ABSTRACT
In the search for innovative, selective, effective, and safer treatment strategies, hybrid drugs have gained worldwide momentum [...].
ABSTRACT
Dysregulation of Fibroblast Growth Factor Receptors (FGFRs) signaling has been associated with breast cancer, yet employing FGFR-targeted delivery systems to improve the efficacy of cytotoxic agents is still sparsely exploited. Herein, we report four new bi-functional ruthenium-peptide conjugates (RuPCs) with FGFR-targeting and pH-dependent releasing abilities, envisioning the selective delivery of cytotoxic Ru complexes to FGFR(+)-breast cancer cells, and controlled activation at the acidic tumoral microenvironment. The antiproliferative potential of the RuPCs and free Ru complexes was evaluated in four breast cancer cell lines with different FGFR expression levels (SKBR-3, MDA-MB-134-VI, MCF-7, and MDA-MB-231) and in human dermal fibroblasts (HDF), at pH 6.8 and pH 7.4 aimed at mimicking the tumor microenvironment and normal tissues/bloodstream pHs, respectively. The RuPCs showed higher cytotoxicity in cells with higher level of FGFR expression at acidic pH. Additionally, RuPCs showed up to 6-fold higher activity in the FGFR(+) breast cancer lines compared to the normal cell line. The release profile of Ru complexes from RuPCs corroborates the antiproliferative effects observed. Remarkably, the cytotoxicity and releasing ability of RuPCs were shown to be strongly dependent on the conjugation of the peptide position in the Ru complex. Complementary molecular dynamic simulations and computational calculations were performed to help interpret these findings at the molecular level. In summary, we identified a lead bi-functional RuPC that holds strong potential as a FGFR-targeted chemotherapeutic agent.
Subject(s)
Antineoplastic Agents , Breast Neoplasms , Peptides , Receptors, Fibroblast Growth Factor , Ruthenium , Female , Humans , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Breast Neoplasms/drug therapy , Breast Neoplasms/pathology , Breast Neoplasms/metabolism , Cell Line, Tumor , Cell Proliferation/drug effects , Coordination Complexes/chemistry , Coordination Complexes/pharmacology , Coordination Complexes/chemical synthesis , Drug Screening Assays, Antitumor , Hydrogen-Ion Concentration , Peptides/chemistry , Peptides/pharmacology , Peptides/therapeutic use , Receptors, Fibroblast Growth Factor/metabolism , Receptors, Fibroblast Growth Factor/antagonists & inhibitors , Ruthenium/chemistry , Ruthenium/pharmacology , Ruthenium/therapeutic useABSTRACT
In recent years, organometallic complexes have attracted much attention as anticancer therapeutics aiming at overcoming the limitations of platinum drugs that are currently marketed. Still, the development of half-sandwich organometallic cobalt complexes remains scarcely explored. Four new cobalt(III)-cyclopentadienyl complexes containing N,N-heteroaromatic bidentate, and phosphane ligands were synthesized and fully characterized by elemental analysis, spectroscopic techniques, and DFT methods. The cytotoxicity of all complexes was determined in vitro by the MTS assay in colorectal (HCT116), ovarian (A2780), and breast (MDA-MB-231 and MCF-7) human cancer cell lines and in a healthy human cell line (fibroblasts). The complexes showed high cytotoxicity in cancer cell lines, mostly due to ROS production, apoptosis, autophagy induction, and disruption of the mitochondrial membrane. Also, these complexes were shown to be nontoxic in vivo in an ex ovo chick embryo yolk sac membrane (YSM) assay.
Subject(s)
Antineoplastic Agents , Coordination Complexes , Ovarian Neoplasms , Animals , Chick Embryo , Humans , Female , Cell Line, Tumor , Antineoplastic Agents/chemistry , Platinum/pharmacology , Cobalt/pharmacology , Coordination Complexes/pharmacology , Coordination Complexes/chemistry , ApoptosisABSTRACT
Four new Cu(I) complexes of the general formula [Cu(PP)(LL)][BF4 ], in which PP is a phosphane ligand (triphenylphosphane or 1,2-bis(diphenylphosphano)ethane (dppe)) and LL is a bioactive thiosemicarbazone ligand (4-(methyl)-1-(5-nitrofurfurylidene)thiosemicarbazone) or 4-(ethyl)-1-(5-nitrofurfurylidene)thiosemicarbazone) were synthesized and fully characterized by classical analytical and spectroscopic methods. The anti-trypanosome and anticancer activities were investigated inâ vitro on Trypanosoma cruzi and in two human cancer cell lines (ovarian OVCAR3 and prostate PC3). To test the selectivity toward parasites and cancer cells, the cytotoxicity on normal monkey kidney VERO and human dermal fibroblasts HDF cells was also evaluated. The new heteroleptic complexes were more cytotoxic on T.â cruzi and chemoresistant prostate PC3 cells than the benchmark drugs nifurtimox and cisplatin. The compounds also showed a high level of cellular internalization by the OVCAR3 cells and, in particular, those containing the dppe phosphane showed activation of the cell death mechanism via apoptosis. On the other hand, the production of reactive oxygen species induced by these complexes was not evident.
