Doxycycline and other tetracyclines in the treatment of bonemetastasisZeina Saikalia and Gurmit Singha,b The tetracycline family includes tetracycline, doxycycline effect is likely due to a combination of multiple roles of and minocycline, all of which have been used as antibiotics doxycycline, including MMP inhibition and a negative effect effectively for decades. New uses emerged for these on osteoclast differentiation and survival. These compounds after their effect on mitochondrial function was encouraging results have now paved the way for an discovered. Cytostatic and cytotoxic activity of these ongoing trial of doxycycline in early combination therapy compounds was shown against cell lines of various tumor for breast cancer and prostate cancer patients.
origins. In addition, tetracyclines and chemically modified tetracyclines inhibit the activity of several matrix metalloproteinases (MMPs). Given the importance of these enzymes in tumor cell invasion and metastatic ability, the potential use of tetracyclines in cancer therapy needed to be investigated. Col-3, a chemically modified tetracycline, is Keywords: bone, Col-3, doxycycline, matrix metalloproteinases, metastasis,minocycline, tetracycline now the subject of clinical trials in cancer patients.
However, the potential of tetracyclines in cancer therapy aDepartment of Pathology and Molecular Medicine, McMaster University, takes on an added dimension in the bone. MMPs have Hamilton, Ontario, Canada and bHamilton Regional Cancer Center, Hamilton, been shown to be important mediators of metastasis formation in the bone, contributing largely to the morbidity of breast cancer and prostate cancer patients. The natural Sponsorship: This research was supported by a Canadian Breast CancerResearch Alliance grant to G. S.
osteotropism of tetracyclines would allow them to be highly effective in the inhibition of MMPs produced by Correspondence to G. Singh, Hamilton Regional Cancer Center, 699 osteoclasts or tumor cells in the bone. This hypothesis has Concession Street, Hamilton, Ontario L8 V 5C2, Canada.
Tel: + 1 905 387-9711; fax: + 1 905 575-6330; now been confirmed by experimental evidence showing that doxycycline reduces tumor burden in a mouse model of breast cancer-derived osteolytic bone metastasis. This Received 29 August 2003 Accepted 4 September 2003 Introduction: new functions for an old class of Because of the similarity between the prokaryotic protein synthesis machinery and that of eukaryotic mitochondria, The tetracyclines are a well-known and widely used tetracyclines are also able to interfere with mitochondrial family of antibiotics. These compounds are particularly protein synthesis in mammalian cells. The selective useful in several types of both common and rare permeability of different mammalian cells to tetracyclines infections including atypical pneumonias, rickettsial led to the hypothesis that these agents could be used to infections, chlamydial infections, Lyme disease and achieve cell proliferation arrest and applied to the ehrlichiosis [reviewed in 1]. Doxycycline is the most treatment of malignancies [7]. As with many emerging widely used of the tetracyclines today, although minocy- new ideas, research into this hypothesis was slow to gain cline is commonly applied to the treatment of acne interest and for more than a decade would remain vulgaris [2]. Doxycycline is frequently used in a first-line confined to a handful of research groups.
therapy, such as in the treatment of uncomplicatedgenital Chlamydia trachomatis infections [3] or acute Q Cytotoxic effect of tetracyclines on cancer fever [4]. In addition, doxycycline may be used after initial therapy has failed due to decreased antibiotic Emerging from a research group’s focus on mitochondrial sensitivity or antibiotic resistance, as in the case of function and the use of antibiotics for selective inhibition infections with penicillin-resistant Streptococcus pneumoniae of mitochondrial processes was the realization that tetracyclines may have cytostatic activity, confirmed byinitial studies showing inhibition of growth of carcinogen- The bacteriostatic activity of tetracyclines lies in their induced tumors [8]. Specific cytostatic activity due to the capacity to inhibit protein synthesis by preventing the selective permeability of different cells to tetracyclines binding of the aminoacyl t-RNA to the ribosome [6].
