ABSTRACT
Nanoparticle-mediated cancer immunotherapy holds great promise, but more efforts are needed to obtain nanoformulations that result in a full scale activation of innate and adaptive immune components that specifically target the tumors. We generated a series of copper-doped TiO2 nanoparticles in order to tune the kinetics and full extent of Cu2+ ion release from the remnant TiO2 nanocrystals. Fine-tuning nanoparticle properties resulted in a formulation of 33% Cu-doped TiO2 which enabled short-lived hyperactivation of dendritic cells and hereby promoted immunotherapy. The nanoparticles result in highly efficient activation of dendritic cells ex vivo, which upon transplantation in tumor bearing mice, exceeded the therapeutic outcomes obtained with classically stimulated dendritic cells. Efficacious but simple nanomaterials that can promote dendritic cancer cell vaccination strategies open up new avenues for improved immunotherapy and human health.
Subject(s)
Cancer Vaccines , Nanoparticles , Neoplasms , Vaccines , Animals , Mice , Humans , Neoplasms/drug therapy , Nanoparticles/chemistry , Immunotherapy/methods , Dendritic Cells , Cancer Vaccines/therapeutic useABSTRACT
Nanoparticle (NP) delivery to solid tumors remains an actively studied field, where several recent studies have shed new insights into the underlying mechanisms and the still overall poor efficacy. In the present study, Au NPs of different sizes were used as model systems to address this topic, where delivery of the systemically administered NPs to the tumor as a whole or to tumor cells specifically was examined in view of a broad range of tumor-associated parameters. Using non-invasive imaging combined with histology, immunohistochemistry, single-cell spatial RNA expression and image-based single cell cytometry revealed a size-dependent complex interaction of multiple parameters that promoted tumor and tumor-cell specific NP delivery. Interestingly, the data show that most NPs are sequestered by tumor-associated macrophages and cancer-associated fibroblasts, while only few NPs reach the actual tumor cells. While perfusion is important, leaky blood vessels were found not to promote NP delivery, but rather that delivery efficacy correlated with the maturity level of tumor-associated blood vessels. In line with recent studies, we found that the presence of specialized endothelial cells, expressing high levels of CD276 and Plvap promoted both tumor delivery and tumor cell-specific delivery of NPs. This study identifies several parameters that can be used to determine the suitability of NP delivery to the tumor region or to tumor cells specifically, and enables personalized approaches for maximal delivery of nanoformulations to the targeted tumor.
Subject(s)
Metal Nanoparticles , Nanoparticles , Neoplasms , Humans , Tumor Microenvironment , Particle Size , Gold/metabolism , Endothelial Cells/metabolism , Neoplasms/metabolism , Drug Delivery Systems/methods , Cell Line, Tumor , B7 Antigens/metabolismABSTRACT
Microtubule targeting agents (MTAs) are extensively used in cancer treatment and many have achieved substantial clinical success. In recent years, targeting microtubules to inhibit cell division has become a widespread pharmaceutical approach for treatment of various cancer types. Nevertheless, the development of multidrug resistance (MDR) in cancer remains a major obstacle for successful application of these agents. Herein, we provided the evidence that CKT0353, α-branched α,ß-unsaturated ketone, possesses the capacity to successfully evade the MDR phenotype as an MTA. CKT0353 induced G2/M phase arrest, delayed cell division via spindle assembly checkpoint activation, disrupted the mitotic spindle formation and depolymerized microtubules in human breast, cervix, and colorectal carcinoma cells. Molecular docking analysis revealed that CKT0353 binds at the nocodazole binding domain of ß-tubulin. Furthermore, CKT0353 triggered apoptosis via caspase-dependent mechanism. In addition, P-glycoprotein overexpressing colorectal carcinoma cells showed higher sensitivity to this agent when compared to their sensitive counterpart, demonstrating the ability of CKT0353 to overcome this classic MDR mechanism involved in resistance to various MTAs. Taken together, these findings suggest that CKT0353 is an excellent candidate for further optimization as a therapeutic agent against tumors with MDR phenotype.
