ABSTRACT
Healthcare systems heavily rely on antibiotics to treat bacterial infections, but the widespread presence of multidrug-resistant bacteria puts this strategy in danger. Novel drugs capable of overcoming current resistances are needed if our ability to treat bacterial infections is to be maintained. Boron clusters offer a valuable possibility to create a new class of antibiotics and expand the chemical space of antibiotics beyond conventional carbon-based molecules. In this work, we identified two promising structural patterns providing cobalta bis(dicarbollide)(COSAN)-based compounds with potent and selective activity toward Staphylococcus aureus (including clinical strains): introduction of the α-amino acid amide and addition of iodine directly to the metallacarborane cage. Furthermore, we found that proper hydrophilic-lipophilic balance is crucial for the selective activity of the tested compounds toward S. aureus over mammalian cells. The patterns proposed in this paper can be useful in the development of metallacarborane-based antibiotics with potent antibacterial properties and low cytotoxicity.
Subject(s)
Methicillin-Resistant Staphylococcus aureus , Staphylococcal Infections , Animals , Anti-Bacterial Agents/chemistry , Staphylococcus aureus , Staphylococcal Infections/drug therapy , Microbial Sensitivity Tests , MammalsABSTRACT
Bacteriolytic enzymes are promising antibacterial agents, but they can cause a typical immune response in vivo. In this study, we used a targeted modification method for two antibacterial endolysins, Pal and Cpl-1. We identified the key immunogenic amino acids, and designed and tested new, bacteriolytic variants with altered immunogenicity. One new variant of Pal (257-259 MKS â TFG) demonstrated decreased immunogenicity while a similar mutant (257-259 MKS â TFK) demonstrated increased immunogenicity. A third variant (280-282 DKP â GGA) demonstrated significantly increased antibacterial activity and it was not cross-neutralized by antibodies induced by the wild-type enzyme. We propose this variant as a new engineered endolysin with increased antibacterial activity that is capable of escaping cross-neutralization by antibodies induced by wild-type Pal. We show that efficient antibacterial enzymes that avoid cross-neutralization by IgG can be developed by epitope scanning, in silico design, and substitutions of identified key amino acids with a high rate of success. Importantly, this universal approach can be applied to many proteins beyond endolysins and has the potential for design of numerous biological drugs.
Subject(s)
Anti-Bacterial Agents , Antibody Formation , Epitopes , Anti-Bacterial Agents/pharmacology , Proteins , Amino AcidsABSTRACT
Breast cancer is one of the major causes of cancerrelated mortality among women worldwide. It metastasizes to distant organs, particularly to bone tissue. Nitrogencontaining bisphosphonates are mainly used as an adjuvant therapy to inhibit skeletalrelated events; however, there is increasing evidence to suggest that these compounds also exert antitumor effects. In previous studies, the authors synthesized two novel aminomethylidenebisphosphonates (BPs), namely benzene1,4bis[aminomethylidene(bisphosphonic)] acid (WG12399C) and naphthalene1,5bis[aminomethylidene(bisphosphonic)] acid (WG12592A). Both BPs exhibited notable antiresorptive activity in a mouse model of osteoporosis. The present study aimed to assess the in vivo anticancer activity of WG12399C and WG12592A in 4T1 breast adenocarcinoma model. WG12399C exerted an antimetastatic effect by reducing the number of spontaneous lung metastases by ~66% in comparison to the control. In the experimental metastasis model of 4T1luc2tdTomato cells, this compound reduced the incidence of tumor metastases in the lungs by approximately half in comparison to the control. Both WG12399C and WG12595A also significantly reduced the size and/or number of bone metastatic foci. Their proapoptotic and antiproliferative activity may, at least in part, explain the observed effects. Incubation with WG12399C induced an almost 6fold increase in caspase3 activity in 4T1 cells. Moreover, cells treated with WG12399C or WG12595A exhibited a 2fold reduction in invasiveness through Matrigel. Furthermore, both the BPs were able to sensitize the 4T1 cells to cytostatics. In summary, the results of the present study indicate that the examined aminomethylideneBPs may be of particular interest in the context of combined treatment in breast cancer therapy.