was tested and confirmed by doxycycline inhibition of Copyright Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
tumor cell proliferation in permeable T cell leukemia of malignant pleural effusions [24]. Thus, doxycycline may the rat, but not in impermeable erythroid and B lymphoid have already found an effective but as-yet-unrecognized cells [9]. These results in an animal model were subsequently tested in tumor systems of human origin;doxycycline was found to be cytostatic to human renal and prostate carcinoma cells, and even cytotoxic after tetracyclines inhibit the activities of matrix prolonged treatment [10]. Cytostatic activity of tetra- cyclines was confirmed in fibroblasts and sarcoma cells,and the proliferation arrest in these cells was shown to be In parallel to the discoveries of the cytostatic and due to an accumulation of the cell population in the G cytotoxic abilities of the tetracyclines was the mounting phase of the cell cycle [11]. Other in vitro studies have evidence that these compounds have the ability to inhibit now confirmed the cytotoxic effects of tetracyclines on the activities of various MMPs. Minocycline was for- cultured human prostate cancer, breast cancer, osteosar- tuitously found to inhibit the collagenase activity of coma and mesothelioma cells [12–15].
gingiva in diabetic rats [25] and this effect wasdetermined to be independent of its antimicrobialactivity. Evidence of collagenase inhibition was confirmed Although tetracycline and at least two of its derivatives, in samples of human synovial tissue or fluid from patients doxycycline and minocycline, all show cytotoxic effects in before and after minocycline treatment [26]. The these experiments, doxycycline was found to be the most collagenase activity produced by a wide variety of tumor effective at inhibiting survival in a side-by-side compar- cell lines in vitro was subsequently found to be inhibited ison of three human adenocarcinoma cell lines [12]. DNA by tetracyclines, including breast and prostate carcinoma, fragmentation indicative of apoptosis was observed after osteosarcoma and mesothelioma cells [12–15,27]. Com- doxycycline cytotoxic treatment of renal and prostate parisons between tetracycline, minocycline and doxycy- carcinoma cells [13,14]. In addition, doxycycline can cline show doxycycline to possess the most potent induce apoptosis in Jurkat T lymphocytes [16], in HL60 collagenase inhibitory activity when tested in an im- leukemia cells [17] and in a T lymphoblastic human munoassay with gelatine as a substrate [28]. In line with leukemia cell line by caspase-3 activation [18]. Con- the potency of its gelatinase inhibitory activity, doxycy- versely, doxycycline has a protective effect against cline has been used consistently to inhibit the activity of apoptosis in polymorphonuclear neutrophils isolated from MMPs from various cell types [12,14,15,29,30]. In healthy donors, both in the presence and the absence of addition to inhibiting the activity of these enzymes, an infective agent [19], and a protective effect against tetracyclines have been shown in some cases to regulate apoptosis in neurons treated with ionizing radiation [20].
the expression of MMPs at the RNA and protein levels, This apparent cell-specific selectivity of the apoptotic or such as in the case of MMP-8 [29]. The confirmed cytotoxic effect of doxycycline does not appear to be a activity of doxycycline in MMP inhibition has already result of differences in experimental methodology, since a found application in one of the many diseases that single study comparing doxycycline toxicity in different present pathological activation of these enzymes, speci- cell types showed a cytotoxic effect on cells of myeloid fically adult periodontitis. In this disease, a low-dose lineage but not on those of mesenchymal origin [21].
doxycycline treatment was found to be a valuable adjunct This apparent cytotoxic selectivity of doxycycline towards to instrumentation therapy [31,32] and is now an FDA- certain cells, in particular those of tumoral origin and not normal neutrophils, is an exciting find in the area ofemerging cancer therapies, in particular in light of the A few studies have gone further to identify the known toxicity of many antineoplastic agents towards collagenolytic enzymes inhibited by tetracyclines, speci- fically MMP-1 [30], MMP-2, MMP-9 [12] and MMP-8[29]. This list may not be exhaustive and the activity of The discovery of the cytotoxic activity of tetracyclines on other MMPs may also be found to be inhibited by tumor cells may help explain the molecular cellular tetracyclines. However, the identity of the MMPs mechanisms underlying the use of these compounds in an identified so far adds to the interest that tetracyclines established treatment setting. A significant subset of present in their potential use in the treatment of cancer.
