ABSTRACT
OPINION STATEMENT: Epithelioid hemangioendothelioma (EHE) is an ultra-rare, translocated vascular sarcoma. EHE can have different clinical presentations from indolent to rapidly evolving cases, behaving as a high-grade sarcoma. Serosal effusion and systemic symptoms such as fever and severe pain are known as adverse prognostic factors; however, outcome prediction at disease onset remains a major challenge. In spite of its rarity, an international collaborative effort is in place with the support of patient advocates to increase the knowledge of EHE biology, develop new treatment options, and improve patient access to new active medications. Currently, systemic therapies are indicated only for patients suffering from progressive and/or symptomatic disease and in patients with a high risk of organ dysfunction. Standard systemic agents available so far for treatment of sarcomas, and in particular anthracycline-based chemotherapy, have marginal activity in EHE. On this background, EHE patients should be always considered for clinical study when available. The MEK inhibitor trametinib has been recently investigated prospectively in advanced EHE showing some activity, but the publication of the full dataset is still awaited to better interpret the results. Besides, there are data on response to antiangiogenics such as sorafenib and bevacizumab and, from retrospective studies, interferon, thalidomide, and sirolimus. Unfortunately, none of these agents is formally approved for EHE patients and access to treatments varies greatly between countries causing a huge disparity in patient care from one country to another.
Subject(s)
Hemangioendothelioma, Epithelioid , Sarcoma , Humans , Hemangioendothelioma, Epithelioid/diagnosis , Hemangioendothelioma, Epithelioid/drug therapy , Hemangioendothelioma, Epithelioid/etiology , Retrospective Studies , Sorafenib/therapeutic use , PrognosisABSTRACT
Pyroptosis is a programmed cell death characterized by the rupture of the plasma membranes and release of cellular content leading to inflammatory reaction. Four cellular mechanisms inducing pyroptosis have been reported thus far, including the (i) caspase 1-mediated canonical, (ii) caspase 4/5/11-mediated non-canonical, (iii) caspase 3/8-mediated and (iv) caspase-independent pathways. Although discovered as a defense mechanism protecting cells from infections of intracellular pathogens, pyroptosis plays roles in tumor initiation, progression and metastasis of tumors, as well as in treatment response to antitumor drugs and, consequently, patient outcome. Pyroptosis induction following antitumor therapies has been reported in several tumor types, including lung, colorectal and gastric cancer, hepatocellular carcinoma and melanoma. This review provides an overview of the cellular pathways of pyroptosis and discusses the therapeutic potential of pyroptosis induction in cancer, particularly in melanoma.
Subject(s)
Melanoma , Pyroptosis , Humans , Apoptosis , Caspase 1/metabolism , Caspases/metabolism , Melanoma/drug therapyABSTRACT
Novel amino-substituted pyridoquinazolinone derivatives have been designed and synthesized as potential c-MYC G-quadruplex (G4) ligands, employing an efficient methodology. All the new compounds exhibited moderate to good antiproliferative activity against the human osteosarcoma U2OS cell line. NMR and docking experiments revealed that the recently synthesized compounds interact with the Pu22 G-quadruplex in the c-MYC promoter region, establishing a 2:1 complex, with each molecule positioned over the tetrads at the 3'- and 5'-ends.