Subject(s)
Bone Neoplasms , Lung Neoplasms , Animals , Mice , Female , Bone Neoplasms/drug therapy , Bone Neoplasms/secondary , Diphosphonates/pharmacology , Lung Neoplasms/secondary , Cell Line, Tumor , Mice, Inbred BALB CABSTRACT
Infections caused by Candida species have increased significantly in the past decades and are among the leading causes of morbidity and mortality worldwide, resulting in serious public health problems. Currently, conventional antifungals are often ineffective as Candida spp. have developed growing resistance to systemic drugs. Since inorganic metallacarboranes are known to affect cellular events, new derivatives of these abiotic compounds were tested against Candida albicans. Compounds based on cobalt bis-dicarbollide [COSAN] were studied on Candida albicans strains, including a panel of 100 clinical isolates. The presented data prove that metallacarborane derivatives are effective against clinical isolates of Candida albicans, even those resistant to systemic drugs, and show synergistic potential in combination with amphotericin B, and low toxicity against human cells and Danio rerio embryos. This paper is a consequential step in the investigations of the broad spectrum and valuable future medical applications of metallacarboranes, especially in the fight against drug-resistant pathogens.
Subject(s)
Antifungal Agents , Candida albicans , Humans , Amphotericin B/pharmacology , Antifungal Agents/pharmacology , Antifungal Agents/therapeutic use , Candida , Cobalt , Microbial Sensitivity TestsABSTRACT
A series of 1,4-disubstituted 1,2,3-triazoles having 10-demethoxy-10-N-methylaminocolchicine core were designed and synthesized via the Cu(I)-catalyzed "click" reaction and screened for their in vitro cytotoxicity against four cancer cell lines (A549, MCF-7, LoVo, LoVo/DX) and one noncancerous cell line (BALB/3T3). Indexes of resistance (RI) and selectivity (SI) were also determined to assess the potential of the analogues to break drug resistance of the LoVo/DX cells and to verify their selectivity toward killing cancer cells over normal cells. The compounds with an ester or amide moiety in the fourth position of 1,2,3-triazole of 10-N-methylaminocolchicine turned out to have the greatest therapeutic potential (low IC50 values and favorable SI values), much better than that of unmodified colchicine or doxorubicin and cisplatin. Thus, they make a valuable clue for the further search for a drug having a colchicine scaffold.
ABSTRACT
Osteoporosis is a skeletal disease associated with excessive bone turnover. Among the compounds with antiresorptive activity, nitrogen-containing bisphosphonates play the most important role in antiosteoporotic treatment. In previous studies, we obtained two aminomethylidenebisphosphonates-benzene-1,4-bis[aminomethylidene(bisphosphonic)] (WG12399C) acid and naphthalene-1,5-bis[aminomethylidene(bisphosphonic)] (WG12592A) acid-which showed a significant antiproliferative activity toward J774E macrophages, a model of osteoclast precursors. The aim of these studies was to evaluate the antiresorptive activity of these aminobisphosphonates in ovariectomized (OVX) Balb/c mice. The influence of WG12399C and WG12592A administration on bone microstructure and bone strength was studied. Intravenous injections of WG12399C and WG12592A bisphosphonates remarkably prevented OVX-induced bone loss; for example, they sustained bone mineral density at control levels and restored other bone parameters such as trabecular separation. This was accompanied by a remarkable reduction in the number of TRAP-positive cells in bone tissue. However, a significant improvement in the quality of bone structure did not correlate with a parallel increase in bone strength. In ex vivo studies, WG12399C and WG12592A remarkably bisphosphonates reduced osteoclastogenesis and partially inhibited the resorptive activity of mature osteoclasts. Our results show interesting biological activity of two aminobisphosphonates, which may be of interest in the context of antiresorptive therapy.