Subject(s)
Anti-Infective Agents , Antineoplastic Agents , Chagas Disease , Coordination Complexes , Ovarian Neoplasms , Thiosemicarbazones , Female , Male , Humans , Copper/chemistry , Cell Line, Tumor , Antiparasitic Agents/pharmacology , Apoptosis , Thiosemicarbazones/pharmacology , Thiosemicarbazones/chemistry , Ligands , Anti-Infective Agents/pharmacology , Antineoplastic Agents/pharmacology , Antineoplastic Agents/chemistry , Coordination Complexes/pharmacology , Coordination Complexes/chemistryABSTRACT
Ruthenium complexes are emerging as one of the most promising classes of complexes for cancer therapy. However, their limited aqueous solubility may be the major limitation to their potential clinical application. In view and to contribute to the progress of this field, eight new water-soluble Ru(II) organometallic complexes of general formula [RuCp(mTPPMS)n(L)] [CF3SO3], where mTPPMS = diphenylphosphane-benzene-3-sulfonate, for n = 2, L is an imidazole-based ligand (imidazole, 1-benzylimidazole, 1-butylimidazole, (1-(3-aminopropyl)imidazole), and (1-(4-methoxyphenyl)imidazole)), and for n = 1, L is a bidentate heteroaromatic ligand (2-benzoylpyridine, (di(2-pyridyl)ketone), and (1,2-(2-pyridyl)benzo-[b]thiophene)) were synthesized and characterized. The new complexes were fully characterized by NMR, FT-IR, UV-vis., ESI-HRMS, and cyclic voltammetry, which confirmed all the proposed molecular structures. The antiproliferative potential of the new Ru(II) complexes was evaluated on MDAMB231 breast adenocarcinoma, A2780 ovarian carcinoma, and HT29 colorectal adenocarcinoma cell lines, showing micromolar (MDAMB231 and HT29) and submicromolar (A2780) IC50 values. The interaction of complex 6 with human serum albumin (HSA) and fatty-acid-free human serum albumin (HSAfaf) was evaluated by fluorescence spectroscopy techniques, and the results revealed that the ruthenium complex strongly quenches the intrinsic fluorescence of albumin in both cases.
ABSTRACT
Chemotherapeutic metallodrugs such as cisplatin and its derivatives are among the most widely applied anticancer treatments worldwide. Despite their clinical success, patients suffer from severe adverse effects while subjected to treatment due to platinum's low selectivity for tumour over healthy tissues. Additionally, intrinsic or acquired resistance to metallodrugs, as well as their inability to reach cancer metastases, often results in therapeutic failure. The evident need for highly efficient and specific treatments has driven the scientific community to research novel ways to surpass the stated limitations. Within this scenario, a rising number of smart drug delivery systems have been lately reported to target primary cancers or metastases, where the metallodrugs are released in a controlled and selective way triggered by specific tumour-related stimuli, thus suggesting a viable and attractive therapeutic approach. Herein, we discuss the main efforts undertaken in the past few years towards the smart delivery of metal-based drugs and drug candidates to tumour sites, particularly focusing on the pH- and/or redox-responsive targeted delivery of platinum and ruthenium anticancer complexes.