Subject(s)
Bone Neoplasms , G-Quadruplexes , Osteosarcoma , Humans , Cell Line , Promoter Regions, GeneticABSTRACT
Malignant mesothelioma (MM) is a highly aggressive and resistant tumor. The prognostic role of key effectors of glycolytic metabolism in MM prompted our studies on the cytotoxicity of new inhibitors of glucose transporter type 1 (GLUT-1) and lactate dehydrogenase-A (LDH-A) in relation to ATP/NAD+ metabolism, glycolysis and mitochondrial respiration. The antiproliferative activity of GLUT-1 (PGL13, PGL14) and LDH-A (NHI-1, NHI-2) inhibitors, alone and in combination, were tested with the sulforhodamine-B assay in peritoneal (MESO-II, STO) and pleural (NCI-H2052 and NCI-H28) MM and non-cancerous (HMEC-1) cells. Effects on energy metabolism were measured by both analysis of nucleotides using RP-HPLC and evaluation of glycolysis and respiration parameters using a Seahorse Analyzer system. All compounds reduced the growth of MM cells in the µmolar range. Interestingly, in H2052 cells, PGL14 decreased ATP concentration from 37 to 23 and NAD+ from 6.5 to 2.3 nmol/mg protein. NHI-2 reduced the ATP/ADP ratio by 76%. The metabolic effects of the inhibitors were stronger in pleural MM and in combination, while in HMEC-1 ATP reduction was 10% lower compared to that of the H2052 cells, and we observed a minor influence on mitochondrial respiration. To conclude, both inhibitors showed cytotoxicity in MM cells, associated with a decrease in ATP and NAD+, and were synergistic in the cells with the highest metabolic modulation. This underlines cellular energy metabolism as a potential target for combined treatments in selected cases of MM.
Subject(s)
Mesothelioma, Malignant , Mesothelioma , Humans , Lactate Dehydrogenase 5 , Glucose Transport Proteins, Facilitative , NAD , Cell Line, Tumor , Glycolysis , Adenosine Triphosphate , Glucose , Mesothelioma/drug therapy , Mesothelioma/pathologyABSTRACT
Despite the significant outcomes attained by scientific research, breast cancer (BC) still represents the second leading cause of death in women. Estrogen receptor-positive (ER+) BC accounts for the majority of diagnosed BCs, highlighting the disruption of estrogenic signalling as target for first-line treatment. This goal is presently pursued by inhibiting aromatase (AR) enzyme or by modulating Estrogen Receptor (ER) α. An appealing strategy for fighting BC and reducing side effects and resistance issues may lie in the design of multifunctional compounds able to simultaneously target AR and ER. In this paper, previously reported flavonoid-related potent AR inhibitors were suitably modified with the aim of also targeting ERα. As a result, homoisoflavone derivatives 3b and 4a emerged as well-balanced submicromolar dual acting compounds. An extensive computational study was then performed to gain insights into the interactions the best compounds established with the two targets. This study highlighted the feasibility of switching from single-target compounds to balanced dual-acting agents, confirming that a multi-target approach may represent a valid therapeutic option to counteract ER+ BC. The homoisoflavone core emerged as a valuable natural-inspired scaffold for the design of multifunctional compounds.
Subject(s)
Aromatase Inhibitors , Aromatase , Breast Neoplasms , Drug Design , Estrogen Receptor alpha , Flavonoids , Breast Neoplasms/drug therapy , Breast Neoplasms/enzymology , Breast Neoplasms/metabolism , Aromatase Inhibitors/chemical synthesis , Aromatase Inhibitors/chemistry , Aromatase Inhibitors/pharmacology , Flavonoids/chemical synthesis , Flavonoids/chemistry , Flavonoids/pharmacology , Humans , Female , Estrogen Receptor alpha/antagonists & inhibitors , Estrogen Receptor alpha/chemistry , Estrogen Receptor alpha/metabolism , Molecular Dynamics Simulation , Aromatase/chemistry , Aromatase/metabolism , Thermodynamics , Inhibitory Concentration 50 , Molecular Docking SimulationABSTRACT
Platinum-based chemotherapy remains widely used in advanced non-small cell lung cancer (NSCLC) despite experimental evidence of its potential to induce long-term detrimental effects, including the promotion of pro-metastatic microenvironments. In this study, we investigated the interconnected pathways underlying the promotion of cisplatin-induced metastases. In tumor-free mice, cisplatin treatment resulted in an expansion in the bone marrow of CCR2+CXCR4+Ly6Chigh inflammatory monocytes (IMs) and an increase in lung levels of stromal SDF-1, the CXCR4 ligand. In experimental lung metastasis assays, cisplatin-induced IMs promoted the extravasation of tumor cells and the expansion of CD133+CXCR4+ metastasis-initiating cells (MICs). Peptide R, a novel CXCR4 inhibitor designed as an SDF-1 mimetic peptide, prevented cisplatin-induced IM expansion, the recruitment of IMs into the lungs, and the promotion of metastasis. At the primary tumor site, cisplatin treatment reduced tumor size while simultaneously inducing tumor release of SDF-1, MIC expansion, and recruitment of pro-invasive CXCR4+ macrophages. Co-recruitment of MICs and CCR2+CXCR4+ IMs to distant SDF-1-enriched sites also promoted spontaneous metastases that were prevented by CXCR4 blockade. In clinical specimens from NSCLC patients SDF-1 levels were found to be higher in platinum-treated samples and related to a worse clinical outcome. Our findings reveal that activation of the CXCR4/SDF-1 axis specifically mediates the pro-metastatic effects of cisplatin and suggest CXCR4 blockade as a possible novel combination strategy to control metastatic disease.