metastatic cancer patients develop malignant pleural Positive or high expression of MMP-1, MMP-2 and MMP- effusions, usually treated surgically by tube thoracostomy 9 is associated with poor prognosis or survival in almost [reviewed in 22]. Doxycycline is often used in this type of every type of human cancer studied [reviewed in 33], treatment as an intrapleural sclerosing agent [23].
partly due to the association of these enzymes with However, evidence from an experimental mouse model mechanisms of basement membrane degradation by suggests that, besides the sclerotic effect, the suppres- cancer cells leading to invasion and metastasis. Therefore, sion of malignant cell growth contributes significantly to MMP inhibition has emerged as a valid therapeutic goal the efficiency of this compound in the management of in malignant disease treatment. To this effect, a number Copyright Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Tetracyclines for bone metastasis Saikali and Singh of MMP inhibitors are in various stages of drug cyclines, demonstrating inhibition of MMP-14 activity development and testing [reviewed in 34]. Doxycycline which leads to lack of activation of MMP-2 [38] and an is, because of the data discussed above, a promising antiangiogenic effect similar to doxycycline in an in vitro compound in this category. To add to its interest is the assay [35]. Col-3 also inhibits colon cancer cell invasive- recent discovery that it is able to inhibit angiogenesis in ness [39], and inhibits cell proliferation, invasion, tumor an in vitro assay [35], a property which would only further growth and metastasis in a metastatic prostate cancer contribute to its anticancer potential given the known model to the same extent as, and in some cases more contribution of angiogenesis to tumor growth and efficiently, than doxycycline [40]. Once again, some invasion. Doxycycline is currently in phase I trials for degree of cell specificity is observed, since in leukemia cancer therapy. One of the issues uncovered in these cell lines the effects of Col-3 are not as strong and trials, however, is dose-limiting toxicity exhibited by comparable to those generated by doxycycline [17].
symptoms such as fatigue and nausea [36]. This is likely Regardless of cell-specificity arguments, the potential of due to the fact that many of the cytostatic, cytotoxic and Col-3 was important enough to warrant clinical testing anticollagenase effects of doxycycline leading to anti- and was the subject of at least two phase I clinical trials.
tumoral behavior were observed at concentrations usually Emerging from one trial was the observed effect of higher than those needed for bacteriostatic effects, and disease stabilization in some patients with a non- thus in an anticancer trial the effects of doxycycline at epithelial form of malignancy [41], although concerns higher doses needed to be tested. Conclusions concern- have also arisen due to drug-induced side-effects such as ing the in vivo acceptability and efficacy of anticancer lupus and anemia [41–43]. Another phase I trial was doxycycline doses in a first-line therapy will have to be conducted in a more homogeneous study population, suspended pending the final outcome of these trials.
eighteen patients with AIDS-related Kaposi’s sarcoma.
The results of this trial indicated antitumor activity in Another interesting MMP inhibitor also belongs to the this population at well-tolerated doses, with adverse tetracycline family, Col-3 (4-dedimethylaminosancycline, effects including photosensitivity and headache [44]. It is also known as CMT-3), a chemically modified tetracy- interesting to note that the variable response noted in cline (Fig. 1). Chemically modified tetracyclines that lack this study may be partially explained by recent evidence antimicrobial activity, but still possess anticollagenase, from animal studies regarding factors that influence activity have been developed and tested for various irregular absorption profiles of Col-3 after oral adminis- properties [reviewed in 37]. In the context of cancer tration [45]. These factors include drug particle size, research, they elicited a certain amount of interest presence of food and levels of endogenous bile, and because they effectively inhibit MMPs and possess some taking them into account in phase II trials may permit degree of selective cytotoxicity, similar to their anti- more homogeneous responses in the patient population.
microbial tetracycline counterparts. Col-3 appears to bethe most promising of the chemically modified tetra- Effect of doxycycline and other tetracyclineson boneThe ability of tetracyclines to inhibit MMP activity of certain cancer cells points to other possible applications for this family of compounds. MMPs are known to beimportant mediators of metastasis formation in bone [reviewed in 46], contributing to significant morbidity incancer patients, especially those with tumors of theprostate or breast. Formation of osteolytic lesions directly by cancer cells is partially mediated by MMPs [47,48].
