Doi:10.1016/j.jaad.2005.10.004

Allen N. Sapadin, MD, and Raul Fleischmajer, MD Tetracyclines are broad-spectrum antibiotics that act as such at the ribosomal level where they interferewith protein synthesis. They were first widely prescribed by dermatologists in the early 1950s when it wasdiscovered that they were effective as a treatment for acne. More recently, biologic actions affectinginflammation, proteolysis, angiogenesis, apoptosis, metal chelation, ionophoresis, and bone metabolismhave been researched. The therapeutic effects of tetracycline and its analogues in various diseases havealso been investigated. These include rosacea, bullous dermatoses, neutrophilic diseases, pyodermagangrenosum, sarcoidosis, aortic aneurysms, cancer metastasis, periodontitis, and autoimmune disorderssuch as rheumatoid arthritis and scleroderma. We review the nonantibiotic properties of tetracycline and itsanalogues and their potential for clinical application. ( J Am Acad Dermatol 2006;54:258-65.) Tetracyclines were discovered in 1948 as Abbreviationsused: natural fermentation products of a soilbacterium, Streptomyces aureofaciens. The first chemically purified tetracycline was chlortetra- cycline Currently, 3 groups of tetracyclinesare available: tetracycline natural products, tetracy-cline semisynthetic compounds, and chemicallymodified tetracyclines (CMTs).Perusal of the The ring structure of tetracyclines is surrounded literature suggests that tetracyclines, besides acting by upper and lower peripheral zones. These contain as antibiotics, may also affect inflammation, immu- various chemical functional groups and substitu- Synthetic modification of the lower peripheral region reduces both antibiotic and nonantibioticproperties. On the other hand, biological targets may be enhanced by modifying the upper peripheral Tetracyclines and analogues with biological zone, particularly in positions C7 through C9 of the effects on bacteria and mammalian targets show a D ring. This has been accomplished with tetracycline basic chemical structure consisting of a tetracyclic semisynthetic compounds such as minocycline and naphthacene carboxamide ring system ().
Tetracyclines with antibiotic activity have a dimethyl-amine group at carbon 4 (C4) in ring A. Removal ofthe dimethylamino group from C4 reduces its anti- biotic properties, but enhances nonantibiotic ac- Ionophores are organic compounds capable of tions.Utilization of this strategy was the basis for forming lipid-soluble complexes with metal cations.
the development of several chemically modified Transportation of these cations across hydrophobic barriers, such as artificial or biological membranes,is an important function of these compounds.
Tetracyclines bind divalent metal cations, mostly From the Department of Dermatology, Mount Sinai School of along the lower peripheral region, and circulate in blood plasma primarily as Ca11 and Mg11 chelates.
Funding sources: None.
Conflicts of interest: None identified.
Their role as calcium ionophores has important Reprint requests: Allen N. Sapadin, MD, Box 1048, Mount Sinai biologic implications. After its intracellular incorpo- School of Medicine, One Gustave L. Levy Place, New York, NY ration, Ca11 can act as a secondary messenger and affect pathways such as secretory processes, receptor activation or inhibition, cell division, and ª 2006 by the American Academy of Dermatology, Inc.
doi:10.1016/j.jaad.2005.10.004 The nonantibiotic properties of tetracyclines are summarized in and discussed in detail below.
Both laboratory and clinical studies have investi- gated the anti-inflammatory properties of tetracy-clines. summarizes inhibitory effects oftetracyclines on inflammation.