Subject(s)
RutheniumABSTRACT
Considering our interest in the use of peptides as potential target-specific drugs or as delivery vectors of metallodrugs for various biomedical applications, it is crucial to explore improved synthetic methodologies to accomplish the highest peptide crude purity in the shortest time possible. Therefore, we compared "classical" fluorenylmethoxycarbonyl (Fmoc)-solid phase peptide synthesis (SPPS) with ultrasound(US)-assisted SPPS based on the preparation of three peptides, namely the fibroblast growth factor receptor 3(FGFR3)-specific peptide Pep1 (VSPPLTLGQLLS-NH2) and the novel peptides Pep2 (RQMATADEA-NH2) and Pep3 (AAVALLPAVLLALLAPRQMATADEA-NH2), which are being developed aimed at interfering with the intracellular protein-protein interaction(PPI) RANK-TRAF6. Our results demonstrated that US-assisted SPPS led to a 14-fold (Pep1) and 4-fold time reduction (Pep2) in peptide assembly compared to the "classical" method. Interestingly, US-assisted SPPS yielded Pep1 in higher purity (82%) than the "classical" SPPS (73%). The significant time reduction combined with high crude peptide purity attained prompted use to apply US-assisted SPPS to the large peptide Pep3, which displays a high number of hydrophobic amino acids and homooligo-sequences. Remarkably, the synthesis of this 25-mer peptide was attained during a "working day" (347 min) in moderate purity (approx. 49%). In conclusion, we have reinforced the importance of using US-SPPS towards facilitating the production of peptides in shorter time with increased efficacy in moderate to high crude purity. This is of special importance for long peptides such as the case of Pep3.
Subject(s)
Peptides/chemical synthesis , Solid-Phase Synthesis Techniques/methods , Humans , Peptides/chemistry , Receptor Activator of Nuclear Factor-kappa B/chemistry , Receptors, Fibroblast Growth Factor/chemistry , Sonication/methods , TNF Receptor-Associated Factor 6/chemistryABSTRACT
The synthesis and antiproliferative activity of Mes- and iPr-substituted gold(I) bis(1,2,3-triazol-5-ylidene) complexes in various cancer cell lines are reported, showing nanomolar IC50 values of 50 nM (lymphoma cells) and 500 nM (leukemia cells), respectively (Mes < iPr). The compounds exclusively induce apoptosis (50 nM to 5 µM) instead of necrosis in common malignant blood cells (leukemia cells) and do not affect non-malignant leucocytes. Remarkably, the complexes not only overcome resistances against the well-established cytostatic etoposide, cytarabine, daunorubicin, and cisplatin but also promote a synergistic effect of up to 182% when used with daunorubicin. The present results demonstrate that gold(I) bis(1,2,3-triazol-5-ylidene) complexes are highly promising and easily modifiable anticancer metallodrugs.
Subject(s)
Antineoplastic Agents/pharmacology , Coordination Complexes/pharmacology , Gold/chemistry , Triazoles/chemistry , Antineoplastic Agents/chemistry , Apoptosis/drug effects , Cell Line, Tumor , Coordination Complexes/chemistry , Daunorubicin/pharmacology , Drug Resistance, Neoplasm/drug effects , Drug Synergism , HumansABSTRACT
The interaction between human serum transferrin (hTf) and three promising organometallic Ru (II)- (η5-C5H5) derived complexes, that have already shown strong in vitro cytotoxicity towards human cancer cell lines, has been investigated using fluorescence spectroscopic techniques. The results suggested that the formation of Ru-hTf systems involves a dynamic collision. The binding process occurs spontaneously (ΔG < 0), mainly driven by hydrophobic interactions. Additional docking studies show that all complexes bind preferably to a specific hydrophobic pocket in the C2-subdomain as already observed for other metal-cyclopentadienyl (MCp) complexes and are in agreement with the experimental results. With these studies we hope to contribute to the understanding of the mechanism of action of these promising cytotoxic agents, thus providing clues for a more rational design.
Subject(s)
Antineoplastic Agents , Coordination Complexes , Ruthenium , Antineoplastic Agents/chemistry , Coordination Complexes/chemistry , Humans , Molecular Docking Simulation , Protein Binding , Ruthenium/chemistry , Spectrometry, Fluorescence , Transferrin/chemistryABSTRACT
Cisplatin and derivatives are highly effective in the treatment of a wide range of cancer types; however, these metallodrugs display low selectivity, leading to severe side effects. Additionally, their administration often results in the development of chemoresistance, which ultimately results in therapeutic failure. This scenario triggered the study of other transition metals with innovative pharmacological profiles as alternatives to platinum, ruthenium- (e.g., KP1339 and NAMI-A) and gold-based (e.g., Auranofin) complexes being among the most advanced in terms of clinical evaluation. Concerning the importance of improving the in vivo selectivity of metal complexes and the current relevance of ruthenium and gold metals, this review article aims to survey the main research efforts made in the past few years toward the design and biological evaluation of target-specific ruthenium and gold complexes. Herein, we give an overview of the inorganic and organometallic molecules conjugated to different biomolecules for targeting membrane proteins, namely cell adhesion molecules, G-protein coupled receptors, and growth factor receptors. Complexes that recognize the progesterone receptors or other targets involved in metabolic pathways such as glucose transporters are discussed as well. Finally, we describe some complexes aimed at recognizing cell organelles or compartments, mitochondria being the most explored. The few complexes addressing targeted gene therapy are also presented and discussed.