Osteoclast-mediated osteolysis is also dependent onMMPs, not in the initial phase of bone mineral resorption but for unmineralized matrix degradation [46]. Thus,MMPs have a 2-fold role in osteolytic cancer lesion formation, being produced directly by the tumor cells andby osteoclasts after induction by tumor cells. The role of MMPs is likewise important in other osteolytic lesions such as osteoporosis. To this effect, MMP inhibitors arebeing studied in the treatment of osteoporosis, including the tetracycline family. In ovariectomized aged rats, amodel for postmenopausal osteoporosis, minocycline was Chemical structures of the tetracycline family members discussed.
able to both increase bone formation and decrease boneloss in trabecular bone, comparatively to estrogen [49,50].
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In a subsequent study, minocycline was found to recently in a mouse bone metastasis model of human stimulate the colony-forming efficiency of marrow breast cancer. The model, first described by Sasaki et al.
stromal cells derived from ovariectomized rats, possibly [55], is produced by intracardiac injection of MDA-MB- explaining the effect of this compound on increased bone 231 human breast carcinoma cells, leading to bone formation [51]. As for the decrease in bone resorption, it metastases. Doxycycline treatment of mice prior to may be explained by the MMP inhibitory activity of injection, reminiscent of early metastatic disease, effec- minocycline and also by other data on osteoclasts.
tively and significantly reduced tumor burden [56]. In Doxycycline has been shown to reduce osteoclast addition, osteolytic lesions were reduced in the treated numbers in rat models of surgically induced osteoclast group and the bone resorption parameters and number of recruitment [52,53]. A range of tetracyclines, including osteoclasts were lower, while bone formation parameters doxycycline and Col-3, were able to induce apoptosis in were higher. This study confirms the potential of mature osteoclasts and inhibit in vitro osteoclastogenesis, doxycycline and possibly other tetracyclines in lowering possibly by functions independent of the antibiotic and tumor burden and osteolytic lesions due to cancer cells in anticollagenase properties of these products [54].
vivo. It is especially interesting in light of the fact thatsimilar animal studies with the bisphosphonate risedro- Multiple effects of doxycycline combine to nate resulted in comparable though less effective out- comes [55], in particular knowing that bisphosphonates It is now clear that doxycycline and other tetracyclines are accepted therapeutic options in the prevention of have many functions that make them of potential interest bone lesions in breast cancer. It remains to be seen in anticancer therapy (Fig. 2). However, the observed whether other tetracyclines, in particular the chemically effects of tumor cytotoxicity, MMP inhibition and modified tetracyclines such as Col-3, have similar or inhibition of osteoclast viability take on an added greater effects and whether this therapy is beneficial in dimension in the bone, in particular in light of the fact patients with established bone metastases.
that tetracyclines are highly osteotropic. Thus, theconcentrations of these drugs needed to achieve the desired effects are present in the bone even while serum concentrations are below toxic levels, and the undesirable Among the many advantages of doxycycline is the fact toxic side-effects observed in clinical trials are not likely that it has been prescribed for years without major side- to be encountered. This hypothesis was validated effects being experienced. Therefore, at the doses used Representative scheme of the putative modes of action of tetracyclines in the bone: (1) inhibition of tumor cell proliferation, (2) inhibition of tumor cellMMP production, (3) inhibition of osteoclast MMP production, (4) induction of osteoclast apoptosis and (5) inhibition of osteoclastogenesis. MMPsare depicted as non-exclusive contributors to bone degradation by tumor cells and osteoclasts.
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