ABSTRACT
Mushrooms produce a great variety of secondary metabolites that can be successful in both prevention and treatment of various cancers. In particular, higher Basidiomycete mushrooms contain various types of biologically active low-molecular compounds in fruiting bodies with suggested anticarcinogenic effects. The polyamine analogue {(2R)-2-[(S)-3-hydroxy-3-methylglutaryloxy] putrescine dicinnamamide} indicated with the name pholiotic acid, isolated for the first time by us from the fruiting bodies of the Basidiomycete Pholiota spumosa (Fr.) Sing. (Strophariaceae), inhibited the viability of human prostate cancer cells, such as other polyamine synthetic analogues that have shown antitumor activity in several types of cancer, including melanoma. Melanoma is an aggressive skin cancer that can metastasize to other organs and presents a high resistance to conventional therapies. In light of these considerations, the present study was therefore designed to assess whether this putrescine derivative could inhibit the growth of human metastatic melanoma cell lines, M14 and A2058. The results obtained demonstrate that this natural compound, at 12.5-50 µM concentration, was able to reduce cell viability of both cancer cells inducing cell death by intrinsic apoptotic pathway that probably involves PTEN activity, inhibition of Hsp70 expression and reactive oxygen species production. On the other hand, the increased expression of enzymes involved in polyamine catabolism trigger apoptotic cell death leading to polyamine depletion and generation of reactive oxygen species as by-products. In conclusion, these findings, starting point for further investigation, implement available our data to support pholiotic acid as an attractive potential chemopreventive agent, and provide a basis for further research into the use of this polyamine derivative as potential anticancer agent for melanoma in combination with existing therapies to improve treatment efficacy and overcome the obstacle of drug resistance.
Subject(s)
Antineoplastic Agents , Melanoma , Male , Humans , Putrescine/pharmacology , Putrescine/therapeutic use , Melanoma/pathology , Reactive Oxygen Species/metabolism , Apoptosis , Polyamines/metabolism , Polyamines/pharmacology , Polyamines/therapeutic use , Antineoplastic Agents/pharmacology , Antineoplastic Agents/therapeutic use , Cell Line, TumorABSTRACT
BACKGROUND: Immune checkpoint blockade (ICB) monotherapy provides poor survival benefit in hepatocellular carcinoma (HCC) due to ICB resistance caused by immunosuppressive tumor microenvironment (TME) and drug discontinuation resulting from immune-related side effects. Thus, novel strategies that can simultaneously reshape immunosuppressive TME and ameliorate side effects are urgently needed. METHODS: Both in vitro and orthotopic HCC models were used to explore and demonstrate the new role of a conventional, clinically used drug, tadalafil (TA), in conquering immunosuppressive TME. In detail, the effect of TA on M2 polarization and polyamine metabolism in tumor-associated macrophages (TAMs) and myeloid-derived suppressor cells (MDSCs) was identified. After making clear the aforementioned immune regulatory effect of TA, we introduced a nanomedicine-based strategy of tumor-targeted drug delivery to make better use of TA to reverse immunosuppressive TME and overcome ICB resistance for HCC immunotherapy. A dual pH-sensitive nanodrug simultaneously carrying both TA and programmed cell death receptor 1 antibody (aPD-1) was developed, and its ability for tumor-targeted drug delivery and TME-responsive drug release was evaluated in an orthotopic HCC model. Finally, the immune regulatory effect, antitumor therapeutic effect, as well as side effects of our nanodrug combining both TA and aPD-1 were analyzed. RESULTS: TA exerted a new role in conquering immunosuppressive TME by inhibiting M2 polarization and polyamine metabolism in TAMs and MDSCs. A dual pH-sensitive nanodrug was successfully synthesized to simultaneously carry both TA and aPD-1. On one hand, the nanodrug realized tumor-targeted drug delivery by binding to circulating programmed cell death receptor 1-positive T cells and following their infiltration into tumor. On the other hand, the nanodrug facilitated efficient intratumoral drug release in acidic TME, releasing aPD-1 for ICB and leaving TA-encapsulated nanodrug to dually regulate TAMs and MDSCs. By virtue of the combined application of TA and aPD-1, as well as the efficient tumor-targeted drug delivery, our nanodrug effectively inhibited M2 polarization and polyamine metabolism in TAMs and MDSCs to conquer immunosuppressive TME, which contributed to remarkable ICB therapeutic efficacy with minimal side effects in HCC. CONCLUSIONS: Our novel tumor-targeted nanodrug expands the application of TA in tumor therapy and holds great potential to break the logjam of ICB-based HCC immunotherapy.