Tetracyclines and their analogues inhibit matrix metalloproteinases (MMPs). MMPs are zinc-depen-dent endopeptidases that play an important role inthe remodeling of the connective tissue and areinvolved in embryogenesis, wound healing, rheu-matoid arthritis, and tumor invasion and metasta-sis.There are MMPs that break down fibrillarcollagens known as collagenases (MMP-1, MMP-8,MMP-13) and those that can affect basement mem-brane collagen (collagen IV) known as gelatinases(MMP-2, MMP-9). Tetracycline and its analogues caninhibit both collagenases and gelat Angiogenesis, the formation of new blood ves- sels, occurs in many diseases. These include benignconditions (eg, rosacea) and malignant processes(eg, cancer). Matrix-degrading enzymes, present inthe extracellular matrix of tissues, facilitate angio-genesis by allowing new blood vessels to penetrateinto the matrix. MMPs represent one such class ofenzymes involved in this process.
Fig 1. Chemical structures of tetracycline, doxycycline, Minocycline and doxycycline inhibit angiogenesis induced by implanted tumors in rabbit cornea.Doxycycline and, to a lesser degree, CMTs inhibitsynthesis of MMPs (MMP-8, MMP-9) by endothelial specific proteinases) play an important role in the cells. This inhibition, noted at the protein and mRNA regulation of mammalian apoptotic cell dea levels, may affect migration of endothelial cells Caspase-1, also known as the interleukin 1b (IL- during angiogenesis.The antiangiogenic effect of 1b)-converting enzyme for its ability to convert the tetracyclines may have therapeutic implications in precursor IL-1b into mature IL-1b, is important in inflammatory processes accompanied by new blood mediating neuronal cell death after experimental vessel formation (eg, autoimmune disorders, rosa- traumatic brain injury in mice. Decreased mature cea, cancer invasion). Well-controlled studies must IL-1b production may be correlated with a reduction be performed, at both the laboratory and clinical in tissue injury and an improvement in neurological levels, to investigate this potential.
Recent experimental data indicate that tetracy- Apoptosis, programmed cell death, is of funda- neal administration of minocycline 12 hours before or mental importance for the homeostasis and devel- 30 minutes after traumatic brain injury was shown to opment of any organism. Disease states such as prevent neuronal cell death in mice by inhibiting cancer and neurodegenerative disorders may result This effect had clinical implications since from its deregulation. Crucial components of the it reduced tissue injury and neurological deficits.
apoptotic pathway have been elucidated. A family Improved neurological function correlated with of proteases termed caspases (cysteinyl aspartate- decreased lesion size and decreased capsase-1 Fig 2. Nonantimicrobial properties of tetracycline and its derivatives.
Table I. Inhibitory effects of tetracyclines on osteoarthritic knees of untreated dogs are signifi- cantly higher than the levels in doxycycline-treateddogs. This effect is accompanied by inhibition of proliferation and hypertrophy of chondrocytes and Recent experimental evidence indicates that min- ocycline, by stimulating new bone formation, pre- vents the decrease in mineral density (osteoporosis) observed in ovariectomized old rats.This model mimics the accelerated bone loss commonly experi- enced by postmenopausal women. The effect could be related to a reduction in osteoclast function by tetracycline and CMTAdditional well-controlled studies must be performed to more clearly elucidate the cellular and molecular mechanisms involved.
Diseases, both dermatologic and nondermato- logic, that have been investigated for the therapeutic The mechanisms of action of the tetracyclines and tetracycline derivatives in the treatment of variousskin diseases discussed in this section are summa- CMT, Chemically modified tetracycline; DCN, doxycycline; IL-10, interleukin 10; MCN, minocycline; MMP, matrix metalloproteinase; Acne. Tetracycline, minocycline, and doxycycline are effective in the treatment of acne, particularly activity, as measured by mature IL-1b production.
during the inflammatory stage. It has previously Minocycline may also have beneficial effects in been suggested that the beneficial effect of tetracy- chronic neurodegenerative diseases such as Hun- cline is due to the inhibition of Propionibacterium tington diseaseand amyotrophic lateral sclerosis.
acnes accompanied by a reduction in sebum freefatty acids and extracellular lipases.However, it is currently believed that the inflammatory reaction Prophylactic administration of doxycycline re- plays an important role in the pathophysiology of duces the severity of canine osteoarthritis in the acne.The exact cascade of events that is respon- dog anterior cruciate model.Levels of active and sible for inflammation in acne is not known.
