ABSTRACT
Aim: Evaluation of the biocompatibility and radiosensitizer potential of citrate-coated cobalt (cit-CF) and nickel (cit-NF) ferrite nanoparticles (NPs). Materials & methods: Normal fibroblast and breast cancer cells were treated with different concentrations of citrate-coated ferrite NPs (cit-NPs) and irradiated with a cobalt-60 source at doses of 1 and 3 Gy. After 24 h, cell metabolism, morphology alterations and nanoparticle uptake were evaluated. Results: Cit-CF and cit-NF NPs showed no toxicity to normal cells up to 250 and 100 µg.ml-1, respectively. Combination of cit-NP and ionizing radiation resulted in up to fivefold increase in the radiation therapeutic efficacy against breast cancer cells. Conclusion: Cit-CF and cit-NF NPs are suitable candidates for application as breast cancer cell radiosensitizers.
Subject(s)
Breast Neoplasms , Nanoparticles , Radiation-Sensitizing Agents , Breast Neoplasms/drug therapy , Citric Acid , Cobalt , Female , Ferric Compounds , Humans , NickelABSTRACT
2-Acetylpyridine acetylhydrazone (H2AcMe), 2-benzoylpyridine acetylhydrazone (H2BzMe) and complexes [Cu(H2AcMe)Cl2] (1) and [Cu(H2BzMe)Cl2] (2) were assayed for their cytotoxicity against wild type p53 U87 and mutant p53 T98 glioma cells, and against MRC-5 fibroblast cells. Compounds 1 and 2 proved to be more active than the corresponding hydrazones against U87, but not against T98 cells. Compound 1 induced higher levels of ROS than H2AcMe in both glioma cell lines. H2AcMe and 1 induced lower levels of ROS in MRC5 than in U87 cells. Compound 2 induced lower levels of ROS in MRC5 than in T98 cells. The cytotoxic effect of 1 in U87 cells could be related to its ability to provoke the release of ROS, suggesting that the cytotoxicity of 1 might be somehow p53 dependent.
Subject(s)
Copper/pharmacology , Glioma/drug therapy , Hydrazones/pharmacology , Reactive Oxygen Species/metabolism , Cell Line , Cell Line, Tumor , Fibroblasts/drug effects , Glioma/metabolism , Humans , Tumor Suppressor Protein p53/metabolismABSTRACT
Complexes [Au(2Ac4oT)Cl][AuCl2] (1), [Au(Hpy2Ac4mT)Cl2]Cl·H2O (2), [Au(Hpy2Ac4pT)Cl2]Cl (3), [Pt(H2Ac4oT)Cl]Cl (4), [Pt(2Ac4mT)Cl]·H2O (5), [Pt(2Ac4pT)Cl] (6) and [Pt(L)Cl2OH], L = 2Ac4mT (7), 2Ac4oT (8), 2Ac4pT (9) were prepared with N(4)-ortho- (H2Ac4oT), N(4)-meta- (H2Ac4mT) and N(4)-para- (H2Ac4pT) tolyl-2-acetylpyridine thiosemicarbazone. The cytotoxic activities of all compounds were assayed against U-87 and T-98 human malignant glioma cell lines. Upon coordination cytotoxicity improved in 2, 5 and 8. In general, the gold(III) complexes were more cytotoxic than those with platinum(II,IV). Several of these compounds proved to be more active than cisplatin and auranofin used as controls. The gold(III) complexes probably act by inhibiting the activity of thioredoxin reductase enzyme whereas the mode of action of the platinum(II,IV) complexes involves binding to DNA. Cells treated with the studied compounds presented morphological changes such as cell shrinkage and blebs formation, which indicate cell death by apoptosis induction.