Subject(s)
AC133 Antigen/metabolism , Carcinoma, Non-Small-Cell Lung/drug therapy , Chemokine CXCL12/metabolism , Cisplatin/administration & dosage , Lung Neoplasms/drug therapy , Monocytes/metabolism , Peptides/administration & dosage , Receptors, CXCR4/metabolism , A549 Cells , Animals , Carcinoma, Non-Small-Cell Lung/metabolism , Cell Line, Tumor , Cisplatin/pharmacology , Drug Interactions , Humans , Lung Neoplasms/immunology , Male , Mice , Neoplasm Metastasis , Neoplastic Stem Cells/drug effects , Neoplastic Stem Cells/immunology , Peptides/pharmacology , RAW 264.7 Cells , Receptors, CXCR4/antagonists & inhibitors , Xenograft Model Antitumor AssaysABSTRACT
Inhibition of c-Src is considered one of the most studied approaches to cancer treatment, with several heterocyclic compounds approved during the last 15 years as chemotherapeutic agents. Starting from the biological evaluation of an in-house collection of small molecules, indolinone was selected as the most promising scaffold. In this work, several functionalised indolinones were synthesised and their inhibitory potency and cytotoxic activity were assayed. The pharmacological profile of the most active compounds, supported by molecular modelling studies, revealed that the presence of an amino group increased the affinity towards the ATP-binding site of c-Src. At the same time, bulkier derivatizations seemed to improve the interactions within the enzymatic pocket. Overall, these data represent an early stage towards the optimisation of new, easy-to-be functionalised indolinones as potential c-Src inhibitors.
Subject(s)
Antineoplastic Agents , Protein Kinase Inhibitors , Antineoplastic Agents/chemistry , Molecular Docking Simulation , Oxindoles , Protein-Tyrosine Kinases , Structure-Activity RelationshipABSTRACT
Prostate cancer (PCa) ranges from indolent to aggressive tumors that may rapidly progress and metastasize. The switch to aggressive PCa is fostered by reactive stroma infiltrating tumor foci. Therefore, reactive stroma-based biomarkers may potentially improve the early detection of aggressive PCa, ameliorating disease classification. Gene expression profiles of PCa reactive fibroblasts highlighted the up-regulation of genes related to stroma deposition, including periostin and sparc. Here, the potential of periostin as a stromal biomarker has been investigated on PCa prostatectomies by immunohistochemistry. Moreover, circulating levels of periostin and sparc have been assessed in a low-risk PCa patient cohort enrolled in active surveillance (AS) by ELISA. We found that periostin is mainly expressed in the peritumoral stroma of prostatectomies, and its stromal expression correlates with PCa grade and aggressive disease features, such as the cribriform growth. Moreover, stromal periostin staining is associated with a shorter biochemical recurrence-free survival of PCa patients. Interestingly, the integration of periostin and sparc circulating levels into a model based on standard clinico-pathological variables improves its performance in predicting disease reclassification of AS patients. In this study, we provide the first evidence that circulating molecular biomarkers of PCa stroma may refine risk assessment and predict the reclassification of AS patients.
