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A review of ruthenium complexes activities on different steps of the metastatic
process in breast cancer cells

Article  in  Mini Reviews in Medicinal Chemistry · February 2017
DOI: 10.2174/1389557517666170206151218


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Cecília Patrícia Popolin Fabiana de Souza Orlandi
8 PUBLICATIONS   2 CITATIONS    Universidade Federal de São Carlos

Sofia Cristina Iost Pavarini Marcia Regina Cominetti
Universidade Federal de São Carlos Universidade Federal de São Carlos


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Ru would be . Over that many of the same molecular functions required for cell the last few years. lungs. SP. we focused on the effects of Ru complexes on breast cancer cells and its impact on different steps of the metastatic process. systemic treatment is made by cell adhesion and acto-myosin contraction. Surgery and invasive behavior is one of the first steps in the metastatic radiotherapy are treatments used for local control of breast process and it is driven by cycles of actin polymerization. Rod. which migration (TEM). metastasis. cancer cells then leave the circulation in a process called Breast cancer is the second most common cancer in the extravasation at potential secondary tumor sites. be cleared by immune the circulatory system. Rod. In this review. their continued use is greatly limited by severe dose Cancer cells enter the bloodstream in a process called limiting side effects and intrinsic or acquired drug resistance intravasation. Universidade Federal de São Carlos. The acquisition of increase survival and improve the quality of life. Washington Luis. Cominettia* a Departamento de Gerontologia. *Address correspondence to this author at Departamento de Gerontologia. continue moving even when one type of motility has been prevented by pharmacological means [3]. 13565-905. Metastases new microenvironment. Universidade Federal de São Carlos. 0. and some of including breast [11]. E-mail: mcominetti@ufscar. 7]. binding of iron to these receptors [14]. Once bound to the transferrin receptor. cancer. 0 1 A review of ruthenium complexes activities on breast cancer cells Cecília P. however. Keywords: Ruthenium complexes. São Carlos. metastatic breast cancer has been one of motility in the primary tumor will be required for the leading causes of death in women due to the metastasis extravasation [3]. Such plasticity can enable tumor cells to only from tumor. breast cancer. 13565-905. Km 235. It has been proposed that tumors contain high amounts of transferrin receptors. compounds. endothelial barrier in a process called transendothelial Metastasis is an exceedingly complex process. where a few of them will give rise to are the cause of 90% of human cancer deaths [2]. Cells can next invasion of adjacent tissues. migration. It is likely world and the most prevalent type of cancer in women. Vol. new research has been (EC) junctions. INTRODUCTION Using the bloodstream to spread throughout the body. proliferation. of tumor-associated macrophages (TAM) [4]. its severe side effects represent a limitation for its clinical use. apoptosis. It has been described that tumor areas with developed with low toxicity compounds. No. proportion of cancer cells from a primary tumor acquire Treatment of breast cancer has as main objectives to invasive and migratory properties. Ruthenium complexes (Ru) with different ligands have been successfully studied as promising antitumor drugs. TAM can promote the invasive behavior of the cancer cells by There are some hypotheses to explain the low toxicity producing epidermal growth factor (EGF) [5] and often and the antitumor and antimetastatic properties of Ru cluster around blood vessels and the tumor margin. since they are able to mimic the intravasation [4]. Rosenberg and colleagues in 1964 were responsible for the discovery of cisplatin. cells [3]. Breast cancer is the most prevalent type of cancer in women and the leading cause of cancer deaths due to its high metastasis to the lymph nodes. The development of antitumor metal-based drugs was originated with the discovery of cisplatin. to form metastasis. not between them. 2017. but also from normal cells. +55 16 3306 6663. Popolina and Márcia R. drugs. and Cominetti. bones and brain [1]. With the limitations of cisplatin. possibly by using that attract tumor cells towards vessels and thereby promote transferrin receptors [13]. allowing Ru complexes to be actively transported into Washington Luis. tissues using one of several types of invasion. intravasation. in which cells migrate through endothelial cell [12]. There are hormone therapy and chemotherapy [8-10]. Phone: neoplastic tissues that require higher iron requirement [15]. Despite the success of platinum-based the cells will migrate towards the neighboring blood vessels. Interactions with the stromal microenvironment surrounding tumor cells facilitate tumor cell migration and invasion of tissues and dissemination to other organs. lungs bones and brain. Km 235. M. SP. transport through undergo apoptosis within 24 hours.Popolin. Ru seems to accumulate preferentially in the establishing EGF gradients within the tumor environment tumors rather than in normal tissues. São Carlos. Drugs used in different modes of motility and some tumor cells can switch chemotherapy cause resistance and damage to DNA. Abstract: Cancer is one of the main causes of death worldwide.R. and afterwards invade the basement occurs through a series of sequential steps that include the membrane that surrounds the blood vessels. such as ruthenium numerous moving breast cancer cells also have high numbers (Ru) complexes. 1. that posteriorly proved to be an Cells that leave a primary tumor invade their surrounding effective complex for the treatment of different cancer types. enter a state of dormancy or proliferate within this extravasation and growth in a secondary organ. Mini-Reviews in Medicinal Chemistry. on the other hand.P. arrest at a secondary site. A small micrometastases and then macrometastases [6. Cancer cells then transmigrate through the formation in lymph nodes.