Subject(s)
Antineoplastic Agents/pharmacology , Glioma/drug therapy , Organogold Compounds/chemistry , Organogold Compounds/pharmacology , Organoplatinum Compounds/chemistry , Organoplatinum Compounds/pharmacology , Thiosemicarbazones/chemistry , Thiosemicarbazones/pharmacology , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Cell Death/drug effects , Cell Proliferation/drug effects , Dose-Response Relationship, Drug , Drug Screening Assays, Antitumor , Glioma/pathology , Humans , Models, Molecular , Molecular Structure , Structure-Activity Relationship , Tumor Cells, CulturedABSTRACT
Complexes [Ga(2Ac4pFPh)(2)]NO(3) (1), [Ga(2Ac4pClPh)(2)]NO(3) (2), [Ga(2Ac4pIPh)(2)]NO(3) (3), [Ga(2Ac4pNO(2)Ph)(2)]NO(3)·3H(2)O (4) and [Ga(2Ac4pT)(2)]NO(3) (5) were obtained with 2-acetylpyridine N(4)-para-fluorophenyl-(H2Ac4pFPh), 2-acetylpyridine N(4)-para-chlorophenyl-(H2Ac4pClPh), 2-acetylpyridine N(4)-para-iodophenyl-(H2Ac4pIPh), 2-acetylpyridine N(4)-para-nitrophenyl-(H2Ac4pNO(2)Ph) and 2-acetylpyridine N(4)-para-tolyl-(H2Ac4pT) thiosemicarbazone. 1-5 presented antimicrobial and cytotoxic properties. Coordination to gallium(III) proved to be an effective strategy for activity improvement against Pseudomonas aeruginosa and Candida albicans. The complexes were highly cytotoxic against malignant glioblastoma and breast cancer cells at nanomolar concentrations. The compounds induced morphological changes characteristic of apoptotic death in tumor cells and showed no toxicity against erythrocytes. 2 partially inhibited tubulin assembly at high concentrations and induced cellular microtubule disorganization, but this does not appear to be the main mechanism of cytotoxic activity.
Subject(s)
Anti-Bacterial Agents/pharmacology , Antifungal Agents/pharmacology , Antineoplastic Agents/pharmacology , Coordination Complexes/pharmacology , Gallium/chemistry , Thiosemicarbazones/chemistry , Tubulin/chemistry , Anti-Bacterial Agents/chemistry , Antifungal Agents/chemistry , Antineoplastic Agents/chemistry , Candida albicans/drug effects , Cell Cycle Checkpoints/drug effects , Cell Shape/drug effects , Coordination Complexes/chemistry , Crystallography, X-Ray , Erythrocytes/drug effects , HeLa Cells , Humans , Inhibitory Concentration 50 , Kinetics , MCF-7 Cells , Microbial Sensitivity Tests , Models, Molecular , Molecular Conformation , Protein Multimerization/drug effects , Pseudomonas aeruginosa/drug effects , Pyridines/chemistry , Staphylococcus aureus/drug effects , Tubulin Modulators/chemistry , Tubulin Modulators/pharmacologyABSTRACT
N(4)-Phenyl 2-acetylpyridine thiosemicarbazone (H2Ac4Ph; N-(phenyl)-2-(1-(pyridin-2-yl)ethylidene)hydrazinecarbothioamide) and its N(4)-ortho-, -meta- and -para-fluorophenyl (H2Ac4oFPh, H2Ac4mFPh, H2Ac4pFPh), N(4)-ortho-, -meta- and -para-chlorophenyl (H2Ac4oClPh, H2Ac4mClPh, H2Ac4pClPh), N(4)-ortho-, -meta- and -para-iodophenyl (H2Ac4oIPh, H2Ac4mIPh, H2Ac4pIPh) and N(4)-ortho-, -meta- and -para-nitrophenyl (H2Ac4oNO(2)Ph, H2Ac4mNO(2)Ph, H2Ac4pNO(2)Ph) derivatives were assayed for their cytotoxicity against human malignant breast (MCF-7) and glioma (T98G and U87) cells. The compounds were highly cytotoxic against the three cell lineages (IC(50): MCF-7, 52-0.16 nM; T98G, 140-1.0 nM; U87, 160-1.4 nM). All tested thiosemicarbazones were more cytotoxic than etoposide and did not present any haemolytic activity at up to 10(-5)M. The compounds were able to induce programmed cell death. H2Ac4pClPh partially inhibited tubulin assembly at high concentrations and induced cellular microtubule disorganization.