Subject(s)
Prostatic Neoplasms , Soft Tissue Neoplasms , Biomarkers , Biomarkers, Tumor/metabolism , Humans , Immunohistochemistry , Male , Prostatectomy , Prostatic Neoplasms/diagnosis , Prostatic Neoplasms/genetics , Prostatic Neoplasms/metabolism , Risk AssessmentABSTRACT
Stilbenoids are natural compounds endowed with several biological activities, including cardioprotection and cancer prevention. Among them, (±)-trans-δ-viniferin, deriving from trans-resveratrol dimerization, was investigated in its ability to target DNA duplex and G-quadruplex structures by exploiting NMR spectroscopy, circular dichroism, fluorescence spectroscopy and molecular docking. (±)-trans-δ-Viniferin proved to bind both the minor and major grooves of duplexes, whereas it bound the 3'- and 5'-ends of a G-quadruplex by stacking on the outer quartets, accompanied by rearrangement of flanking residues. Specifically, (±)-trans-δ-viniferin demonstrated higher affinity for the investigated DNA targets than its monomeric counterpart. Additionally, the methoxylated derivatives of (±)-trans-δ-viniferin and trans-resveratrol, i. e. (±)-pterostilbene-trans-dihydrodimer and trans-pterostilbene, respectively, were evaluated, revealing similar binding modes, affinities and stoichiometries with the DNA targets as their parent analogues. All tested compounds were cytotoxic at µM concentration on several cancer cell lines, showing DNA damaging activity consistent with their ability to tightly interact with duplex and G-quadruplex structures.
Subject(s)
G-Quadruplexes , Stilbenes , Circular Dichroism , DNA , Molecular Docking Simulation , ResveratrolABSTRACT
Epithelioid sarcoma (ES) is an aggressive ultra-rare soft-tissue sarcoma marked by SMARCB1/INI1 deficiency. SMARCB1/INI1 deficiency leads to elevated expression of EZH2, a component of polycomb repressive complex 2, which mediates gene silencing by catalyzing H3K27me3. Tazemetostat is an oral, SAM-competitive inhibitor of EZH2, whose blockade prevents the methylation of histone H3K27, thus decreasing the growth of EZH2 mutated or over-expressing cancer cells. Tazemetostat has been approved for the treatment of patients aged 16 years and older with metastatic or advanced ES not eligible for complete resection, based on the positive results of a single-arm Phase II basket study. Tazemetostat though represents a new treatment option for ES patients, although clinical/molecular predictors of response are still to be identified. The combination of tazemetostat with other drugs like doxorubicin and immunotherapeutic agents is currently under investigation in ES patients.
Subject(s)
Antineoplastic Agents/therapeutic use , Benzamides/therapeutic use , Biphenyl Compounds/therapeutic use , Morpholines/therapeutic use , Pyridones/therapeutic use , Sarcoma/drug therapy , Sarcoma/pathology , Antineoplastic Agents/administration & dosage , Antineoplastic Agents/adverse effects , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Benzamides/administration & dosage , Benzamides/adverse effects , Biphenyl Compounds/administration & dosage , Biphenyl Compounds/adverse effects , Enhancer of Zeste Homolog 2 Protein/antagonists & inhibitors , Histones/metabolism , Humans , Morpholines/administration & dosage , Morpholines/adverse effects , Pyridones/administration & dosage , Pyridones/adverse effects , Sarcoma/etiology , Sarcoma/mortality , Soft Tissue Neoplasms/drug therapy , Soft Tissue Neoplasms/mortality , Soft Tissue Neoplasms/pathology , Treatment OutcomeABSTRACT
Nucleic acid sequences able to adopt a G-quadruplex conformation are overrepresented within the human genome. This evidence strongly suggests that these genomic regions have been evolutionary selected to play a pivotal role in several aspects of cell biology. In the present review article, we provide an overview on the biological impact of targeting G-quadruplexes in cancer. A variety of small molecules showing good G-quadruplex stabilizing properties has been reported to exert an antitumor activity in several preclinical models of human cancers. Moreover, promiscuous binders and multiple targeting G-quadruplex ligands, cancer cell defense responses and synthetic lethal interactions of G-quadruplex targeting have been also highlighted. Overall, evidence gathered thus far indicates that targeting G-quadruplex may represent an innovative and fascinating therapeutic approach for cancer. The continued methodological improvements, the development of specific tools and a careful consideration of the experimental settings in living systems will be useful to deepen our knowledge of G-quadruplex biology in cancer, to better define their role as therapeutic targets and to help design and develop novel and reliable G-quadruplex-based anticancer strategies.