Subject(s)
Carcinoma, Hepatocellular , Liver Neoplasms , Humans , Carcinoma, Hepatocellular/pathology , Tadalafil/pharmacology , Tadalafil/therapeutic use , Liver Neoplasms/pathology , Immune Checkpoint Inhibitors/therapeutic use , T-Lymphocytes , Immunosuppression Therapy , Polyamines/pharmacology , Polyamines/therapeutic use , Tumor MicroenvironmentABSTRACT
Chagas disease, also known as American trypanosomiasis, is a neglected tropical disease caused by the protozoa Trypanosoma cruzi, affecting nearly 7 million people only in the Americas. Polyamines are essential compounds for parasite growth, survival, and differentiation. However, because trypanosomatids are auxotrophic for polyamines, they must be obtained from the host by specific transporters. In this investigation, an ensemble of QSAR classifiers able to identify polyamine analogs with trypanocidal activity was developed. Then, a multi-template homology model of the dimeric polyamine transporter of T. cruzi, TcPAT12, was created with Rosetta, and then refined by enhanced sampling molecular dynamics simulations. Using representative snapshots extracted from the trajectory, a docking model able to discriminate between active and inactive compounds was developed and validated. Both models were applied in a parallel virtual screening campaign to repurpose known drugs as anti-trypanosomal compounds inhibiting polyamine transport in T. cruzi. Montelukast, Quinestrol, Danazol, and Dutasteride were selected for in vitro testing, and all of them inhibited putrescine uptake in biochemical assays, confirming the predictive ability of the computational models. Furthermore, all the confirmed hits proved to inhibit epimastigote proliferation, and Quinestrol and Danazol were able to inhibit, in the low micromolar range, the viability of trypomastigotes and the intracellular growth of amastigotes.
Subject(s)
Chagas Disease , Trypanocidal Agents , Trypanosoma cruzi , Humans , Putrescine/therapeutic use , Ligands , Danazol/therapeutic use , Quinestrol/therapeutic use , Polyamines/chemistry , Polyamines/therapeutic use , Chagas Disease/drug therapy , Chagas Disease/parasitology , Membrane Transport Proteins/therapeutic use , Trypanocidal Agents/pharmacology , Trypanocidal Agents/chemistryABSTRACT
Sevelamer hydrochloride (SH) and calcium carbonate (CaCO3) are two agents included in the phosphate-binding group which are frequently prescribed in the treatment of patients with hyperphosphatemia. However, there are no satisfactory studies on the genotoxic effects of SH in vitro. This study was conducted to reveal the genotoxic and/or cytotoxic potential of these two drugs in cultured human peripheral lymphocytes. Human peripheral lymphocytes were treated with SH and CaCO3 at sublethal concentrations for 24 or 48 h for micronucleus assay and 1 h in the comet assay. CaCO3 and SH stimulated a slight increase in micronucleus formation however this increase was not significant compared to the control group. According to the findings of the comet test, only one concentration of the SH caused significant DNA damage (2 mg/ml, 48 h) whereas CaCO3 did not cause important DNA breakage. No significant oxidative damage or anti-radical effect caused by test substances was observed on the pure pBR322 plasmid DNA in a cell-free medium. Also, it was found that the drugs were devoid of mutagenic activity in the Ames test, but had a weak cytotoxic effect. Both test substances, particularly SH, significantly reduced the nuclear division index compared to the control group. In conclusion, the cytotoxic effect of SH was evident on the basis of in vitro tests and slightly higher than CaCO3.
Subject(s)
Hyperphosphatemia , Kidney Failure, Chronic , Humans , Sevelamer/pharmacology , Sevelamer/therapeutic use , Hyperphosphatemia/drug therapy , Hyperphosphatemia/etiology , Calcium Carbonate/therapeutic use , Phosphates/therapeutic use , Kidney Failure, Chronic/complications , Kidney Failure, Chronic/drug therapy , Polyamines/therapeutic use , Renal Dialysis/adverse effects , CalciumABSTRACT
Identifying and leveraging unique points of metabolic dysregulation in different disease settings is vital for safe and effective incorporation of metabolism-targeted therapies in the clinic. In addition, it has been shown identification of master metabolic transcriptional regulators (MMTR) of individual metabolic pathways, and how they relate to the disease in question, may offer the key to understanding therapeutic response. In prostate cancer, we have previously demonstrated polyamine biosynthesis and the methionine cycle were targetable metabolic vulnerabilities. However, the MMTRs of these pathways, and how they affect treatment, have yet to be explored. We sought to characterize differential sensitivity of prostate cancer to polyamine- and methionine-targeted therapies by identifying novel MMTRs. We began by developing a gene signature from patient samples, which can predict response to metabolic therapy, and further uncovered a MMTR, JAZF1. We characterized the effects of JAZF1 overexpression on prostate cancer cells, basally and in the context of treatment, by assessing mRNA levels, proliferation, colony formation capability, and key metabolic processes. Lastly, we confirmed the relevance of our findings in large publicly available cohorts of prostate cancer patient samples. We demonstrated differential sensitivity to polyamine and methionine therapies and identified JAZF1 as a MMTR of this response. IMPLICATIONS: We have shown JAZF1 can alter sensitivity of cells and its expression can segregate patient populations into those that do, or do not highly express polyamine genes, leading to better prediction of response to a polyamine targeting therapy.