Subject(s)
Cancellous Bone , Cell Differentiation/drug effects , Diphosphonates/pharmacology , Osteoclasts/metabolism , Osteoporosis, Postmenopausal , Animals , Cancellous Bone/metabolism , Cancellous Bone/pathology , Cell Line , Female , Humans , Mice , Mice, Inbred BALB C , Osteoporosis, Postmenopausal/drug therapy , Osteoporosis, Postmenopausal/metabolism , Osteoporosis, Postmenopausal/pathology , OvariectomyABSTRACT
Pseudomonas aeruginosa is an opportunistic human pathogen that has become a nosocomial health problem worldwide. The pathogen has multiple drug removal and virulence secretion systems, is resistant to many antibiotics, and there is no commercial vaccine against it. Yersinia pestis is a zoonotic pathogen that is on the Select Agents list. The bacterium is the deadliest pathogen known to humans and antibiotic-resistant strains are appearing naturally. There is no commercial vaccine against the pathogen, either. In the current work, novel compounds based on metallacarborane cage were studied on strains of Pseudomonas aeruginosa and a Yersinia pestis substitute, Yersinia enterocolitica. The representative compounds had IC50 values below 10 µM against Y. enterocolitica and values of 20-50 µM against P. aeruginosa. Artificial generation of compound-resistant Y. enterocolitica suggested a common mechanism for drug resistance, the first reported in the literature, and suggested N-linked metallacarboranes as impervious to cellular mechanisms of resistance generation. SEM analysis of the compound-resistant strains showed that the compounds had a predominantly bacteriostatic effect and blocked bacterial cell division in Y. enterocolitica. The compounds could be a starting point towards novel anti-Yersinia drugs and the strategy presented here proposes a mechanism to bypass any future drug resistance in bacteria.
Subject(s)
Anti-Bacterial Agents/pharmacology , Boranes/chemistry , Organometallic Compounds/pharmacology , Pseudomonas Infections/drug therapy , Pseudomonas aeruginosa/drug effects , Yersinia Infections/drug therapy , Yersinia enterocolitica/drug effects , Humans , Pseudomonas Infections/microbiology , Yersinia Infections/microbiologyABSTRACT
A new series of 10-demethoxy-10-methylaminocolchicines bearing urea, thiourea or aguanidine moieties at position C7 has been designed, synthesized and evaluated for in vitro anticancer activity against different cancer cell lines (A549, MCF-7, LoVo, LoVo/DX). The majority of the new derivatives were active in the nanomolar range and were characterized by lower IC50 values than cisplatin or doxorubicin. Two ureas (4 and 8) and thioureas (19 and 25) were found to be good antiproliferative agents (low IC50 values and high SI) and could prove to be promising candidates for further research in the field of anticancer drugs based on the colchicine skeleton.
Subject(s)
Antineoplastic Agents/pharmacology , Colchicine/pharmacology , Guanidine/pharmacology , Thiourea/pharmacology , Urea/pharmacology , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Cell Line, Tumor , Cell Proliferation/drug effects , Colchicine/chemical synthesis , Colchicine/chemistry , Dose-Response Relationship, Drug , Drug Screening Assays, Antitumor , Guanidine/chemistry , Humans , Molecular Structure , Structure-Activity Relationship , Thiourea/chemistry , Urea/chemistryABSTRACT
Retinol-binding protein 4 (RBP4) is proposed as an adipokine that links obesity and cancer. We analyzed the role of RBP4 in metastasis of breast cancer in patients and in mice bearing metastatic 4T1 and nonmetastatic 67NR mammary gland cancer. We compared the metastatic and angiogenic potential of these cells transduced with Rbp4 (4T1/RBP4 and 67NR/RBP4 cell lines). Higher plasma levels of RBP4 were observed in breast cancer patients with metastatic tumors than in healthy donors and patients with nonmetastatic cancer. Increased levels of RBP4 were observed in plasma, tumor tissue, liver, and abdominal fat. Moreover, the blood vessel network was highly impaired in mice bearing 4T1 as compared to 67NR tumors. RBP4 transductants showed further impairment of blood flow and increased metastatic potential. Exogenous RBP4 increased lung settlement by 67NR and 4T1 cells. In vitro studies showed increased invasive and clonogenic potential of cancer cells treated with or overexpressing RBP4. This effect is not dependent on STAT3 phosphorylation. RBP4 enhances the metastatic potential of breast cancer tumors through a direct effect on cancer cells and through increased endothelial dysfunction and impairment of blood vessels within the tumor.