total collagenase activity in extracts of cartilage from However, there is evidence of chemotaxis of Table II. Therapeutic use of tetracyclines in Table III. Mechanisms of action of tetracycline and tetracycline derivatives in the treatment ofskin disease inflammatory reaction involving lymphocytes andneutrophils. The mechanism of action may includeinhibition of neutrophil and eosinophil chemotaxis neutrophils,which are known to store MMP-9.
or inhibition of protease release from granulocytes.
Thus the therapeutic effect of tetracyclines in acne Tetracycline or minocycline, alone or in combination may at least in part be due to reduction in neutro- with nicotinamide, were shown to be effective in philic chemotaxisas well as their inhibitory effect bullous dermatoses affecting the dermoepidermal on proinflammatory cytokines and MMP-9. This junction, such as bullous pemphigoid, cicatricial contention is supported by a recent study that pemphigoid, linear IgA disease, and lichen planus showed that subantimicrobial-dose doxycycline (20 pemphigoides.These reports are generally un- mg taken twice daily) reduced the number of both controlled, and it is possible that a selection bias inflammatory and noninflammatory lesions in pa- toward patients with milder disease or spontaneous tients with moderate facial acne.No detectable remission may be operative. Additional studies are also necessary to evaluate whether tetracycline in combination with nicotinamide is more effective than Rosacea. Tetracyclines and their analogues are either of the two drugs administered as monotherapy.
effective in the treatment of rosacea and related Nevertheless, this therapeutic option represents an disorders, such as perioral dermatitis, ocular rosacea, attractive alternative to systemic corticosteroids in the and steroid-related rosaceaA single daily dose initial treatment of bullous dermatoses affecting the of doxycycline may be effective for ocular rosacea.
dermoepidermal junction. While avoiding the poten- The anti-inflammatory effects of tetracyclines already tial complications of immunosuppressive agents, the mentioned may explain, at least in part, their bene- combination of tetracycline and nicotinamide offers ficial effects in rosacea. Inhibition of angiogenesis obvious advantages for older patients who may have may be a contributory factor in the therapeutic effect concomitant osteoporosis, diabetes mellitus, or of tetracyclines in this group of disorders. Features hypertension. Finally, if the administration of an that favor angiogenesis may contribute to the telan- immunosuppressive agent is deemed necessary, giectasia of rosacea. These include protease-trig- tetracycline may be administered concomitantly as gered release of angiogenetic factors stored in the combination therapy so that the dosage of the extracellular matrix, release of inhibition of endo- immunosuppressant may be tapered more rapidly.
thelial factors, and release of angiogenic factors from Cutaneous sarcoidosis. More recently, the use of minocycline for the treatment of sarcoidosis was Bullous dermatoses. Subepidermal bullae are reported.Minocycline, 200 mg daily for 12 months, frequently accompanied by splitting or dissolution was administered to 12 patients. The median follow- of the basement membrane accompanied by an demonstrated complete clearing of their lesions, collagenase activity in synovial fluid and synovial whereas 2 patients showed a partial response. The fibroblasts.Oral administration of minocycline in duration of response ranged from 10 to 41 months.
adjuvant and collagen-induced arthritis in rats re- No relapse occurred during the 12-month treatment duced the incidence of arthritisFurthermore, period. However, maintenance of remission re- minocycline administration reduced collagenase ac- quired concomitant administration of corticosteroids tivity in the synovial fluid derived from patients with in several of the patients. In addition, a moderately severe hypersensitivity reaction to minocycline was There have been several double-blind, placebo- experienced by one patient in the study.
controlled clinical trials using 200 mg daily of min- It is interesting to note that tetracyclines, minocy- ocycline in patients with rheumatoid arthritis.