Subject(s)
Antineoplastic Agents/pharmacology , G-Quadruplexes/drug effects , Neoplasms/genetics , Animals , Cell Line, Tumor , Humans , LigandsABSTRACT
BACKGROUND: Expression of proton-coupled folate transporter (PCFT) is associated with survival of mesothelioma patients treated with pemetrexed, and is reduced by hypoxia, prompting studies to elucidate their correlation. METHODS: Modulation of glycolytic gene expression was evaluated by PCR arrays in tumour cells and primary cultures growing under hypoxia, in spheroids and after PCFT silencing. Inhibitors of lactate dehydrogenase (LDH-A) were tested in vitro and in vivo. LDH-A expression was determined in tissue microarrays of radically resected malignant pleural mesothelioma (MPM, N = 33) and diffuse peritoneal mesothelioma (DMPM, N = 56) patients. RESULTS: Overexpression of hypoxia marker CAIX was associated with low PCFT expression and decreased MPM cell growth inhibition by pemetrexed. Through integration of PCR arrays in hypoxic cells and spheroids and following PCFT silencing, we identified the upregulation of LDH-A, which correlated with shorter survival of MPM and DMPM patients. Novel LDH-A inhibitors enhanced spheroid disintegration and displayed synergistic effects with pemetrexed in MPM and gemcitabine in DMPM cells. Studies with bioluminescent hypoxic orthotopic and subcutaneous DMPM athymic-mice models revealed the marked antitumour activity of the LDH-A inhibitor NHI-Glc-2, alone or combined with gemcitabine. CONCLUSIONS: This study provides novel insights into hypoxia/PCFT-dependent chemoresistance, unravelling the potential prognostic value of LDH-A, and demonstrating the preclinical activity of LDH-A inhibitors.
Subject(s)
Antigens, Neoplasm/genetics , Carbonic Anhydrase IX/genetics , Enzyme Inhibitors/administration & dosage , L-Lactate Dehydrogenase/genetics , Mesothelioma, Malignant/drug therapy , Peritoneal Neoplasms/drug therapy , Pleural Neoplasms/drug therapy , Proton-Coupled Folate Transporter/genetics , Animals , Antigens, Neoplasm/metabolism , Carbonic Anhydrase IX/metabolism , Cell Culture Techniques , Cell Hypoxia , Cell Line, Tumor , Deoxycytidine/administration & dosage , Deoxycytidine/analogs & derivatives , Deoxycytidine/pharmacology , Drug Resistance, Neoplasm/drug effects , Drug Synergism , Enzyme Inhibitors/pharmacology , Female , Gene Expression Regulation, Neoplastic/drug effects , Humans , Mesothelioma, Malignant/genetics , Mesothelioma, Malignant/metabolism , Mice , Pemetrexed/administration & dosage , Pemetrexed/pharmacology , Peritoneal Neoplasms/genetics , Peritoneal Neoplasms/metabolism , Pleural Neoplasms/genetics , Pleural Neoplasms/metabolism , Proton-Coupled Folate Transporter/metabolism , Xenograft Model Antitumor Assays , GemcitabineABSTRACT
In a recent study, we investigated the antimicrobial activity of a collection of resveratrol-derived monomers and dimers against a series of foodborne pathogens. Out of the tested molecules, dehydro-δ-viniferin and dehydro-ε-viniferin emerged as the most promising derivatives. To define the structural elements essential to the antimicrobial activity against the foodborne pathogen L. monocytogenes Scott A as a model Gram-positive microorganism, the synthesis of a series of simplified benzofuran-containing derivatives was carried out. The systematic removal of the aromatic moieties of the parent molecules allowed a deeper insight into the most relevant structural features affecting the activity. While the overall structure of compound 1 could not be altered without a substantial loss of antimicrobial activity, the structural simplification of compound 2 (minimal inhibitory concentration (MIC) 16 µg/mL, minimal bactericidal concentration (MBC) >512 µg/mL) led to the analogue 7 with increased activity (MIC 8 µg/mL, MBC 64 µg/mL).