ABSTRACT
Calcitriol and its analogues are considered drugs supporting the anticancer treatment of breast cancer and preventing the osteoporosis that results from the development of cancer or from chemotherapy or hormone therapy. Following the orthotopic implantation of 4T1 mammary carcinoma cells into aged ovariectomized (OVX) mice, we evaluated the effects of calcitriol and its two analogues, PRI-2191 and PRI-2205, on metastatic spread and bone homeostasis. Calcitriol and its analogues temporarily inhibited the formation of metastases in the lungs. Unexpectedly, only mice treated with calcitriol analogues showed a deterioration of bone-related parameters, such as bone column density, marrow column density and the CaPO4 coefficient. These findings correlated with an increased number of active osteoclasts differentiated from bone marrow-derived macrophages in mice treated with the analogues. Interestingly, in the tumours from mice treated with PRI-2191 and PRI-2205, the expression of Tnfsf11 (RANKL) was increased. On the other hand, osteopontin (OPN) levels in plasma and tumour tissue, as well as TRAC5b levels in tumours, were diminished by calcitriol and its analogues. Despite a similar action of both analogues towards bone metabolism, their impact on vitamin D metabolism differed. In particular, PRI-2191 and calcitriol, not PRI-2205 treatment significantly diminished the levels of both 25(OH)D3 and 24,25(OH)2D3. In conclusion, though there is evident antimetastatic activity in old OVX mice, signs of increased bone metabolism and deterioration of bone mineralization during therapy with calcitriol analogues were observed.
ABSTRACT
Nitrogen-containing bisphosphonates (N-BPs) inhibit bone resorption by preventing osteoclast activity. Most clinically used BPs are hydroxybisphosphonates with the exception of incadronate, which belongs to the class of aminomethylidenebisphosphonic acids. The aim of this study was to evaluate the antiproliferative activity of two previously reported aminobisphosphonates (WG8185B2 and WG9001B) in combination with doxorubicin and cisplatin toward J774E cells (a model of osteoclast precursors in vitro). WG8185B2 and WG9001B BPs enhanced the cytotoxic activity of doxorubicin and cisplatin, especially when applied 24 hr prior to cytostatics. The antiproliferative effect of studied BPs was related to the changes in cell cycle progression. WG8185B2 leads to significant accumulation of J774E cells in S phase, whereas WG9001B causes transient arrest in G2 /M phase, followed by an increase in the percentage of cells in S phase. Moreover, WG8185B2 and WG9001B BPs showed enhanced proapoptotic activity in osteoclast precursors, which was manifested by an increase in caspase-3 activity and percentage of apoptotic cells. In addition, both compounds influenced the motility of J774E cells. The exact molecular mechanism of action of examined BPs remains to be determined; however, results show an interesting biological activity of these compounds, which may be of interest in the context of antiresorptive therapy.
Subject(s)
Apoptosis/drug effects , Diphosphonates , G2 Phase Cell Cycle Checkpoints/drug effects , M Phase Cell Cycle Checkpoints/drug effects , Osteoclasts/metabolism , S Phase/drug effects , Animals , Bone Resorption/drug therapy , Bone Resorption/metabolism , Bone Resorption/pathology , Caspase 3/metabolism , Cell Line , Cisplatin/pharmacology , Diphosphonates/chemical synthesis , Diphosphonates/chemistry , Diphosphonates/pharmacology , Doxorubicin/pharmacology , Mice , Osteoclasts/pathologyABSTRACT
Bioreactivity of superparamagnetic iron oxide nanoparticles (SPION) coated with thin layers of either cationic or anionic chitosan derivatives and serving as contrast agents in magnetic resonance imaging (MRI) was studied in vivo using BALB/c mouse model. Synthesized dual-modal fluorescing SPION were tracked in time using both fluorescent imaging and MRI. Although SPION started to be excreted by kidneys relatively shortly after administration they were uptaken by liver enhancing MRI contrast even up to 7 days. Importantly, chitosan-coated SPION caused only mild activation of acute phase response not affecting biochemical parameters of blood. Liver histology indicated the presence of SPION and modest increase in the number of Kupffer cells. The overall results indicated that SPION coated with ultrathin layers of chitosan ionic derivatives can serve as T2 contrast agents for diagnosis of liver diseases or imaging of other organs assuming the dose is optimized according to the need.