Subject(s)
Drug Resistance, Neoplasm/drug effects , Microtubules/drug effects , Neoplasms/drug therapy , Paclitaxel/pharmacology , Tubulin Modulators/pharmacology , ATP Binding Cassette Transporter, Subfamily B, Member 1/metabolism , Antineoplastic Agents/pharmacology , Apoptosis/drug effects , Cell Cycle Checkpoints/drug effects , Cell Division/drug effects , Cell Line, Tumor , Cell Proliferation/drug effects , Drug Resistance, Multiple/drug effects , G2 Phase/drug effects , HeLa Cells , Humans , Microtubules/metabolism , Mitosis/drug effects , Molecular Docking Simulation/methods , Neoplasms/metabolism , Spindle Apparatus/drug effects , Spindle Apparatus/metabolism , Tubulin/metabolismABSTRACT
The progress in nanomedicine (NM) using nanoparticles (NPs) is mainly based on drug carriers for the delivery of classical chemotherapeutics. As low NM delivery rates limit therapeutic efficacy, an entirely different approach was investigated. A homologous series of engineered CuO NPs was designed for dual purposes (carrier and drug) with a direct chemical composition-biological functionality relationship. Model-based dissolution kinetics of CuO NPs in the cellular interior at post-exposure conditions were controlled through Fe-doping for intra/extra cellular Cu2+ and biological outcome. Through controlled ion release and reactions taking place in the cellular interior, tumors could be treated selectively, inâ vitro and inâ vivo. Locally administered NPs enabled tumor cells apoptosis and stimulated systemic anti-cancer immune responses. We clearly show therapeutic effects without tumor cells relapse post-treatment with 6 % Fe-doped CuO NPs combined with myeloid-derived suppressor cell silencing.
Subject(s)
Copper/chemistry , Metal Nanoparticles/chemistry , Nanomedicine/methods , Nanotechnology/methods , Oxides/chemistry , HumansABSTRACT
Over the past decades, the medical exploitation of nanotechnology has been largely increasing and finding its way into translational research and clinical applications. Despite their biomedical potential, uncertainties persist regarding the intricate role that nanomaterials may play on altering physiology in healthy and diseased tissues. Extracellular vesicles (EVs) are recognized as an important pathway for intercellular communication and known to be mediators of cellular stress. EVs are currently explored for targeted delivery of therapeutic agents, including nanoformulations, to treat and diagnose cancer or other diseases. Here, we aimed to investigate whether nanomaterials could have a possible impact on EV functionality, their safety, and whether EVs can play a role in nanomaterial toxicity profiles. To evaluate this, the impact of inorganic nanomaterial administration on EVs derived from murine melanoma and human breast cancer cells was tested. Cells were incubated with subtoxic concentrations of 4 different biomedically relevant inorganic nanoparticles (NPs): gold, silver, silicon dioxide, or iron oxide. The results displayed a clear NP and cell-type-dependent effect on increasing or decreasing EV secretion. Furthermore, the expression pattern of several EV-derived miRNAs was significantly changed upon NP exposure, compared to nontreated cells. Detailed pathway analysis and additional studies confirmed that EVs obtained from NP-exposed cells could influence immunological responses and cellular physiology. Together, these data reveal that NPs can have wide-ranging effects which can result in toxicity concerns or enhanced therapeutic potential as a secondary enhanced effect mediated and enhanced by EVs.
Subject(s)
Extracellular Vesicles , MicroRNAs , Nanoparticles , Neoplasms , Humans , Mice , Animals , Extracellular Vesicles/metabolism , Neoplasms/drug therapy , MicroRNAs/metabolism , Cell CommunicationABSTRACT
Having identified a novel human DNA topoisomerase IIα (TOP2) catalytic inhibitor from a small and structure-focused library of propargylic enol ethers, we decided to analyze if the chirality of these compounds plays a determinant role in their antiproliferative activity. In this study, we describe for the first time the synthesis of the corresponding enantiomers and the biological evaluation against a panel of representative human solid tumor cell lines. Experimental results show that chirality does not influence the reported antiproliferative activity of these compounds. Docking studies of corresponding enantiomers against TOP2 reinforce the finding that the biological effect is not chiral-dependent and that these family of compounds seem to act as TOP2 catalytic inhibitors.