MCF-7 and . to the best of our knowledge. a family of enzymes that act as effector molecules OF RUTHENIUM COMPLEXES ON BREAST in various forms of cell death [31]. The in vitro and in vivo effects in breast cancer cancer treatment [34]. treatment of MDA-MB-231 special octahedral structure and ligand geometries [20]. anti-migratory. metalloproteinases) [26]. Similar results were found for cell such as non-small cell lung cancer. induce SOS repair. a non-irradiated tissues and can become toxic in tumor cells negative regulator of MMP [25]. at least in part. their photoactivated demonstrated by western blotting analysis that RAWQ11 biological applications make these complexes still more reduce cell invasion and migration. Apoptosis is carried out by two major pathways.Popolin. In another study it was demonstrated that Ru polypyridyl Currently. including cell adhesion. due to their slow ligand exchange ruthenium(II) complex (RAWQ11) against migration and kinetics. chemotherapy drives tumor cells to develop proliferative. anti-invasive and resistance to cytotoxic agents and radiation. M. they present general inertness. Ru metallo-intercalator ruthenium(II) complexes with the complex with -phenylenediamine as the N-N ligand (. Ru evaluated by wound healing assay. complex (RuPOP) inhibits MDA-MB-231 cell migration and [tetrachloridobis(1H-indazole)ruthenate(III). only one study described the Nhukeaw and colleagues [35] evaluated the effects of effects on both breast tumor and non-tumor cell lines. which eventually result in the activation of IN VITRO ANTITUMOR EFFECTS caspases. cells with RAWQ11 showed a small decrease in the time of These would allow them to inhibit DNA replication. In addition. The inhibitory effect of microseconds to seconds. the Excluding works using other compounds or cell lines. using the keywords process critical to the maintenance of tissue homeostasis “ruthenium” and “breast cancer”. Compared to control cells complexes have unique DNA binding patterns due to their that spontaneously migrated. using different proteins such as fibronectin. Ru complexes that arrest cell cycle models are summarized in Table 1. from nano to micromolar IC50 concentrations. Authors their reported effects [14]. Frequently. Evasion of apoptosis is CANCER CELLS one of the hallmarks of cancer and represents an important mechanism in clinical resistance to therapies [32. through downregulation of MMP-9 expression more soluble alternative to the indazolium compound and upregulation of TIMP-1 (a tissue inhibitor of KP1019 [22] and shows promising results in solid tumors. could be explained. No. [29] investigated the influence of [Ru(dip)2(bpy- breast cancer. [25] have demonstrated the effect of arene tumors [18]. 0 2 internalized by the tumor [16]. at least in part. Photocaged Ru complexes are usually nontoxic to inhibition of proMMP-9 secretion and increased GSK3. RAWQ11 against migration of MDA-MB-231 cells was preventing rapid equilibration reactions [19]. In addition. bind to nuclear DNA The invasion of MDA-MB-231 cells was also blocked in a and reduce of RNA synthesis. reactive Ru(II) occurs [17]. and migration in MDA-MB-231 and MCF-7 cells with an most distinctively in gastrointestinal neuroendocrine tumors organometallic Ru complex (RAPTA-T) [27]. through photoactivation [21]. triple negative cell line (4T1) and the ability of treated cells invasion and describe the effects on each of these steps. This review is divided significant decrease of cell adhesion to ECM proteins at into two parts describing first results from in vitro studies concentrations 1. [23]. in a concentration-dependent manner. instead of invasion of MDA-MB-231 cells. Mazuryk et vitro and in vivo studies on action of Ru complexes on the al.R. C. which are all consistent with concentration-dependent manner starting from 1µM. This selective cytotoxicity against tumor cells inactive Ru(III) oxidation state until it reaches the tumor site.8H2O in the induction of apoptosis in MDA-MB-231 and MCF-7. is ongoing invasion at concentrations ranging from 1 to 4µM after 24h clinical trials. MCF- could be considered pro-drugs. 