Subject(s)
Chitosan/chemistry , Contrast Media/pharmacokinetics , Ferric Compounds/administration & dosage , Liver/pathology , Magnetic Resonance Imaging/methods , Magnetite Nanoparticles/administration & dosage , Animals , Female , Ferric Compounds/chemistry , Liver/drug effects , Liver/metabolism , Magnetite Nanoparticles/chemistry , Mice , Mice, Inbred BALB C , Tissue DistributionABSTRACT
We report a study of a series of isoquinoline derivatives, including their synthesis, in vitro microsomal leucine aminopeptidase (LAP) inhibition and antiproliferative activity on cancer cell lines. Among fourteen tested compounds, one (compound 3b) was determined to have good activity against LAP and significant antiproliferative activity against HL-60 human promyelocytic leukemia, Burkitt's lymphoma Raji, camptothecin resistant CEM/C2 leukemia cells with mutated catalytic site of topoisomerase I, its parental cell line CCRF/CEM and LoVo colon cancer. Its influence on the cell cycle was also observed. Moreover, we have confirmed that antiproliferative activity towards cancer cells is due to LAP inhibition. Docking simulation based on positioning compound 3b into the LAP active site was performed to explore the possible binding mode. The compound was able to form hydrogen bonds with Gly362 and coordinate zinc ions, which was previously suggested to be essential for inhibitory activity. Compound 3b was also characterized with a good selectivity index for cancer versus normal mammalian cells. Toxicological studies involving examination of skin sensitization, acute skin irritation/corrosion, acute dermal toxicity, acute oral toxicity and acute eye irritation/corrosion established that compound 3b is safe for use.
Subject(s)
Antineoplastic Agents/pharmacology , Isoquinolines/pharmacology , Molecular Docking Simulation , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Cell Proliferation/drug effects , Dose-Response Relationship, Drug , Drug Screening Assays, Antitumor , HL-60 Cells , Humans , Isoquinolines/chemical synthesis , Isoquinolines/chemistry , Molecular Structure , Structure-Activity RelationshipABSTRACT
BACKGROUND: 1-methylnicotinamide (1-MNA), an endogenous metabolite of nicotinamide, has recently gained interest due to its anti-inflammatory and anti-thrombotic activities linked to the COX-2/PGI2 pathway. Given the previously reported anti-metastatic activity of prostacyclin (PGI2), we aimed to assess the effects of 1-MNA and its structurally related analog, 1,4-dimethylpyridine (1,4-DMP), in the prevention of cancer metastasis. METHODS: All the studies on the anti-tumor and anti-metastatic activity of 1-MNA and 1,4-DMP were conducted using the model of murine mammary gland cancer (4T1) transplanted either orthotopically or intravenously into female BALB/c mouse. Additionally, the effect of the investigated molecules on cancer cell-induced angiogenesis was estimated using the matrigel plug assay utilizing 4T1 cells as a source of pro-angiogenic factors. RESULTS: Neither 1-MNA nor 1,4-DMP, when given in a monotherapy of metastatic cancer, influenced the growth of 4T1 primary tumors transplanted orthotopically; however, both compounds tended to inhibit 4T1 metastases formation in lungs of mice that were orthotopically or intravenously inoculated with 4T1 or 4T1-luc2-tdTomato cells, respectively. Additionally, while 1-MNA enhanced tumor vasculature formation and markedly increased PGI2 generation, 1,4-DMP did not have such an effect. The anti-metastatic activity of 1-MNA and 1,4-DMP was further confirmed when both agents were applied with a cytostatic drug in a combined treatment of 4T1 murine mammary gland cancer what resulted in up to 80 % diminution of lung metastases formation. CONCLUSIONS: The results of the studies presented below indicate that 1-MNA and its structural analog 1,4-DMP prevent metastasis and might be beneficially implemented into the treatment of metastatic breast cancer to ensure a comprehensive strategy of metastasis control.