Subject(s)
Alkynes/chemistry , Antigens, Neoplasm/chemistry , DNA Topoisomerases, Type II/chemistry , DNA-Binding Proteins/chemistry , Ethers/chemistry , Molecular Docking Simulation , Alkenes/chemistry , Alkenes/pharmacology , Alkynes/pharmacology , Binding Sites , Cell Line, Tumor , Cell Proliferation/drug effects , Crystallography, X-Ray , DNA-Binding Proteins/antagonists & inhibitors , Ethers/pharmacology , Humans , Models, Molecular , Nitric Oxide Synthase Type III , Poly-ADP-Ribose Binding Proteins , StereoisomerismABSTRACT
The ability to improve nanoparticle delivery to solid tumors is an actively studied domain, where various mechanisms are looked into. In previous work, the authors have looked into nanoparticle size, tumor vessel normalization, and disintegration, and here it is aimed to continue this work by performing an in-depth mechanistic study on the use of ciRGD peptide co-administration. Using a multiparametric approach, it is observed that ciRGD can improve nanoparticle delivery to the tumor itself, but also to tumor cells specifically better than vessel normalization strategies. The effect depends on the level of tumor perfusion, hypoxia, neutrophil levels, and vessel permeability. This work shows that upon characterizing tumors for these parameters, conditions can be selected that can optimally benefit from ciRGD co-administration as a means to improve NP delivery to solid tumors.
Subject(s)
Nanoparticles , Neoplasms , Humans , Neuropilin-1/therapeutic use , Neutrophils , Drug Delivery Systems , Neoplasms/drug therapy , Neoplasms/pathology , Nanoparticles/chemistry , HypoxiaABSTRACT
Six diiodido-diamine platinum(II) complexes, either cis or trans configured, were prepared, differing only in the nature of the amine ligand (isopropylamine, dimethylamine, or methylamine), and their antiproliferative properties were evaluated against a panel of human tumor cell lines. Both series of complexes manifested pronounced cytotoxic effects, with the trans isomers being, generally, more effective than their cis counterparts. Cell cycle analysis revealed different modes of action for these new Pt(II) complexes with respect to cisplatin. The reactivity of these platinum compounds with a number of biomolecules, including cytochrome c, two sulfur containing modified amino acids, 9-ethylguanine, and a single strand oligonucleotide, was analyzed in depth by mass spectrometry and NMR spectroscopy. Interestingly, significant differences in the reactivity of the investigated compounds toward the various model biomolecules were observed: in particular we observed that trans complexes preferentially release their iodide ligands upon biomolecule binding, while the cis isomers may release the amine ligands with retention of iodides. Such differences in reactivity may have important mechanistic implications and a relevant impact on the respective pharmacological profiles.
Subject(s)
Antineoplastic Agents/chemistry , Platinum/chemistry , Antineoplastic Agents/pharmacology , Cell Proliferation/drug effects , Flow Cytometry , Isomerism , Magnetic Resonance Spectroscopy , Platinum/pharmacology , Spectrometry, Mass, Electrospray IonizationABSTRACT
A Phenotypic Drug Discovery strategy was applied to study a set of pyrimidine analogs prepared by means of intramolecular oxidation-reduction reactions of N-substituted-N-(2,6-disubstituted-5-nitro-4-pyrimidinyl)aminoacetic acid methyl esters in basic media. The combined and rational use of specific assays allowed in short time reducing from all possible cellular targets to those involved in metaphase to anaphase transition.
Subject(s)
Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Cell Cycle/drug effects , Drug Discovery , Pyrimidines/chemistry , Pyrimidines/pharmacology , Anaphase/drug effects , Antineoplastic Agents/chemical synthesis , Cell Line, Tumor , Humans , Metaphase/drug effects , Neoplasms/drug therapy , Oxidation-Reduction , Pyrimidines/chemical synthesis , Structure-Activity RelationshipABSTRACT
The biological evaluation of new Ru(II) complexes carrying dmoPTA (dmoPTA=3,7-dimethyl-1,3,7-triaza-5-phosphabicyclo[3.3.1]nonane) ligands is reported. The results on the biological activity revealed that the organometallic complexes are active against all cell lines with GI(50) values in the range 1.1-2.6 µM. When compared to the standard anticancer drug cisplatin, the bimetallic Ru(II) complexes showed a greater activity profile. The cell cycle analysis revealed that the new compounds induced arrest in G(1) phase. Contrary to cisplatin, these Ru(II) complexes do not interact with DNA. This result suggests that DNA might not be the key pharmacological target.
