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Sunday, 2 March 2003 05:50 PM GMT
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Tetracyclines possess properties
that are independent of their antimicrobial characteristics
e.g. arthritis.
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Tetracyclines are primarily bacteriostatic broad-spectrum
antimicrobial agents, they are thought to exert their effect by the inhibiting
protein synthesis. However, in the early 1980?s, tetracyclines have surprised
researchers with unexpected properties that are entirely independent of
their antimicrobial characteristics.
Researchers have since sought to find out the potential
role of these novel properties of the old well known class of antibiotics
in diverse types of diseases. The clinical applications and the pharmaceutical
uses of these compounds appears to be emerging in the coming few years.
Tetracyclines at low doses were found to interfere
with the production of prostaglandins and leukotrienes (1-3), scavenges
oxygen radicals (4), interferes with the expression of nitrous oxide synthase
(5), and enhances natural inhibitors of matrix metalloproteinases (6,7).
after this novel discovery nonantimicrobial chemically modified tetracyclines
(CMT) were prepared and widely investigated in different type of diseases.
Worth noting, low dose doxycycline, sub-antimicrobialdoxycycline
(Periostat), is the first FDA-approved matrix metalloproteinase inhibitor
or collagenase inhibitor for any connective tissue disease.
Matrix Metalloproteinases (MMPS)
These are a family of very important
enzymes that are involved in many physiological and pathological process
in our body. Embryological development, growth morphological changes, ovulation,
pregnancy and wound healing are the processes where their physiological
role can be studied. Atherosclerosis, aortic aneurysms, corneal ulcers of
the eye, inflammation, tumour invasion and metastasis reflects their involvement
in pathological processes which has been turned out as major research target
to find out different therapeutic interventions and drug development
for treatment of these diseases.
What is the key mechanism involved
in all these diverse processes and in what way are tetracyclines related?
All these processes are mediated
by degradation and breakdown of extracellular matrix proteins (collagens,
glycoproteins and proteoglycans). This degradation is mediated by this family
of enzymes (matrix metalloproteinases). These are very potent enzymes that
are highly regulated by transcriptional (at the mRNA level) and posttranscriptional
mechanisms( protein level). It is the main substrate for the nonantimicrobial
action of tetracyclines.
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1- Inflammatory processes
Tetracyclines in rheumatoid arthritis
Rheumatoid arthritis (RA) is a chronic
systemic disorder that causes pain, swelling, stiffness, and loss of function
in the joints. A major step in the parthenogenesis of rheumatoid arthritis
(RA) is the destruction of the extracellular matrix (ECM) of cartilage,
bone, and soft tissues through the release of matrix-degrading enzymes ,matrix
metalloproteinases (MMPs). MMPs are important mediators of tissue destruction
in rheumatoid arthritis and other chronic inflammatory and non-inflammatory
arthropathies (8-10). Different studies have proved the efficacy of
CMT in improving diverse forms of arthritis.
Periodontal disease (a disease of
the gums).
Researchers have found that collagenase
enzyme level is 4 times higher in some populations who show higher risk
for periodontal disease. CMTs have been proved to be effective treatment
of these patients. Dentists also use tetracycline periodontal fibers are
placed in the inflamed mouth areas in part due to its antibacterial action
and as antinflamatory (6,11).
2- Cancer development
Matrix metalloproteinases being
enzymes responsible for remodelling and degradation of the extracellular
matrix (ECM), they help tumour cells to create new space for their
own growth as well as forming new blood vessels important for their feeding.
In this way they also can sneak into blood vessels reaching the circulation.
Modified tetracyclines as inhibitors for collagenase (major component of
CT matrix) and other metalloprotienases have been studied and proved to
be useful in treating cancer and decreasing the metastasic potentials of
cancer cells in conjunction to the treatment of the primary disease by conventional
methods(12-14). Recently, doxycycline was found to regulate the level of
expression of different genes regulationg cell cycle proliferation and migration.
SPARC (secreted protein acidic and
rich in cysteine)/BM40/Osteonectin is a matricellular protein with multiple
effects on cell behaviour. In vitro, its major known functions are anti-adhesive
and anti-proliferative, and it is associated with tissue remodelling and
cancer in vivo. SPARC is overexpressed in many cancers, including breast
cancer (found to be involved mainly in controlling cell proliferation),
in melanoma (controlling cell proliferation and migaration as well), and
in glioma controlling cell migration(15).
?Growth-inhibitory effect of doxycycline
and induction of apoptosis mediated by caspase 3 on CCRF-CEM, a T-lymphoblastic
human leukemic cell line suggest that this well tolerated oral drug has
the potential to be of value in treatment of leukaemia(16).
?Caspase 3, poly(ADP-ribose) polymerase
(PARP), and BCL2 which are apoptotic factors have been found to be upregulated
bye doxycycline in neuroblastoma cell lines(17).
Other Medical conditions
Aortic aneurysms
Aortic aneurysm is a life-threatening
disease, and again is related to the excess collagenase in the walls of
these blood vessels, thinning out the wall, causing expansion .CMTs block
these enzymes and may stabilise the aneurysm and may prevent urgent surgical
need in elderly atherosclerotic patients.