0. NKP-1339 has entered clinical trials as the treatment. However. to have wound closure at 48h. [Ru(Clazpy)2bpy]Cl2. colorectal carcinoma. Vol. Clazpy ligand. anti-adhesive. Cell adhesion plays a critical role in regulating tumor cell The aim of this review is to summarize the most recent in migration and invasion during metastasis [28]. but was ineffective to inhibit three breast tumor cell lines (MDA-MB-231. and Cominetti. totaling 109 papers. Moreover. Treatments with both Ru complexes resulted in processes and to induce apoptosis. Cell adhesion effects were and then those performed in different animal models in vivo. mutagenic activity. a total receptor (extrinsic) pathway and the mitochondrial (intrinsic) of 27 articles were consulted for this review. in the range of minutes to days. collagen complexes and their ability to inhibit the above cited and plastic.5 and 3µM.P. Finally. Mini-Reviews in Medicinal Chemistry. NKP-1339 (sodium trans. It was prepared using publications reported on the NLM- Apoptosis or programmed cell death is a basic cellular Pubmed online bibliographic database. consequently pro-apoptotic effects of several Ru complexes on breast leading to resistance to apoptosis and in inefficiency in cancer cells. This reaction causes selective tumor targeting by direct cytotoxic activity toward hypoxic Wu et al. more effective for [Ru(dip)2(bpy)]2+[29].7H2O and PDA) significantly inhibited growth of breast cell lines [Ru(Clazpy)2phen]Cl2. [30]. migration. We will focus on specific steps of the NitroIm)]2+ and [Ru(dip)2(bpy)]2+ on adhesion of a murine metastatic process. 2017. as described compared to normal tissues and reduction to the more earlier. Ru complexes growth of human non-tumor breast epithelial cells. one Ru complex. pathway. Ru remains in its relatively 10A [24]. In to attach to different types of extracellular matrix (ECM) particular we will discuss the antitumor effects of Ru coating. 33]. due to the attractive. by the Ru ability to be Tumors have a lower oxygen content and higher acidity internalized preferentially by tumor cells. Our search of the literature identified the anti. The vast majority of the and/or (re)induce apoptosis in tumor cells could be a complexes inhibits breast tumor cell proliferation ranging promising strategy for breast cancer treatment.

[42] ruthenium(II)-cyclopentadienyl N:NIH(S)II-nu/nu nude mice 10 (2. with the lower right authors showed that significant increase in apoptotic cells in count increasing four fold over a 24h period and six fold the triple negative MDA-MB-231 cells could result from the over 48h.P. termed apoptotic cells was observed.5 and 3 .154 + [37] Λ-RM0627 MDA-MB-231 40 . and Cominetti.7±0. [27] Invasion RAWQ11 MDA-MB-231 1 to 20 .O}Cl]Cl UNICAM-1 FVB/NCrl mice 4 (52. Effects in vitro and in vivo of ruthenium complexes on different breast cancer cell lines.038 to 0. respectively.5 + [35] [Ru(Clazpy)2bpy]Cl2.5) . [38] In vivo Ruthenium complexes Animal Dose (mg/Kg/day) Effect Reference [(η6-p-Cymene)Ru{(Ph3P=N-CO-2-N.CB17-Prkdc scid/J mice 14 (5) . [29] Migration RAWQ11 MDA-MB-231 1 and 2 . . NOD. No. These data suggest that the co-treatment of the RuPOP and TRAIL.7H2O HCC1932 9. Results showed that after a 24h treatment Ru cysteine acid proteases that play roles in control of apoptosis complexes caused a reduction in the G0/G1 phase by activation of various cellular substrates. [43] HCC1932).2 + [35] [Ru(Clazpy)2phen]Cl2. Symbols (+) or (-) represent induction or inhibition of the process. To further confirm antiproliferative mechanism of tested Ru polypyridyl these data. with a correlated decrease in the lower left count over-expression of the epidermal growth factor (EGF).3 + [35] [Ru(dip)2-(bpy)]2+ 4T1 2 and 4 + [29] [Ru(dip)2(bpy-NitroIm)]2+ 4T1 2 and 4 + [29] ethaRAPTA MCF-7 20 + [36] RuPOP+TRAIL MDA-MB-231 2¹ + [26] DiRu-1 MCF-7 0.5) . [29] investigated the influence of Ru TRAIL (tumor necrosis factor-related apoptosis-inducing polypyridyl complexes [Ru(dip)2(bpy-NitroIm)]2+ and ligand). induced nuclear factor NF-κB that controls the cell-cycle Apoptosis was detected in MDA-MB-231 cells after progression [35].6 + [35] [Ru(Clazpy)2bpy]Cl2.7H2O MDA-MB-231 14. Results showed that exposure of MDA-MB-231 [Ru(dip)2-(bpy)]2+ on cell cycle progression in 4T1 cell line cells to RuPOP and/or TRAIL resulted in an increase in the determined by flow cytometry using staining with propidium number of apoptotic cells. [41] G26b BALB/c mice 6 (17. 