Subject(s)
Antineoplastic Agents/chemistry , Coordination Complexes/chemistry , Ruthenium/chemistry , Antineoplastic Agents/therapeutic use , Antineoplastic Agents/toxicity , Cell Line, Tumor , Coordination Complexes/therapeutic use , Coordination Complexes/toxicity , Drug Screening Assays, Antitumor , Humans , Neoplasms/drug therapyABSTRACT
A series of 2-substituted 1,2-dihydro-3-phenyl-1-(trichloromethyl)benzo[b][1,6]naphthyridines were synthesized and their in vitro antiproliferative activities were examined against human solid tumor cell lines and relevant strains of bacteria and Candida. The compounds induced considerably growth inhibition in all cancer cell lines, whilst showed inactive against microbial strains. Furthermore, we found analog 2-ethoxy-1H-pyrano[4,3-b]quinoline as selective inhibitor of microbial strains.
Subject(s)
Anti-Bacterial Agents/chemistry , Antifungal Agents/chemistry , Antineoplastic Agents/chemistry , Naphthyridines/chemistry , Anti-Bacterial Agents/chemical synthesis , Anti-Bacterial Agents/pharmacology , Antifungal Agents/chemical synthesis , Antifungal Agents/pharmacology , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/pharmacology , Cell Line, Tumor , Drug Screening Assays, Antitumor , Humans , Naphthyridines/chemical synthesis , Naphthyridines/pharmacologyABSTRACT
A series of 5-hydroxy-1,4-naphthoquinones analogues was synthesized from juglone (6) and their antiproliferative activity against a representative panel of six human solid tumor cell lines has been investigated. The 2,5-dihydroxy-3-(3-methylbut-2-enyl)naphthalene-1,4-dione (4) and 2,3-dihydro-5-hydroxy-2-(prop-1-en-2-yl)naphtho[2,3-b]furan-4,9-dione (27) were the most potent antiproliferative agents with GI(50) values of 0.42-8.1 and 0.80-2.2microM, respectively. The results provide insight into the correlation between some structural properties of 5-hydroxynaphthoquinones and their antiproliferative activity.
Subject(s)
Antineoplastic Agents, Phytogenic/chemical synthesis , Antineoplastic Agents, Phytogenic/pharmacology , Naphthoquinones/chemistry , Naphthoquinones/chemical synthesis , Naphthoquinones/pharmacology , Cell Line, Tumor , Drug Screening Assays, Antitumor , Humans , Indicators and Reagents , Lipids/chemistry , Magnetic Resonance Spectroscopy , Prenylation , Structure-Activity RelationshipABSTRACT
Two iridoid scaffolds were synthesized enantioselectively using as key step an l-proline-catalyzed alpha-formyl oxidation. The in vitro antiproliferative activities were evaluated against a representative panel of human solid tumor cell lines. Both iridoids induced considerably growth inhibition in the range 0.38-1.86muM. Cell cycle studies for these compounds showed the induction of cell cycle arrest at the G(1) phase. This result was consistent with a decrease in the expression of cyclin D1. Damaged cells underwent apoptosis as indicated by specific Annexin V staining.