Subject(s)
Anti-Bacterial Agents/chemistry , Benzofurans/chemistry , Listeria monocytogenes/drug effects , Resorcinols/chemistry , Stilbenes/chemistry , Anti-Bacterial Agents/pharmacology , Benzofurans/chemical synthesis , Benzofurans/pharmacology , Cell Line , Fibroblasts/drug effects , Food Microbiology , Humans , Microbial Sensitivity Tests , Resorcinols/pharmacology , Resveratrol/chemistry , Resveratrol/pharmacology , Skin/drug effects , Stilbenes/pharmacologyABSTRACT
The molecular chaperone Hsp90 is a ubiquitous ATPase-directed protein responsible for the activation and structural stabilization of a large clientele of proteins. As such, Hsp90 has emerged as a suitable candidate for the treatment of a diverse set of diseases, such as cancer and neurodegeneration. The inhibition of the chaperone through ATP-competitive inhibitors, however, was shown to lead to undesirable side effects. One strategy to alleviate this problem is the development of molecules that are able to disrupt specific protein-protein interactions, thus modulating the activity of Hsp90 only in the particular cellular pathway that needs to be targeted. Here, we exploit novel computational and theoretical approaches to design a set of peptides that are able to bind Hsp90 and compete for its interaction with the co-chaperone Cdc37, which is found to be responsible for the promotion of cancer cell proliferation. In spite of their capability to disrupt the Hsp90-Cdc37 interaction, no important cytotoxicity was observed in human cancer cells exposed to designed compounds. These findings imply the need for further optimization of the compounds, which may lead to new ways of interfering with the Hsp90 mechanisms that are important for tumour growth.
Subject(s)
Antineoplastic Agents/pharmacology , Cell Cycle Proteins/antagonists & inhibitors , Chaperonins/antagonists & inhibitors , Drug Design , HSP90 Heat-Shock Proteins/antagonists & inhibitors , Neoplasms/drug therapy , Peptide Fragments/pharmacology , Protein Interaction Domains and Motifs/drug effects , Cell Cycle Proteins/metabolism , Chaperonins/metabolism , HSP90 Heat-Shock Proteins/metabolism , Humans , Neoplasms/metabolism , Neoplasms/pathology , Protein Binding , Protein ConformationABSTRACT
microRNAs (miRNAs) are small non-coding RNAs that negatively regulate gene expression at the post-transcriptional level. Increasing evidence emerging from human tumor preclinical models clearly indicates that specific miRNAs, collectively termed "metastamirs," play a functional role in different steps of the metastatic cascade, by exerting either pro- or anti-metastatic functions, and behave as signaling mediators to enable tumor cell to colonize a specific organ. miRNAs also actively participate in the proficient interaction of cancer cells with tumor microenvironment, either at the primary or at the metastatic site. Circulating miRNAs, released by multiple cell types, following binding to proteins or encapsulation in extracellular vesicles, play a main role in this cross-talk by acting as transferrable messages. The documented involvement of specific miRNAs in the dissemination process has aroused interest in the development of miRNA-based strategies for the treatment of metastasis. Preclinical research carried out in tumor experimental models, using both miRNA replacement and miRNA inhibitory approaches, is encouraging towards translating miRNA-based strategies into human cancer therapy, based on the observed therapeutic activity in the absence of main toxicity. However, to accelerate their adoption in the clinic, further improvements in terms of efficacy and targeted delivery to the tumor are still necessary.