Subject(s)
Antineoplastic Agents/pharmacology , Coordination Complexes/pharmacology , Gold Compounds/pharmacology , Ruthenium Compounds/pharmacology , Antineoplastic Agents/administration & dosage , Cell Adhesion Molecules/drug effects , Cell Line, Tumor , Coordination Complexes/administration & dosage , Gold Compounds/administration & dosage , Humans , Receptors, G-Protein-Coupled/drug effects , Receptors, Growth Factor/drug effects , Ruthenium Compounds/administration & dosageABSTRACT
The biomedical application of discrete supramolecular metal-based structures, specifically self-assembled metallacages, is still an emergent field of study. Capitalizing on the knowledge gained in recent years on the development of 3-dimensional (3D) metallacages as novel drug delivery systems and theranostic agents, we explore here the possibility to target [Pd2L4]4+ cages (L = 3,5-bis(3-ethynylpyridine)phenyl ligand) to the brain. In detail, a new water-soluble homoleptic cage (CPepH3) tethered to a blood brain barrier (BBB)-translocating peptide was synthesized by a combination of solid-phase peptide synthesis (SPPS) and self-assembly procedures. The cage translocation efficacy was assessed by inductively coupled mass spectrometry (ICP-MS) in a BBB cellular model in vitro. Biodistribution studies of the radiolabeled cage [[99mTcO4]- â CPepH3] in the CD1 mice model demonstrate its brain penetration properties in vivo. Further DFT studies were conducted to model the structure of the [[99mTcO4]- â cage] complex. Moreover, the encapsulation capabilities and stability of the cage were investigated using the [ReO4]- anion, the "cold" analogue of [99mTcO4]-, by 1H NMR spectroscopy. Overall, our study constitutes another proof-of-concept of the unique potential of supramolecular coordination complexes for modifying the physiochemical and biodistribution properties of diagnostic species.
Subject(s)
Blood-Brain Barrier , Palladium/chemistry , Animals , Density Functional Theory , Drug Delivery Systems/methods , In Vitro Techniques , Ligands , Mass Spectrometry/methods , Mice , Proton Magnetic Resonance Spectroscopy/methods , Tissue Distribution , Tomography, Emission-Computed, Single-PhotonABSTRACT
Cancer is one of the worst health issues worldwide, representing the second leading cause of death. Current chemotherapeutic drugs face some challenges like the acquired resistance of the tumoral cells and low specificity leading to unwanted side effects. There is an urgent need to develop new compounds that may target resistant cells. The synthesis and characterization of two Cu(i) complexes of general formula [Cu(PP)(LL)][BF4], where PP is a phosphane ligand (triphenylphosphine or 1,2-bis(diphenylphosphano) ethane) and LL = is a heteroaromatic bidentate ligand (4,4'-dimethyl-2,2'-bipyridine and 6,3-(2-pyridyl)-5,6-diphenyl-1,2,4-triazine). The new compounds were fully characterized by spectroscopic techniques (NMR, FTIR and UV-vis.), elemental analysis (C, H, N and S) and two structures were determined by single X-ray diffraction studies. The antiproliferative potential of the new Cu(i) complexes were studied in tumor (breast adenocarcinoma, ovarian carcinoma and in colorectal carcinoma sensitive and resistant to doxorubicin) and normal (fibroblasts) cell lines. Complexes 1-4 did not show any antiproliferative potential. Amongst the complexes 5-8, complex 8 shows high cytotoxic potential against colorectal cancer sensitive and resistant to doxorubicin and low cytotoxicity towards healthy cells. We show that complexes 5-8 can cleave pDNA and, in particular, the in vitro pDNA cleavage is due to an oxidative mechanism. This oxidative mechanism corroborates the induction of reactive oxygen species (ROS), that triggers HCT116 cell death via apoptosis, as proved by the increased expression of BAX protein relative to BCL-2 protein and the depolarization of mitochondrial membrane potential, and via autophagy. Additionally, complex 8 can block the cell cycle in the G1 phase, also exhibiting a cytostatic potential. Proteomic analysis confirmed the apoptotic, autophagic and cytostatic potential of complex 8, as well as its ability to produce ROS and cause DNA damage. The interference of the complex in folding and protein synthesis and its ability to cause post-translational modifications was also verified. Finally, it was observed that the complex causes a reduction in cellular metabolism. The results herein demonstrated the potential of Cu(i) complexes in targeting doxorubicin sensitive and resistant cells which is positive and must be further explored using in vivo animal models.