Subject(s)
Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Cell Proliferation/drug effects , Glucosides/chemistry , Glucosides/pharmacology , Iridoids/chemistry , Iridoids/pharmacology , Annexin A5/metabolism , Antineoplastic Agents/chemical synthesis , Blotting, Western , Cell Cycle/drug effects , Cell Line, Tumor , Enzyme Inhibitors/metabolism , Glucosides/chemical synthesis , Humans , Iridoid Glucosides , Iridoids/chemical synthesis , Models, Molecular , Molecular Conformation , Structure-Activity RelationshipABSTRACT
Small molecule inhibitors (TKIs) of HER2 have demonstrated clinical benefit in HER2-positive breast tumors. One of them, lapatinib, is used once advanced tumors become refractory to the HER2 antibody trastuzumab. Another one, neratinib, has shown benefit in high-risk early-stage breast cancer after trastuzumab-based therapies. A common characteristic is that patients are formerly treated with trastuzumab. We have explored whether trastuzumab previous therapy affects its antitumoral action. Long time exposure of the HER2+ cell line BT474 to trastuzumab resulted in trastuzumab-insensitive cells (BTRH cells). While treatment of wild type BT474 cells with lapatinib or neratinib resulted in decreased viability, BTRH cells were resistant to the action of these TKIs. Analogous results were obtained using trastuzumab-resistant cells derived from a PDX. Functional transcriptomic analyses and biochemical studies demonstrated that the TKIs caused DNA damage and apoptosis in wild type cells, but not in BTRH. Moreover, previous treatment with trastuzumab impairs response to small TKIs, by eliminating their proapoptotic action. Moreover, actioning on the apoptotic machinery using a chemical library of proapoptotic compounds led to the identification of clinical-stage drugs that may be used to fight trastuzumab-TKI resistance.
Subject(s)
Antineoplastic Agents, Immunological/pharmacology , Antineoplastic Combined Chemotherapy Protocols/pharmacology , Breast Neoplasms/drug therapy , Drug Resistance, Neoplasm/drug effects , Protein Kinase Inhibitors/pharmacology , Trastuzumab/pharmacology , Animals , Antineoplastic Agents, Immunological/therapeutic use , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Apoptosis/drug effects , Apoptosis/genetics , Breast Neoplasms/genetics , Breast Neoplasms/immunology , Breast Neoplasms/pathology , Cell Line, Tumor , DNA Damage/drug effects , Female , Gene Expression Profiling , Humans , Imidazoles/pharmacology , Imidazoles/therapeutic use , Lapatinib/pharmacology , Lapatinib/therapeutic use , Mice , Naphthoquinones/pharmacology , Naphthoquinones/therapeutic use , Protein Kinase Inhibitors/therapeutic use , Pyridines/pharmacology , Pyridines/therapeutic use , Quinolines/pharmacology , Quinolines/therapeutic use , Receptor, ErbB-2/antagonists & inhibitors , Receptor, ErbB-2/genetics , Receptor, ErbB-2/immunology , Trastuzumab/therapeutic use , Xenograft Model Antitumor AssaysABSTRACT
A series of 2,4-disubstituted 6-aryl-7H-pyrrolo[3,2-d]pyrimidin-7-one 5-oxides were synthesized and in vitro antiproliferative activities were examined in the human solid tumor cell lines A2780, HBL-100, HeLa, SW1573, T-47D, and WiDr. The most potent analog induced considerably growth inhibition in the range 0.35-2.0microM. Cell cycle studies in the breast and lung cancer cells revealed arrest in the G(2)/M compartment. The results showed that the title compounds bearing alkylamino or dialkylamino moieties in position 2 of the pyrimidine ring are more active than those bearing hydrogen or methylthio groups.
Subject(s)
Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/pharmacology , Cell Proliferation/drug effects , Oxides/chemical synthesis , Oxides/pharmacology , Pyrimidines/chemical synthesis , Pyrimidines/pharmacology , Pyrroles/chemical synthesis , Pyrroles/pharmacology , Antineoplastic Agents/chemistry , Breast Neoplasms/drug therapy , Cell Cycle/drug effects , Cell Line, Tumor , Drug Screening Assays, Antitumor , Humans , Lung Neoplasms/drug therapy , Oxides/chemistry , Pyrimidines/chemistry , Pyrroles/chemistryABSTRACT
The appearance of resistance to the anti-HER2 targeted drug trastuzumab constitutes, nowadays, an important challenge in the oncology clinic. To fight such resistance, we searched for potential vulnerabilities in cells resistant to that drug. To that end, we used cell lines primary resistant to trastuzumab, as well as cells made secondarily resistant to the drug upon continuous exposure. Using genomic and proteomic approaches, a deregulation in cell death pathways was identified in trastuzumab-resistant cells. More precisely, an increased response to the death factor TRAIL, caused by an increase in the cellular receptors for this factor, was observed. In parallel, a decrease in inhibitory components of the pathway was detected. This combination produces a more efficient assembly of the functional complex in the trastuzumab-resistant cells that translates in the observed increased response to TRAIL. Analysis of HER2 positive patient samples confirmed deregulation of this pathway in trastuzumab-resistant patients. Taken together our data identify a vulnerability of trastuzumab-resistant cells that could be used to design new targeted therapies in that context.