Subject(s)
Biomarkers, Tumor/blood , MicroRNAs/blood , Neoplasm Metastasis/therapy , Neoplasms/therapy , Gene Expression Regulation, Neoplastic/genetics , Humans , MicroRNAs/genetics , Neoplasm Metastasis/pathology , Neoplasms/blood , Neoplasms/genetics , Neoplasms/pathology , Neoplastic Cells, Circulating/metabolism , Signal Transduction/genetics , Tumor Microenvironment/geneticsABSTRACT
We have shown that human B-cell non-Hodgkin lymphomas (B-NHLs) express heat shock protein (HSP)H1/105 in function of their aggressiveness. Here, we now clarify its role as a functional B-NHL target by testing the hypothesis that it promotes the stabilization of key lymphoma oncoproteins. HSPH1 silencing in 4 models of aggressive B-NHLs was paralleled by Bcl-6 and c-Myc downregulation. In vitro and in vivo analysis of HSPH1-silenced Namalwa cells showed that this effect was associated with a significant growth delay and the loss of tumorigenicity when 10(4) cells were injected into mice. Interestingly, we found that HSPH1 physically interacts with c-Myc and Bcl-6 in both Namalwa cells and primary aggressive B-NHLs. Accordingly, expression of HSPH1 and either c-Myc or Bcl-6 positively correlated in these diseases. Our study indicates that HSPH1 concurrently favors the expression of 2 key lymphoma oncoproteins, thus confirming its candidacy as a valuable therapeutic target of aggressive B-NHLs.
Subject(s)
DNA-Binding Proteins/metabolism , HSP110 Heat-Shock Proteins/antagonists & inhibitors , Lymphoma, B-Cell/drug therapy , Lymphoma, B-Cell/metabolism , Proto-Oncogene Proteins c-myc/metabolism , Animals , Cell Line, Tumor , DNA-Binding Proteins/genetics , Down-Regulation , Gene Knockdown Techniques , HSP110 Heat-Shock Proteins/genetics , Humans , Lymphoma, B-Cell/pathology , Mice , Mice, SCID , Proto-Oncogene Proteins c-bcl-6 , Proto-Oncogene Proteins c-myc/genetics , Xenograft Model Antitumor AssaysABSTRACT
Allosteric compounds that stimulate Hsp90 adenosine triphosphatase (ATPase) activity were rationally designed, showing anticancer potencies in the low micromolar to nanomolar range. In parallel, the mode of action of these compounds was clarified and a quantitative model that links the dynamic ligand-protein cross-talk to observed cellular and in vitro activities was developed. The results support the potential of using dynamics-based approaches to develop original mechanism-based cancer therapeutics.
Subject(s)
Adenosine Triphosphatases/metabolism , Antineoplastic Agents/pharmacology , HSP90 Heat-Shock Proteins/metabolism , Adenosine Triphosphatases/chemistry , Allosteric Regulation , Antineoplastic Agents/chemistry , Drug Design , HSP90 Heat-Shock Proteins/chemistry , Ligands , Protein BindingABSTRACT
Synthetic tubulysins 24 a-m, containing non-hydrolysable N-substituents on tubuvaline (Tuv), were obtained in high purity and good overall yields using a multistep synthesis. A key step was the formation of differently N-substituted Ile-Tuv fragments 10 by using an aza-Michael reaction of azido-Ile derivatives 8 with the α,ß-unsaturated oxo-thiazole 5. A structure-activity relationship study using a panel of human tumour cell lines showed strong anti-proliferative activity for all compounds 24 a-m, with IC50 values in the sub-nanomolar range, which were distinctly lower than those of tubulysinâ A, vinorelbine and paclitaxel. Furthermore, 24 a-m were able to overcome cross-resistance to paclitaxel and vinorelbine in two tumour cell lines with acquired resistance to doxorubicin. Compounds 24 e and 24 g were selected as leads to evaluate their mechanism of action. In vitro assays showed that both 24 e and 24 g interfere with tubulin polymerization in a vinca alkaloid-like manner and prevent paclitaxel-induced assembly of tubulin polymers. Both compounds exerted antimitotic activity and induced apoptosis in cancer cells at very low concentrations. Compound 24 e also exhibited potent antitumor activity at well tolerated doses on in vivo models of diffuse malignant peritoneal mesothelioma, such as MESOII peritoneal mesothelioma xenografts, the growth of which was not significantly affected by vinorelbine. These results indicate that synthetic tubulysins 24 could be used as standalone chemotherapeutic agents in difficult-to-treat cancers.