0 3 Table 1.5) . a biomarker of apoptosis. with slightly less apoptotic ethaRAPTA gives rise to a significant increase in the rates in HCC1937 and MCF-7 cells. [27] RM175 CBA mice 6 (10) . [27] RAPTA-T MCF-7 100 . western blot analysis was used to determine the complexes is based on S-phase arrest.8H2O MDA-MB-231 13.7H2O MCF-7 10. [40] RAPTA-T CBA mice 3 (80) . [26] RAPTA-T MDA-MB-231 100 . [25] RuPOP MDA-MB-231 1 to 4 . [25] RuPOP MDA-MB-231 1 to 4 . The apoptotic population on MCF-7 cells. the above inhibitor ruthenium(II) (ethacrynic acid-g6-benzylamide) evidences suggest that RuPOP potentiated TRAIL-induced apoptosis though intrinsic and extrinsic apoptotic pathways in breast tumor cells [26].3. incubation with Ru polypyridyl complex (RuPOP) and Mazuryk et al.5-triaza-7-phosphaadamantane) dichloride. [36]. C.R. Mini-Reviews in Medicinal Chemistry.9±0.5 and 3 . [26] RAPTA-T MDA-MB-231 100 . In vitro Ruthenium complexes Cell line Concentration (µM±SD) Effect Reference Adhesion [Ru(dip)2(bpy-NitroIm)]2+ 4T1 1.1±0. 2017. [27] Apoptosis [Ru(Clazpy)2bpy]Cl2. respectively. M. caspase activation and PARP cleavage. A significant increase in MDA-MB-231 (1. Caspases are important class of iodide.Popolin. Vol. 0. Taken together. 1 Represents co-treatment with TRAIL (2 and 4ng/ml). Co-treatment with RuPOP and TRAIL effectively Chartterjee and colleagues [36] demonstrated that the triggered the activation of caspases-3/-8/-9 and cleaved treatment with an organometallic glutathione S-transferase PARP in MDA-MB-231 cells. [39] C5H4)-κ-N. [29] [Ru(dip)2(bpy)]2+ 4T1 1. Results revealed accompanied by a corresponding increase in the percentage a remarkably increase in caspase-3 activity induced by the of cells in the S phase. [27] RAPTA-T MCF-7 100 .2±0.

effect on MDA-MB-231 cells. Cl) fill the remaining three sites. [(g6-arene)Ru(ethylenediamine)Cl]+ complexes associated with weight loss. organize several well-established bioactive organic pharmacophores around the metal center [44. addition. whereas × 4. migration and invasion and induction of apoptosis indicates fragmentation and cell-cycle arrest at the G2 /M checkpoint that Ru complexes may have direct anti-tumor and/or anti- in a concentration and time-dependent manner [37].8% cells in the early stage of apoptosis. were the most toxic for 4T1 cells. facilitated by H-bonding between the ethylenediamine concluded that UNICAM-1 exhibits a marked anti-tumor activity in vivo against an experimental TNBC model. inhibition of cell proliferation. and Cominetti. 0. COO-. suggesting The Ru ligands were found to play a critical role in their the absence of drug toxicity at the selected dose level.7-diphenyl-1. which should facilitate their uptake.5 mg/kg/day). and to inhibit the cell cycle and proliferation. mitotic catastrophe. the cell types. Montani and colleagues [40] investigated the in vivo R2 = H. in its cytotoxicity and pro-apoptotic activity. which are able determine the level of their intracellular uptake in 4T1 cells.3-dicyclohexyl-1-carbonyl-urea) were demonstrated and cymene)(bis(3. 0 4 The activity of the dinuclear trithiolato-bridged arene Ru complexes. the results above demonstrate the effects of Ru complexes on the function of multiple breast tumor on both the intrinsic and extrinsic pathways. Moreover. cisplatin (3 mg/Kg/day) the rise of the accumulation for dicationic complexes or NAMI-A (52. One explanation for this two of the total ten mice treated with UNICAM-1 did not effect is the higher lipophilicity of the former and smaller develop palpable tumors until the end of the experiment.5 mg/kg/day). The in vivo effects of an organometallic ruthenium(II) Structure-activity relationships of Ru complexes on [(η6-p-Cymene)Ru{(Ph3P=N-CO-2-N-C5H4)-κ-N. In size of the later one. 2017. Ru has been used as a scaffold to doses of 5mg/kg every other day) with low systemic toxicity. despite the highest