Subject(s)
Breast Neoplasms/drug therapy , Receptor, ErbB-2/metabolism , Receptors, TNF-Related Apoptosis-Inducing Ligand/metabolism , Trastuzumab/pharmacology , Antineoplastic Agents, Immunological/pharmacology , Apoptosis/drug effects , Breast Neoplasms/genetics , Breast Neoplasms/metabolism , Breast Neoplasms/pathology , Cell Line, Tumor , Drug Resistance, Neoplasm , Female , HEK293 Cells , Humans , Receptor, ErbB-2/antagonists & inhibitors , Receptor, ErbB-2/genetics , Receptors, TNF-Related Apoptosis-Inducing Ligand/genetics , Recombinant Proteins/pharmacology , Signal Transduction/drug effects , TNF-Related Apoptosis-Inducing Ligand/pharmacology , TranscriptomeABSTRACT
Trastuzumab-emtansine (T-DM1) is an antibody-drug conjugate (ADC) that was approved recently to treat HER2+ breast cancers. Despite its impressive clinical efficacy in many patients, intrinsic and acquired resistance to T-DM1 has emerged as a challenge. To identify mechanisms of T-DM1 resistance, we isolated several resistant HER2+ clones exhibiting stable drug refractoriness in vitro and in vivo Genomic comparisons showed substantial differences among three of the isolated clones, indicating several potential mechanisms of resistance to T-DM1. However, we observed no differences in HER2 levels and signaling among the resistant models and parental HER2+ cells. Bioinformatics studies suggested that intracellular trafficking of T-DM1 could underlie resistance to T-DM1, and systematic analysis of the path followed by T-DM1 showed that the early steps in the internalization of the drug were unaltered. However, in some of the resistant clones, T-DM1 accumulated in lysosomes. In these clones, lysosomal pH was increased and the proteolytic activity of these organelles was deranged. These results were confirmed in T-DM1-resistant cells from patient-derived HER2+ samples. We postulate that resistance to T-DM1 occurs through multiple mechanisms, one of which is impaired lysosomal proteolytic activity. Because other ADC may use the same internalization-degradation pathway to deliver active payloads, strategies aimed at restoring lysosomal functionality might overcome resistance to ADC-based therapies and improve their effectiveness. Cancer Res; 77(17); 4639-51. ©2017 AACR.
Subject(s)
Antibodies, Monoclonal, Humanized/pharmacology , Breast Neoplasms/pathology , Drug Resistance, Neoplasm , Immunoconjugates/pharmacology , Lysosomes/metabolism , Maytansine/analogs & derivatives , Proteolysis/drug effects , Receptor, ErbB-2/antagonists & inhibitors , Ado-Trastuzumab Emtansine , Animals , Antineoplastic Agents/pharmacology , Breast Neoplasms/drug therapy , Breast Neoplasms/enzymology , Female , Gene Expression Profiling , Humans , Lysosomes/drug effects , Maytansine/pharmacology , Mice, Inbred BALB C , Mice, Inbred NOD , Mice, Nude , Mice, SCID , Trastuzumab , Tumor Cells, Cultured , Xenograft Model Antitumor AssaysABSTRACT
The efficacy of microtubule targeting agents in cancer treatment has been compromised by the development of drug resistance that may involve both, P-glycoprotein overexpression and the changes in ß-tubulin isoforms' expression. The anti-Topoisomerase II activity of methyl 4-((E)-2-(methoxycarbonyl)vinyloxy)oct-2-ynoate (DTA0100) was recently reported. Herein, we further evaluated this propargylic enol ether derivative and found that it exerts inhibitory effect on tubulin polymerization by binding to colchicine binding site. DTA0100 mitotic arrest properties were investigated in two multi-drug resistant cancer cell lines with P-glycoprotein overexpression (colorectal carcinoma and glioblastoma). The sensitivity of multi-drug resistant cancer cell lines to DTA0100 was not significantly changed in contrast to microtubule targeting agents such as paclitaxel, vinblastine and colchicine. DTA0100 clearly induced microtubule depolymerization, leading to disturbance of cell cycle kinetics and subsequent apoptosis. The fine-tuning in ß-tubulin isoforms expression observed in multi-drug resistant cancer cells may influence the efficacy of DTA0100. Importantly, DTA0100 blocked the P-glycoprotein function in both multi-drug resistant cancer cell lines without inducing the increase in P-glycoprotein expression. Therefore, DTA0100 acting as dual inhibitor of Topoisomerase II and microtubule formation could be considered as multi-potent anticancer agent. Besides, it is able to overcome the problem of drug resistance that emerges in the therapeutic approaches with either Topoisomerase II or microtubule targeting agents.