Subject(s)
Antineoplastic Agents/chemical synthesis , Tubulin Modulators/chemical synthesis , Tubulin/metabolism , Valine/analogs & derivatives , Animals , Antineoplastic Agents/therapeutic use , Antineoplastic Agents/toxicity , Apoptosis/drug effects , Cell Line, Tumor , Cell Proliferation/drug effects , Drug Screening Assays, Antitumor , HT29 Cells , Humans , Mice , Microscopy, Fluorescence , Neoplasms/drug therapy , Neoplasms/pathology , Paclitaxel/toxicity , Structure-Activity Relationship , Transplantation, Heterologous , Tubulin/chemistry , Tubulin Modulators/therapeutic use , Tubulin Modulators/toxicity , Valine/chemistry , Vinblastine/analogs & derivatives , Vinblastine/therapeutic use , Vinblastine/toxicity , VinorelbineABSTRACT
Metastatic prostate cancer is a lethal disease that remains incurable despite the recent approval of new drugs, thus making the development of alternative treatment approaches urgently needed. A more precise understanding of the molecular mechanisms underlying prostate cancer dissemination could lead to the identification of novel therapeutic targets for the design of efficient anti-metastatic strategies. MicroRNA (miRNAs) are endogenous, small non-coding RNA molecules acting as key regulators of gene expression at post-transcriptional level. It has been clearly established that altered miRNA expression is a common hallmark of cancer. In addition, emerging evidence suggests their direct involvement in the metastatic cascade. In this review, we present a comprehensive overview of the data generated in experimental tumor models indicating that specific miRNAs may impinge on the different stages of prostate cancer metastasis, including (i) the regulation of epithelial-to-mesenchymal transition and cell migration/invasion, (ii) the interplay between cancer cells and the surrounding stroma, (iii) the control of angiogenesis, (iv) the regulation of anoikis, and (v) the colonization of distant organs. Moreover, we show preliminary evidence of the clinical relevance of some of these miRNAs, in terms of association with tumor aggressiveness/dissemination and clinical outcome, as emerged from translation studies carried out in prostate cancer patient cohorts. We also discuss the potential and the current limitations of manipulating metastasis-related miRNAs, by mimicking or inhibiting them, as a strategy for the development of novel therapeutic approaches for the advanced disease.
Subject(s)
MicroRNAs/genetics , Neoplasm Metastasis/genetics , Prostate/pathology , Prostatic Neoplasms/genetics , Animals , Cell Movement , Epithelial-Mesenchymal Transition , Gene Expression Regulation, Neoplastic , Humans , Male , MicroRNAs/analysis , Neoplasm Metastasis/pathology , Neoplasm Metastasis/therapy , Prostate/blood supply , Prostatic Neoplasms/blood supply , Prostatic Neoplasms/pathology , Prostatic Neoplasms/therapyABSTRACT
Platinum-containing molecules are widely used as anticancer drugs. These molecules exert cytotoxic effects by binding to DNA through various mechanisms. The binding between DNA and platinum-based drugs hinders the opening of DNA, and therefore, DNA duplication and transcription are severely hampered. Overall, impeding the above-mentioned important DNA mechanisms results in irreversible DNA damage and the induction of apoptosis. Several molecules, including multinuclear platinum compounds, belong to the family of platinum drugs, and there is a body of research devoted to developing more efficient and less toxic versions of these compounds. In this study, we combined different biophysical methods, including single-molecule assays (magnetic tweezers) and bulk experiments (ultraviolet absorption for thermal denaturation) to analyze the differential stability of double-stranded DNA in complex with either cisplatin or multinuclear platinum agents. Specifically, we analyzed how the binding of BBR3005 and BBR3464, two representative multinuclear platinum-based compounds, to DNA affects its stability as compared with cisplatin binding. Our results suggest that single-molecule approaches can provide insights into the drug-DNA interactions that underlie drug potency and provide information that is complementary to that generated from bulk analysis; thus, single-molecule approaches have the potential to facilitate the selection and design of optimized drug compounds. In particular, relevant differences in DNA stability at the single-molecule level are demonstrated by analyzing nanomechanically induced DNA denaturation. On the basis of the comparison between the single-molecule and bulk analyses, we suggest that transplatinated drugs are able to locally destabilize small portions of the DNA chain, whereas other regions are stabilized.