Subject(s)
Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Thiosemicarbazones/chemistry , Thiosemicarbazones/pharmacology , Adenocarcinoma/drug therapy , Adenocarcinoma/pathology , Apoptosis/drug effects , Breast Neoplasms/drug therapy , Breast Neoplasms/pathology , Cell Death/drug effects , Cell Line, Tumor , Central Nervous System Neoplasms/drug therapy , Central Nervous System Neoplasms/pathology , Crystallography, X-Ray , Dose-Response Relationship, Drug , Drug Screening Assays, Antitumor , Etoposide/pharmacology , Female , Glioblastoma/drug therapy , Glioblastoma/genetics , Glioblastoma/pathology , Glioma/drug therapy , Glioma/genetics , Glioma/pathology , Humans , Inhibitory Concentration 50 , Microtubules/drug effects , Molecular Structure , Structure-Activity Relationship , Tubulin/metabolism , Tumor Suppressor Protein p53/geneticsABSTRACT
2-Acetylpyridine-phenylhydrazone (H2AcPh), its para-chlorophenylhydrazone (H2AcpClPh) and para-nitrophenylhydrazone (H2AcpNO(2)Ph) analogues, the corresponding 2-benzoylpyridine-derived hydrazones (H2BzPh, H2BzpClPh and H2BzpNO(2)Ph) and their gallium(III) complexes were assayed for their cytotoxic activity against U87 (expressing wild-type p53 protein) and T98 (expressing mutant p53 protein) glioma cells. IC(50) values against both glioma cells and against the MRC5 (human fetal lung fibroblast) lineage were obtained for the hydrazones, but not for their gallium(III) complexes, due to their low solubility. Hydrazones were highly cytotoxic at nanomolar doses against U87 and T98 cells. The therapeutic indexes (TI = IC(50MRC5)/IC(50glioma)) were 2-660 for T98 cells and 28-5000 for U87 cells, indicating that the studied hydrazones could be good antitumor drug candidates to treat brain tumors.
Subject(s)
Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/pharmacology , Apoptosis/drug effects , Gallium/chemistry , Glioma/drug therapy , Glioma/pathology , Hydrazones/chemistry , Pyridines/chemistry , Brain Neoplasms/drug therapy , Brain Neoplasms/pathology , Cell Proliferation/drug effects , Cells, Cultured , Crystallography, X-Ray , Fetus/cytology , Fetus/metabolism , Fibroblasts/cytology , Fibroblasts/metabolism , Humans , Lung/cytology , Lung/metabolism , Models, Molecular , Molecular Structure , Quantitative Structure-Activity RelationshipABSTRACT
2-acetylpyridine N(4)-phenyl thiosemicarbazone (H2Ac4Ph), and its N(4)-ortho-tolyl (H2Ac4oT), N(4)-meta-tolyl (H2Ac4mT), N(4)-para-tolyl (H2Ac4pT), N(4)-ortho-chlorophenyl (H2Ac4oClPh), N(4)-meta-chlorophenyl (H2Ac4mClPh) and N(4)-para-chlorophenyl (H2Ac4pClPh) derivatives were assayed for their cytotoxicity against RT2 (expressing p53 protein) and against T98 (expressing mutant p53 protein) glioma cells. The compounds were highly cytotoxic against RT2 (IC50=24-1.4 nM) and T98 cells (IC50=50-1.0 nM). IC50 for cisplatin=5 (RT2) and 17 µM (T98). The thiosemicarbazones presented haemolytic activity with IC50>10(-3)M, indicating a very good therapeutic index. SAR studies suggested that stereo properties are critical to define the potential activity of the studied compounds against the RT2 cell line, while electronic properties seem to be important for interaction with the biological target in T98 cells.
Subject(s)
Apoptosis/drug effects , Glioma/drug therapy , Thiosemicarbazones/pharmacology , Animals , Crystallography, X-Ray , Dose-Response Relationship, Drug , Glioma/pathology , Models, Molecular , Molecular Structure , Rats , Stereoisomerism , Structure-Activity Relationship , Thiosemicarbazones/chemistry , Tumor Cells, CulturedABSTRACT
The gallium(III) complexes [Ga(2Am4DH)(2)]NO(3) (1), [Ga(2Am4Me)(2)]NO(3) (2) and [Ga(2Am4Et)(2)]NO(3) (3) were prepared with 2-pyridineformamide thiosemicarbazone (H2Am4DH) and its N(4)-methyl (H2Am4Me) and N(4)-ethyl (H2Am4Et) derivatives. The thiosemicarbazones were cytotoxic against malignant RT2 glioblastoma cells (expressing p53 protein) with IC(50) values in the 7.3-360 microM range, and against malignant T98 glioblastoma cells (expressing mutant p53 protein) with IC(50) values in the 3.6-143 microM range. Coordination to gallium strongly increased the cytotoxic potential in complexes 2 and 3, which showed IC(50) values in the 0.81-9.57 microM range against RT2 cells and in the 3.6-11.30 microM range against T98 cells, and were 20-fold more potent than cisplatin. All thiosemicarbazones and gallium complexes were able to induce cell death by apoptosis.