Subject(s)
Lung Neoplasms/prevention & control , Mammary Neoplasms, Experimental/drug therapy , Niacinamide/analogs & derivatives , Pyridinium Compounds/administration & dosage , Animals , Cadherins/metabolism , Cdh1 Proteins/metabolism , Cell Line, Tumor , Epoprostenol , Female , Gene Expression Regulation, Neoplastic/drug effects , Lung Neoplasms/blood supply , Lung Neoplasms/secondary , Mammary Neoplasms, Experimental/blood supply , Mice , Mice, Inbred BALB C , Niacinamide/administration & dosage , Niacinamide/pharmacology , Pyridinium Compounds/pharmacology , Xenograft Model Antitumor AssaysABSTRACT
AIMS: Novel anticancer strategies have employed bacteriophages as drug carriers and display platforms for anticancer agents; however, bacteriophage-based platforms maintain their natural antibacterial activity. This study provides the assessment of combined anticancer (engineered) and antibacterial (natural) phage activity in therapies. MATERIALS & METHODS: An in vivo BALB/c mouse model of 4T1 tumor growth accompanied by surgical wound infection was applied. The wounds were located in the areas of tumors. Bacteriophages (T4) were modified with anticancer Tyr-Ile-Gly-Ser-Arg (YIGSR) peptides by phage display and injected intraperitoneally. RESULTS & CONCLUSION: Tumor growth was decreased in mice treated with YIGSR-displaying phages. The acuteness of wounds, bacterial load and inflammatory markers in phages-treated mice were markedly decreased. Thus, engineered bacteriophages combine antibacterial and anticancer activity.
Subject(s)
Anti-Bacterial Agents/administration & dosage , Antineoplastic Agents/administration & dosage , Bacterial Infections/therapy , Bacteriophage T4/genetics , Biological Therapy , Drug Delivery Systems/methods , Neoplasms/drug therapy , Peptides/administration & dosage , Peptides/genetics , Animals , Anti-Bacterial Agents/metabolism , Antineoplastic Agents/metabolism , Bacteriophage T4/metabolism , Escherichia coli/virology , Female , Gene Expression , Humans , Mice , Mice, Inbred BALB C , Peptides/metabolismABSTRACT
A series of aromatic and aliphatic bis[aminomethylidene(bisphosphonic)] acids was synthesized in the reaction of triethylphosphite with isonitriles followed by hydrolysis or dealkylation. The in vitro anti-proliferative effect of all synthesized tetraphosphonic acids against MCF-7 breast cancer cells, J774E macrophages and HL-60 promyelocytic leukemia cells was determined. Three aromatic derivatives (5a, 5f and 5j) showed a similar or higher anti-proliferative activity than zoledronic acid.
Subject(s)
1-Naphthylamine/analogs & derivatives , Aniline Compounds/pharmacology , Antineoplastic Agents/pharmacology , Diphosphonates/pharmacology , Macrophages/drug effects , Phenylenediamines/pharmacology , 1-Naphthylamine/chemical synthesis , 1-Naphthylamine/chemistry , 1-Naphthylamine/pharmacology , Aniline Compounds/chemical synthesis , Aniline Compounds/chemistry , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Cell Line, Tumor , Cell Proliferation/drug effects , Diphosphonates/chemical synthesis , Diphosphonates/chemistry , Dose-Response Relationship, Drug , Drug Screening Assays, Antitumor , HL-60 Cells , Humans , MCF-7 Cells , Molecular Structure , Phenylenediamines/chemical synthesis , Phenylenediamines/chemistry , Structure-Activity RelationshipABSTRACT
Integrins comprise a large family of αß heterodimeric cell-surface receptors that mediate diverse processes involved in cell-cell and cell-matrix interactions such as cellular adhesion and migration, cell survival and differentiation. It is now well documented that integrins play a crucial role in cancer metastasis and angiogenesis. The ß3 integrins appear to have an important stimulatory role in tumour progression and metastasis and, thus, have been often proposed as potential targets for cancer diagnosis and therapy. In this study, we evaluated the in vitro and in vivo properties of B16 mouse melanoma cells with low expression of integrin ß3. Proliferation rate, adhesive properties and the ability to migrate and metastasize were studied. Over 90% inhibition of integrin ß3 expression was achieved as a result of the transfection with siRNA. No changes in the proliferation rate were observed in siRNA-transfected B16 cells; however, they showed impaired ability to bind to fibronectin. Moreover, inhibition of integrin ß3 expression caused almost complete impairment of the ability of B16 cells to migrate through matrigel and metastasize. The mean number of lung metastatic colonies in mice inoculated intravenously with B16 expressing low levels of integrin ß3 was decreased to 14 colonies compared to 101 in the control group. These results provide evidence for a direct role of integrin ß3 in the adhesion, migration and metastasis processes of mouse melanoma cells and point to the potential therapeutic advantages of siRNAs.