Subject(s)
Acrylates/pharmacology , Antineoplastic Agents, Phytogenic/pharmacology , Caprylates/pharmacology , Drug Resistance, Neoplasm/drug effects , Paclitaxel/pharmacology , Topoisomerase II Inhibitors/pharmacology , Tubulin Modulators/pharmacology , ATP Binding Cassette Transporter, Subfamily B, Member 1/metabolism , Apoptosis/drug effects , Cell Cycle Checkpoints/drug effects , Cell Line, Tumor , Humans , Neoplasms/drug therapy , Neoplasms/metabolism , Tubulin/genetics , Tubulin/metabolismABSTRACT
The antiproliferative activities of a series of 36 naphthoquinone derivatives were subjected to a Quantitative Structure-Activity Relationships (QSAR) study. For this purpose a panel of four human cancer cell lines was used, namely HBL-100 (breast), HeLa (cervix), SW-1573 (non-small cell lung) and WiDr (colon). A conformation-independent representation of the chemical structure was established in order to avoid leading with the scarce experimental information on X-ray crystal structure of the drug interaction. The 1179 theoretical descriptors derived with E-Dragon and Recon software were simultaneously analyzed through linear regression models based on the Replacement Method variable subset selection technique. The established models were validated and tested through the use of external test sets of compounds, the Leave-One-Out Cross Validation method, Y-Randomization and Applicability Domain analysis.
Subject(s)
Naphthoquinones/pharmacology , Quantitative Structure-Activity Relationship , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Cell Proliferation/drug effects , Cell Survival/drug effects , Dose-Response Relationship, Drug , Drug Screening Assays, Antitumor , HeLa Cells , Humans , Molecular Conformation , Naphthoquinones/chemical synthesis , Naphthoquinones/chemistry , Structure-Activity Relationship , Tumor Cells, CulturedABSTRACT
Two new and five known withanolides (jaborosalactones 2, 3, 4, 5, and 24) were isolated from the leaves of Jaborosa runcinata Lam. We also obtained some derivatives from jaborosalactone 5, which resulted to be the major isolated metabolite. The natural compounds as well as derivatives were evaluated for their antiproliferative activity and the induction of quinone reductase 1 (QR1; NQ01) activity. Structure-activity relationships revealed valuable information on the pharmacophore of withanolide-type compounds. Three compounds of this series showed significantly higher antiproliferative activity than jaborosalactone 5. The effect of these compounds on the cell cycle was determined. Furthermore, the ability of major compounds to induce QR1 was evaluated. It was found that all the active test compounds are monofunctional inducers that interact with Keap1. The most promising derivatives prepared from jaborosalactone 5 include (23R)-4ß,12ß,21-trihydroxy-1,22-dioxo-12,23-cycloergostan-2,5,17,24-tetraen-26,23-olide (18) and (23R)-21-acetoxy-12ß-hydroxy-1,22-dioxo-12,23-cycloergostan-2,5,17,24-tetraen-26,23-lactame (20).