contributed to the PGE2 produced. The results indicate that COX-1, as well as COX-2, plays a key role in intestinal tumorigenesis and that COX-1 may also be a chemotherapeutic target for nonsteroidal anti-inflammatory drugs.
View
Lipoxygenase Modulation to Reverse Carcinogenesis
Article
  • Oct 2001
New studies of the relationship between polyunsaturated fatty acid metabolismand carcinogenesis have led to novel molecular targets for cancer chemoprevention research. These targets include procarcinogenic lipoxygenases (LOXs), including 5-, 8-, and 12-LOX, and anticarcinogenic LOXs, including 15-LOX-1 and possibly 15-LOX-2. Recent studies indicate that 15-LOX-1 is down-regulated in colorectal cancer cells and that the ability of nonsteroidal anti-inflammatory drugs, a class of clinically active cancer chemopreventive agents, to induce apoptosis and growth inhibition in these cells was dependent on the induction of 15-LOX-1 and its metabolic product 13-S-hydroxyoctadecadienoic acid. Consistent with the colorectal studies, 15-LOX very recently has shown anticarcinogenic activity in esophageal and prostatic carcinogenesis. Inhibitors of other LOXs (e.g., 5-LOX) have preclinical anticarcinogenic activity and are being developed for clinical chemoprevention study. These and other LOX data led us to propose that the various LOX pathways exist in a dynamic balance that shifts during carcinogenesis toward 5-, 8-, and 12-LOX (and cyclooxygenase-2) and away from 15-LOX. A novel approach for cancer chemoprevention would involve LOX modulators, i.e., agents that can induce the anticarcinogenic and/or inhibit the procarcinogenic LOXs, thereby shifting the balance of LOX activities from procarcinogenic to anticarcinogenic metabolism of polyunsaturated fatty acids.
View