Subject(s)
Integrin beta3/genetics , Integrin beta3/metabolism , Melanoma, Experimental/metabolism , RNA Interference , Animals , Cell Adhesion , Cell Line, Tumor , Cell Movement , Cell Proliferation , Fibronectins/metabolism , Melanoma, Experimental/genetics , Melanoma, Experimental/pathology , Melanoma, Experimental/secondary , Mice , Mice, Inbred C57BL , Neoplasm Metastasis , RNA, Small InterferingABSTRACT
Imatinib mesylate (Gleevec, STI571) is a specific inhibitor of the Bcr/Abl fusion tyrosine kinase that exhibits potent antileukemic effects in chronic myelogenous leukemia. Bcr/Abl-positive K562 and Bcr/Abl-negative HL-60 human leukemia cells were used to investigate the effect of PRI-2191, a calcitriol analog, on the biological effects of imatinib combined with other anticancer drugs. The results show that PRI-2191 enhances the antiproliferative effect of imatinib on HL-60 cells. When these two agents together are applied with either docetaxel or cisplatin, but not with idarubicin, the antiproliferative effect could still be enhanced. Moreover, when the interaction between the chemotherapy agents was antagonistic or additive, PRI-2191 could even shift it to synergism. This effect correlated with an accumulation of HL-60 cells in the G0/G1 phase of the cell cycle and a decrease in the percentage of cells in the G2/M and S stage in the ternary combinations used. PRI-2191 did not influence apoptosis induced by imatinib alone or in ternary combinations with all the chemotherapy agents used. These results may suggest that the stronger antiproliferative effect of the combined treatment with PRI-2191 on HL-60 cells is related to cell cycle arrest rather than to the induction of apoptosis.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/pharmacology , Dihydroxycholecalciferols/pharmacology , Leukemia/drug therapy , Piperazines/pharmacology , Pyrimidines/pharmacology , Apoptosis/drug effects , Benzamides , Cell Cycle Checkpoints/drug effects , Cell Proliferation/drug effects , Cisplatin/administration & dosage , Dihydroxycholecalciferols/administration & dosage , Docetaxel , G1 Phase Cell Cycle Checkpoints/drug effects , HL-60 Cells/drug effects , Humans , Idarubicin/administration & dosage , Imatinib Mesylate , K562 Cells/drug effects , Leukemia/pathology , Piperazines/administration & dosage , Pyrimidines/administration & dosage , Taxoids/administration & dosageABSTRACT
We have previously shown that a low Magnesium (Mg)-containing diet reversibly inhibits the growth of primary tumors that develop after the injection of Lewis lung carcinoma (LLC) cells in mice. Here we investigate some of the mechanisms responsible for the Mg-dependent regulation of tumor development by studying cell cycle regulation, tumor angiogenesis, and gene expression under Mg deficiency. The inhibition of LLC tumor growth in Mg-deficient mice is due to a direct effect of low Mg on LLC cell proliferation and to an impairment of the angiogenic switch. We also observed an increase of nitric oxide synthesis and oxidative DNA damage. Complementary DNA arrays reveal that Mg deficiency modulates tumor expression of genes involved in the control of cell cycle, stress response, proteolysis, and adhesion. Our results suggest that Mg has multiple and complex roles in tumor development.