Subject(s)
Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Coordination Complexes/chemistry , Coordination Complexes/pharmacology , Copper/chemistry , Doxorubicin/pharmacology , Drug Resistance, Neoplasm/drug effects , Antineoplastic Agents/chemical synthesis , Apoptosis/drug effects , Cell Proliferation/drug effects , Chemistry Techniques, Synthetic , Coordination Complexes/chemical synthesis , HCT116 Cells , Humans , Reactive Oxygen Species/metabolismABSTRACT
A new family of eighteen Cu(i) complexes of the general formula [Cu(PP)(LL)][BF4], where PP is a phosphane ligand and LL represents an N,O-heteroaromatic bidentate ligand, has been synthesized and fully characterized by classical analytical and spectroscopic methods. Five complexes of this series were also characterized by single crystal X-ray diffraction studies. The cytotoxicity of all compounds was evaluated in breast (MCF7) and prostate (LNCap) human cancer cells and in a normal prostate cell line (RWPE). In general, all compounds showed higher cytotoxicity for the prostate cancer cells than for the breast cells, with IC50 values in the range 0.2-2 µM after 24 h of treatment. The most cytotoxic compound, [Cu(dppe)(2-ap)][BF4] (16), where dppe = 1,2-bis(diphenylphosphano) ethane and 2-ap = 2-acetylpyridine, showed a high level of cellular internalization, generation of intracellular ROS and activation of the cell death mechanism via apoptosis/necrosis. Owing to its high cytotoxic activity for LNCap cells, being 70-fold higher than that for normal prostate cells (RWPE), complex (16) was found to be the most promising for further research in prostate cancer models.
Subject(s)
Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Coordination Complexes/chemistry , Coordination Complexes/pharmacology , Copper/chemistry , Prostatic Neoplasms/pathology , Apoptosis/drug effects , Drug Design , Humans , Inhibitory Concentration 50 , Intracellular Space/drug effects , Intracellular Space/metabolism , MCF-7 Cells , Male , Reactive Oxygen Species/metabolismABSTRACT
The anticancer, antimicrobial and antiplasmodial activities of six gold(iii) bis(dithiolene) complexes were studied. Complexes 1-6 showed relevant anticancer properties against A2780/A2780cisR ovarian cancer cells (IC50 values of 0.08-2 µM), also being able to overcome cisplatin resistance in A2780cisR cells. Complex 1 also exhibited significant antimicrobial activity against Staphylococcus aureus (minimum inhibitory concentration (MIC) values of 12.1 ± 3.9 µg mL-1) and both Candida glabrata and Candida albicans (MICs of 9.7 ± 2.7 and 19.9 ± 2.4 µg mL-1, respectively). In addition, all complexes displayed antiplasmodial activity against the Plasmodium berghei parasite liver stages, even exhibiting better results than the ones obtained using primaquine, an anti-malarial drug. Mechanistic studies support the idea that thioredoxin reductase, but not DNA, is a possible target of these complexes. Complex 1 is stable under biological conditions, which would be important if this compound is ever to be considered as a drug. Overall, the results obtained evidenced the promising biological activity of complex 1, which might have potential as a novel anticancer, antimicrobial and antiplasmodial agent to be used as an alternative to current therapeutics.