lipophilicity. and Ru(III) allowing them to exhibit their biological effects DNA damage. as well as the reactive oxygen species (ROS). and autophagy.R. UNICAM-1 treated mice developed very small [Ru(dip)2(CH3bpy-COO)]+ was less toxic for 4T1 cells tumors. myriad of different combinations.10-phenanthroline (dip) ligands and functionalized bipyridine (R1bpy-R2. Therefore. CH3. and the two nitrogens of ethylenediamine (en) and the cytotoxic against MCF-7 and MDA-MB-231 cells. apoptosis. about 70% of the cells were not affected by Λ-RM0627 treatment [38]. both NAMI-A and cisplatin treatments were activities. DiRu-1 increases the intracellular levels of concentrations to act on breast tumor cells can be explained by the variability in the complexes structure. 4. termed it was shown that the lipophilicity and complex charge UNICAM-1 against triple negative A17 cells.2% cells in the late stage and 21. metastatic activities in vivo. this may be due to its lower Interestingly. into syngeneic mice.O}Cl]Cl complex has been demonstrated on xenografted breast breast tumor cells have been demonstrated. possibly presence of an arene greatly stabilizes Ru(II) compared to due to its ability to induce oxidative stress. No. repeated 4 times at 3 days correlates with their increased lipophilicity [46]. 45] allowing a Pharmacokinetic studies showed a rapid absorption of the complex in plasma with an elimination half-life of 12 hours. DiRu-1 triggers caspase-dependent apoptosis in this cell line Taken together. which may contribute to the In contrast. Finally. with only 6. IN VIVO ANTITUMOR AND ANTIMETASTATIC EFFECTS OF RUTHENIUM COMPLEXES. However. among the tested compounds reducing tumor growth. While all control mice developed [Ru(dip)2(CH3bpy-DCU)]2+ and [Ru(dip)2(CH3bpyCH3)]2+ palpable tumors after two weeks after A17 cell challenge. Vol. such as the size and the lipophilicity of the complex and the type of Prkdc scid/J mice. Regarding intervals. but to give few examples. a -bonded arene occupies three coordination complex diruthenium-1 (DiRu-1) was demonstrated to be sites. The cells were more responsive to the effects of DiRu-1. NAMI-A treatment was less effective in cytotoxicity. which play a significant role origins and specificities of the cells lines used in the assays. adhesion.5-dimethylpyrazol-1-l)methane)Cl]Cl. despite having the highest logP value. between UNICAM-1-treated and control mice. MCF-7 leaving group (e.. C. to give rise to aggressive mesenchymal tumors when injected which explains their cytotoxicity and imaging properties. UNICAM-1 (52. In this sense. with an average diameter never exceeding 3 mm. An impressive tumor reduction (shrinkage) of 56% was observed after 28 days treatment (14 ligand. DiRu-1 appears to be the induce DNA lesions. Results revealed that A17 tumor cells The monocationic [Ru(dip)2(CH3bpy-COO)]+ complex has grow rate and the final tumor dimensions were significantly much smaller accumulation compared to the other studied reduced in the animals treated with according to protocol q3 complexes. mainly due to apoptotic DNA Nonetheless. On the contrary. Mini-Reviews in Medicinal Chemistry. It is not the focus of this Authors conclude that the complex is a good candidate for review. M.CB17- properties of Ru complexes influence their activities. Zeng and coworkers [38] found that 40µM of development of new antitumor drugs to be applied in Ru complex Λ-RM0627 exhibited little apoptosis inducing chemotherapy. the photophysical properties of five ruthenium(II) complexes comprising two further evaluation as a potential chemotherapeutic agent [39].g. in this work authors display significant selectivity for binding DNA guanine bases. The high variability found among effective Ru complex also caused necrosis.Popolin. Several carcinoma MDA-MB-231 tumors grown on NOD. body weight did not significantly differ accumulation as confirmed by uptake studies [46]. in the pseudo octahedral “piano-stool” Ru(II) . thus.P.4-[3-(2-nitro-1H-imidazol-1-yl)propyl] antineoplastic effects of the Ru complex [Ru(p- or 1. where R1 = H or CH3. associated with low toxicity [40]. NH2 groups and the exocyclic oxygens of guanine [45].