Diabetes
These novel properties directed
investigators to try Tetracyclines as inhibitors for collagenase in the
blocking diabetes induced retinopathy and atherosclerosis with promising
results. What is very interesting is that in vivo animal studies have shown
that retinal detachment is mediated by activation of caspase-3, -7, and
-9 and PARP which have been shown to be regulated by doxycline in different
cell lines(18).
CMTs are a
very interesting clinical and research area for
future studies.
References
1.
Pruzanski W, Greenwald RA, Street IP, et al. Inhibition of enzymatic activity
of phospholipases A2 by minocycline and doxycycline. Biochem Pharmacol 1992;44(6):1165-70
2. ElAttar TM, Lin HS, Shultz
R. Effect of minocycline on prostaglandin formation in gingival fibroblasts.
J Periodontal Res 1988;23(5):285-6
3.
Golub LM, McNamara TF, D'Angelo G, et al. A non-antibacterial chemically-modified
tetracycline inhibits mammalian collagenase activity. J Dent Res 1987;66(8):1310-4
4. van Barr HM, van de Kerkhof
PC, Mier PD, et al. Tetracyclines are potent scavengers of the superoxide
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Amin AR, Attur MG, Thakker GD, et al. A novel mechanism of action of tetracyclines:
effects on nitric oxide synthases. Proc Natl Acad Sci USA 1996;93(24):14014-9
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Golub LM, Ramamurthy N, McNamara TF, et al. Tetracyclines
inhibit tissue collagenase activity: a new mechanism in the treatment of
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7.
Smith RL, Schurman DJ, Kajiyama G, et al. The effect of antibiotics on the
destruction of cartilage in experimental infectious arthritis. J Bone Joint
Surg [Am] 1987;69(7):1063-8
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Krane SM. Mechanisms of tissue destruction in rheumatoid arthritis. In:
McCarty DJ, Koopman WJ, eds. Arthritis and allied conditions: a textbook
of rheumatology. 12th ed. Philadelphia: Lea & Febiger, 1993:763-9
9.
Zvaifler NJ, Firestein GS. Pannus and pannocytes: alternative models of
joint destruction in rheumatoid arthritis. Arthritis Rheum 1994;37(6):783-9
10. Ishiguro
N, Ito T, Ito H, Iwata H, Jugessur H, Ionescu M, Poole AR. Relationship
of matrix metalloproteinases and their inhibitors to cartilage proteoglycan
and collagen turnover: analyses of synovial fluid from patients with osteoarthritis.
Arrthritis Rheum 1999;41:129?36
11.
Golub LM, Goodson JM, Lee HM, et al.
Tetracyclines inhibit tissue collagenases: effects of ingested
low-dose and local delivery systems. J Periodontol. 1985;56(suppl):93-97.
12. Johansson
N, Airola K, Gr?man R, Kariniemi A-L, Saarialho-Kere U, K??i V-M. (1997)
Expression of collagenase-3 (matrix metalloproteinase-13) in squamous cell
carcinomas of the head and neck. Am J Pathol 151:499-508.
13. Bramhall,
S. R., Stamp, G. W., Dunn, J., Lemoine, N. R., and Neoptolemos, J. P. (1996).
Expression of collagenase (MMP2), stromelysin (MMP3) and tissue inhibitor
of the metalloproteinases (TIMP1) in pancreatic and ampullary disease. Br.
J. Cancer 73: 972-978
14. Wang, M.,
Liu, Y. E., Greene, J., Sheng, S., Fuchs, A., Rosen, E. M., and Shi, Y.
E. (1997). Inhibition of tumor growth and metastasis of human breast cancer
cells transfected with tissue inhibitor of metalloproteinase 4. Oncogene
14: 2767-2774.
15.
Dhanesuan N, Sharp JA, Blick T, Price JT, Thompson EW.Doxycycline-inducible
expression of SPARC/Osteonectin/BM40 in MDA-MB-231 human breast cancer cells
results in growth inhibition.Breast Cancer Res Treat. 2002 Sep;75(1):73-85
16.
Iwasaki H, Inoue H, Mitsuke Y, Badran A, Ikegaya S, Ueda T.Doxycycline
induces apoptosis by way of caspase-3 activation with inhibition of matrix
metalloproteinase in human T-lymphoblastic leukemia CCRF-CEM cells. . .
Journal of Laboratory and Clinical Medicine, Volume 140, Issue 6, Pages
382-386
17. Zhonghua
Bing Li Xue Za Zhi .Effects of tetracycline-controlled antisense bcl-2 expression
on the growth and apoptosis of human neuroblastoma cell line SK-N-MC.. 2002
Apr;31(2):135-9.
PMID: 12419161
18.
Zacks DN, Hanninen V, Pantcheva M, Ezra E, Grosskreutz C, Miller JW.Caspase
activation in an experimental model of retinal detachment. Invest Ophthalmol
Vis Sci. 2003 Mar;44(3):1262-7.
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