Subject(s)
Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/pharmacology , Antimalarials/pharmacology , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Gold/chemistry , Antimalarials/chemistry , Cell Line, Tumor , Female , Humans , Microbial Sensitivity Tests , Ovarian Neoplasms/metabolism , Plasmodium berghei/drug effects , Prospective Studies , Spectrometry, Fluorescence , Staphylococcus aureus/drug effects , Staphylococcus aureus/metabolism , Structure-Activity Relationship , Thioredoxin-Disulfide Reductase/metabolismABSTRACT
In this work we explored the possibility of improving the selectivity of a cytotoxic Ru complex [RuCp(PPh3)(2,2'-bipy)][CF3SO3] (where Cp = η5-cyclopentadienyl) TM34 towards FGFR(+) breast cancer cells. Molecular dynamics (MD) simulations of TM34 in a phosphatidylcholine membrane model pinpointed the cyclopentadienyl group as a favorable derivatization position for the peptide conjugation approach. Three new Ru(ii) complexes presenting a functionalized η5-cyclopentadienyl were synthesized, namely [Ru(η5-C5H4COOH)(2,2'-bipy)(PPh3)][CF3SO3] (TM281) and its precursors, [Ru(η5-C5H4COOCH2CH3)(η2-2,2'-bipy)(PPh3)][CF3SO3] (3) and [Ru(η5-C5H4COOCH2CH3)(PPh3)2Cl] (2). Complex TM281 was prepared by the hydrolysis of the ethyl ester group appended to the η5-cyclopentadienyl ligand of complex 3 with K2CO3 in water/acetonitrile, followed by mild protonation using an ion exchange resin. The newly synthesized complexes were fully characterized by NMR, FTIR and UV-vis spectroscopic techniques. Also, electrochemical studies were carried out by means of cyclic voltammetry in order to evaluate the stability of the compounds. Single crystal X-ray diffraction studies were carried out for compounds 3 and TM281 which crystallized in the monoclinic system, space group P21/n. The unprecedented synthesis and characterization of three half-sandwich ruthenium(ii)-cyclopentadienyl peptide conjugates and their preliminary biological evaluation against human FGFR(+) and FGFR(-) breast cancer cells are also reported.
Subject(s)
Antineoplastic Agents/pharmacology , Breast Neoplasms/drug therapy , Coordination Complexes/pharmacology , Cyclopentanes/pharmacology , Peptides/pharmacology , Receptors, Fibroblast Growth Factor/antagonists & inhibitors , Ruthenium/pharmacology , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Breast Neoplasms/metabolism , Breast Neoplasms/pathology , Cell Proliferation/drug effects , Cell Survival/drug effects , Coordination Complexes/chemical synthesis , Coordination Complexes/chemistry , Cyclopentanes/chemistry , Dose-Response Relationship, Drug , Drug Screening Assays, Antitumor , Electrochemical Techniques , Female , Humans , Molecular Dynamics Simulation , Molecular Structure , Peptides/chemistry , Receptors, Fibroblast Growth Factor/metabolism , Ruthenium/chemistry , Structure-Activity Relationship , Tumor Cells, CulturedABSTRACT
BACKGROUND: Ruthenium complexes have been extensively investigated for their prospective value as alternatives to cisplatin. Recently, we reported the in vitro anticancer properties of a family of organometallic ruthenium( II)-cyclopentadienyl complexes and have explored their mechanism of action. OBJECTIVE: The purpose of this study was to evaluate the in vivo antitumour efficacy and toxicity of one of these Ru(II) compounds, [RuCp(mTPPMSNa)(2,2'-bipy)][CF3SO2] (TM85) which displayed an interesting spectrum of activity against several cancer cells. METHODS: Studies to assess the antitumour activity and toxicity were performed in a metastatic prostate (PC3) mice model using ICP-MS, nuclear microscopy, elemental analysis and Transmission Electron Microscopy (TEM). RESULTS: TM85 showed low systemic toxicity but no significant tumour reduction, when administered at tolerated dose (20mg/kg) over 10 days. Ru was mainly retained in the liver and less in kidneys, with low accumulation in tumour. Increased bilirubin levels, anomalous Ca and Fe concentrations in liver and mitochondria alterations were indicative of liver injury. The hepatotoxicity observed was less severe than that of cisplatin and no nephrotoxicity was found. CONCLUSION: Under the experimental conditions of this study, TM85 is less toxic than cisplatin, induces similar tumour reduction and avoids the formation of metastatic foci. No renal toxicity was observed by the analysis of creatinine levels and the effective renal plasma flow by 99mTc-MAG3 clearance. Hence, it can be considered a valuable compound for further studies in the field of Ru-based anticancer drugs.