cline and doxycycline inhibit in vitro granuloma Kloppenburg et al treated a cohort of 80 patients formation by monocytes exposed to dextrin beads.
and noted significant improvement in joint tender- This effect is thought to be due to inhibition of ness, number of swollen joints, and levels of C- protein kinase C by tetracycline. These in vitro results reactive protein. In another study involving 219 provided the rationale for the successful use of patients with mild to moderate arthritis treated for minocycline in the treatment of other granulomatous 48 weeks with minocycline, there was alleviation of dermatoses, such as silicone-induced subcutaneous joint swelling and tenderness, although the effect was moderate.A more significant result was noted Kaposi’s sarcoma. Kaposi’s sarcoma is charac- in a study involving 60 patients with early (\1 year terized by proliferation of endothelial cells and duration) rheumatoid arthritis treated for 2 years with increase in MMP activity. A preliminary clinical trial 200 mg daily of minocycline versus hydroxychlor- involved 18 patients with AIDS-related Kaposi’s sarcoma who were treated with a chemical modified Scleroderma. In an uncontrolled study, mino- tetracycline, COL-3.After receiving 25, 50, or 70 cycline 200 mg daily was administered for 12 months mg/m2 per day for 25 weeks, one patient showed to 11 patients with early diffuse scleroderma. Four complete resolution and 7 demonstrated partial patients showed complete resolution.Confirma- improvement of skin lesions. The overall response tion from a larger scale, controlled study would add rate was 44%, and median time to response was 4 validity to this spectacular response. It would be of weeks. There was also a reduction in MMP-2 serum interest to determine whether minocycline specifi- levels. On the basis of these preliminary data, addi- cally alters the inflammatory response in sclero- tional studies investigating the use of COL-3 as derma. If so, it would be worthwhile to conduct a monotherapy in patients with early Kaposi’s sarcoma similar study with localized scleroderma.
and in combination with other therapies in patients Cancer. Carcinogenesis is a 3-step process in- with more severe disease seem warranted.
volving tumor cell adhesion, extracellular matrix Miscellaneous dermatoses. There have been proteolysis, and cell migration.Degradation of isolated reports describing the effectiveness of tetra- basement membrane and its surrounding connective cyclines in pyoderma gangrenosum,hidradenitis tissue stroma plays a major role in cancer invasion and metastasis. MMP-2 and MMP-9 (gelatinases A drome,a1-antitrypsin deficiency panniculitis, and B) are frequently expressed in various malignant and pityriasis lichenoides chrEvaluation of tumors.Experimental data using various carci- larger numbers of patients in well-controlled studies noma cell lines and animal carcinogenesis models is necessary before any conclusions can be drawn showed that doxycycline, minocycline, and CMTs regarding the efficacy of tetracycline and its deriva- may inhibit tumor growth by inhibiting MMPs and by tives in the treatment of these conditions.
a direct effect on cell proliferation.Few clinicaltrials investigating the use of tetracyclines in cancer treatment have been conducted. Recently, a phase I The immunomodulatory and anti-inflammatory clinical trial of oral COL-3 (6-demethyl, 6-deoxy, 4- properties of minocycline suggested that this drug dedimethylaminotetracycline) was administered to might be effective in the treatment of autoimmune 35 patients with multiple refractory metastasizing tumors. Although COL-3 appeared to have stabilized Rheumatoid arthritis. Rheumatoid arthritis is nonepithelial-type malignancies, additional follow- a chronic inflammatory disease affecting about 2 mil- up studies are necessary to determine its true efficacy lion Americans. Although the cause of rheumatoid in the prevention of progression of cancer metastasis arthritis is not entirely known, it has been shown that Cardiovascular system. Abdominal aortic an- joint destruction is at least in part due to enhanced associated with a life-threatening risk of rupture.
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a comparative multi-center trial of 2 treatment approaches.
Inhibition of cell proliferation, invasion, tumor growth and

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