In a 2649-56. 2014. demonstrated to be only moderately tolerated by patients and . of action in pre clinic studies. Intriguingly. 409-22. recent study. 6(6): p. Administration of FAPESP (Fundação de Amparo à Pesquisa do Estado de São 2. The review per day. summarized on Figure 1.P. their future use in biphenyl)M(ethylenediamine)Cl]+) complex reduced by chemotherapy remains uncertain at present. P. in view of these properties. Although Ru lung metastases originated from MCa mammary carcinoma complexes could be considered as potential candidates for primary tumor at concentrations of 80mg/kg/day for 3 days.B. M. 0 5 Fig 1. with no retinal toxicity or definitely prove the clinical efficacy of Ru complexes for hepatotoxicity [42]. Direct visualization of metastasis in different animal models. et al. from tumor cell Recently.. and C. Mini-Reviews in Medicinal Chemistry. new antimetastatic drugs showing a variety of mechanisms In the same mammary carcinoma model. but not in the lungs of all control mice [43]. 7(10): p. adhesion to other processes such as cell migration. However. named G26b and G94a. inducing tumor growth sponsored by CNPq (Conselho Nacional de suppression of about 50% in treated animals when compared Desenvolvimento Científico e Tecnológico). but also inhibited metastases in the REFERENCES main organs of treated animals. Scheme of the possible biological mechanisms of ruthenium complexes in vivo. 2007. 0. at this daily dose a significant efficacy results. CPP has a scholarship necrosis (in vitro and in vivo). due to their about 95% the size of measurable lung metastasis at toxicity profile and the lack of convincing preliminary 10mg/Kg/day.5 mg/kg/day during ten days caused cell death mostly by Paulo.V. to controls. 737-49. Ru p. toxicity was registered in 6 out of 10 mice. RM175 ([(g6. significantly reduced the occurrence and highlighted a number of in vitro and in vivo results indicating development of lung metastases in mice bearing the 4T1 that additional studies should be performed in order to mammary carcinoma. In general. E. 67(6): p. Furthermore. Puisieux. C.5mg/kg apoptosis in different breast cancer cell lines. of life or death.Popolin. and A. 2017. Nat Rev Cancer. invasion. 449- The possible biological mechanisms of action are 58. Ru complexes induce were evaluated. RM175 showed significant activity against cancer metastases CONCLUSION but had minimal effects on the growing of primary tumor It is possible to conclude that Ru complexes act on [41]. therapeutic potential for inhibition of tumor growth and 4. Sahai.R. NAMI-A in combination with gemcitabine. A derivatives containing pyridine.. Nat models using Ru complexes showed low toxicity and Rev Cancer. in vivo studies in animal 3. different steps of the metastatic process. the macrophage-assisted tumor cell intravasation in therapeutic failure of NAMI-A and KP-1019 to surpass mammary tumors. Illuminating the metastatic process. 2006.. Mehlen. No. Bergamo and colleagues [27] described that RAPTA-T less active in non-small cell lung cancer patients after first [Ru(η6-toluene)Cl2(PTA)] selectively reduces the growth of line treatment than gemcitabine alone [19]. at a dose of 17. Metastasis: a question antitumor and antimetastatic activities and clinical toxicity. Vol. Ban. J. complexes are predicted to show distinct patterns of 2. grant #2013/00798-2). Wyckoff. the antimetastatic effects of two novel NAMI. 23(3): Taken together. Very recently. Godellas. The former G26b. Cancer Res. Epidemiology of breast cancer. and Cominetti. 2007. and proliferation. The complex not only suppressed the growth of primary tumor tissue. Surg Oncol Clin N Am.A. clinical trials has concerned researchers in the field. However. K. cancer chemotherapy. Mendes and co-workers [43] reported that new organometallic ruthenium(II)-cyclopentadienyl ACKNOWLEDGEMENTS complexes have anti-tumor and anti-metastatic effects in vivo on N:NIH(S)II-nu/nu nude female mice bearing triple The authors are grateful for the financial support of negative breast cancer orthotopic tumors. 1.

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