Subject(s)
Antineoplastic Agents/chemistry , Coordination Complexes/chemistry , Cyclopentanes/chemistry , Prostatic Neoplasms/drug therapy , Ruthenium/chemistry , Antineoplastic Agents/adverse effects , Antineoplastic Agents/pharmacology , Cell Line, Tumor , Cisplatin/adverse effects , Cisplatin/pharmacology , Coordination Complexes/adverse effects , Coordination Complexes/pharmacology , Dose-Response Relationship, Drug , Humans , Liver/metabolism , Male , Prostatic Neoplasms/pathologyABSTRACT
A family of six phosphane Cu(i) complexes bearing N,N, N,O and N,S bidentate ligands was synthesized. All the compounds were fully characterized by classical analytical and spectroscopic methods, and five of them were also characterized by X-ray diffraction studies. All the compounds exhibit high cytotoxicity against the human breast cancer cell line MCF7 with IC50 values far lower than those found for cisplatin, a current chemotherapeutic in clinical use. Compounds 1[combining low line] and 3[combining low line] induce cell cycle arrest in the G2/M phase and cell death by apoptosis. The cytotoxic and cytostatic effects of these compounds on MCF7 cells suggest that they are suitable for further in vivo studies with breast cancer models.
ABSTRACT
A new family of copper(I) complexes of general formula [Cu(dppe)(NN)]+ have been synthesized and fully characterized, with dppe=1.2-bis(diphenylphosphino)ethane and NN representing several bidentate heteroaromatic ligands: 2,2'-bipy=2.2'-bipyridine (1), Me2bpy=4.4'-dimethyl-2,2'-bipyridine (2), dpytz=3-(2-pyridyl)-5,6-diphenyl-1,2,4-triazine (3), dpp=2.3-bis(2-pyridyl)pyrazine (4), and the metallaligand [Ru(η5-C5H5)(PPh3)(dpp)]+ (5), yielding the bimetallic copper(I)-ruthenium(II) complex [Cu(dppe)(µ-dpp)Ru(η5-C5H5)(PPh3)]2+ (6). The single crystal structures of complexes (2) and (4) were determined by X-ray diffraction studies. All the complexes exhibit high cytotoxicity against the human cancer cells A2780 and MCF7 with IC50 values far lower than those found for the antitumor drug cisplatin in the same cell lines and even surpassing cisplatin resistance in the A2780cisR cells. They display IC50 values on the human embryonic kidney HEK293 non-tumoral cells of the same order of magnitude as those found for the tumoral cells. In the ovarian cells the compounds induce rapid production of reactive oxygen species (ROS) probably through mitochondrial pathways. According to the results reported here, these compounds can be considered as prospective antitumoral agents that deserve further evaluation.
Subject(s)
Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Coordination Complexes/chemistry , Coordination Complexes/pharmacology , Copper/chemistry , Ruthenium/chemistry , Cell Line, Tumor , Cell Survival/drug effects , Humans , Inhibitory Concentration 50 , MCF-7 Cells , X-Ray DiffractionABSTRACT
BACKGROUND: Ruthenium-based anti-cancer compounds are proposed as viable alternatives that might circumvent the disadvantages of platinum-based drugs, the only metallodrugs in clinical use for chemotherapy. Organometallic complexes in particular hold great potential as alternative therapeutic agents since their cytotoxicity involves different modes of action and present reduced toxicity profiles. OBJECTIVE: During the last few years our research group has been reporting on a series of organometallic ruthenium(II)- cyclopentadienyl complexes with important cytotoxicity against several cancer cell lines, surpassing cisplatin in activity. We report herein preliminary in vivo studies with one representative compound of this family, with exceptional activity against several human cancer cell lines, including the glycolytic and highly metastatic MDAMB231 cell line used in this study. METHOD: The anti-tumor activity of our compound was studied in vivo on N:NIH(S)II-nu/nu nude female mice bearing triple negative breast cancer (TNBC) orthotopic tumors. Administration of 2.5 mg/kg/day during ten days caused cell death mostly by necrosis (in vitro and in vivo), inducing tumor growth suppression of about 50% in treated animals when compared to controls. RESULTS: The most remarkable result supporting the effectiveness and potential of this drug was the absence of metastases in the main organs of treated animals, while metastases were present in the lungs of all control mice, as revealed by histopathological and immunohistochemical analysis. CONCLUSION: These in vivo studies suggest a dual effect for our drug not only by suppressing growth at the primary tumor tissue but also by inhibiting its metastatic behavior. Altogether, these results represent a benchmark and a solid starting point for future studies.