Subject(s)
Polyamines , Prostatic Neoplasms , Male , Humans , Polyamines/metabolism , Polyamines/therapeutic use , Prostatic Neoplasms/drug therapy , Prostatic Neoplasms/genetics , Prostatic Neoplasms/metabolism , Methionine/metabolism , Metabolic Networks and Pathways , DNA-Binding Proteins/metabolism , Co-Repressor Proteins/metabolismABSTRACT
A series of sixteen A-ring modified (2,3-indolo-, 2-benzylidene) oleanonic acid derivatives, holding some cyclic amines, linear polyamines and benzylaminocarboxamides at C28, has been synthesized and screened for antiviral activity against influenza A/PuertoRico/8/34 (H1N1) and Dengue virus serotypes of DENV-1, -2, -3, -4. It was found that 28-homopiperazine 2 and 3-N-phthalyl 22 amides of oleanonic acid demonstrated high potency with selectivity index SI 27 (IC50 21 µM) and 42 (IC50 12 µM). Oleanonic acid aminoethylpiperazine amide 6 and C-azepano-erythrodiol 23 appeared to be the most effective compounds against DENV-1 (IC50's 67 and 107 µM) and -2 (IC50's 86 and 68 µM correspondingly) serotypes.
Subject(s)
Influenza A Virus, H1N1 Subtype , Influenza, Human , Triterpenes , Humans , Polyamines/pharmacology , Polyamines/therapeutic use , Influenza, Human/drug therapy , Triterpenes/therapeutic use , Antiviral Agents/therapeutic use , Amides/therapeutic useABSTRACT
The polyamines putrescine, spermidine and spermine are nutrient-like polycationic molecules involved in metabolic processes and signaling pathways linked to cell growth and cancer. One important pathway is the PI3K/Akt pathway where studies have shown that polyamines mediate downstream growth effects. Downstream of PI3K/Akt is the mTOR signaling pathway, a nutrient-sensing pathway that regulate translation initiation through 4EBP1 and p70S6K phosphorylation and, along with the PI3K/Akt, is frequently dysregulated in breast cancer. In this study, we investigated the effect of intracellular polyamine modulation on mTORC1 downstream protein and general translation state in two breast cancer cell lines, MCF-7 and MDA-MB-231. The effect of mTORC1 pathway inhibition on the growth and intracellular polyamines was also measured. Results showed that polyamine modulation alters 4EBP1 and p70S6K phosphorylation and translation initiation in the breast cancer cells. mTOR siRNA gene knockdown also inhibited cell growth and decreased putrescine and spermidine content. Co-treatment of inhibitors of polyamine biosynthesis and mTORC1 pathway induced greater cytotoxicity and translation inhibition in the breast cancer cells. Taken together, these data suggest that polyamines promote cell growth in part through interaction with mTOR pathway. Similarly intracellular polyamine content appears to be linked to mTOR pathway regulation. Finally, dual inhibition of polyamine and mTOR pathways may provide therapeutic benefits in some breast cancers.
Subject(s)
Breast Neoplasms , Polyamines , Breast Neoplasms/drug therapy , Breast Neoplasms/metabolism , Female , Humans , Mechanistic Target of Rapamycin Complex 1 , Phosphatidylinositol 3-Kinases , Polyamines/metabolism , Polyamines/therapeutic use , Proto-Oncogene Proteins c-akt , Putrescine/metabolism , Putrescine/therapeutic use , RNA, Small Interfering/therapeutic use , Ribosomal Protein S6 Kinases, 70-kDa/therapeutic use , Spermidine/metabolism , Spermidine/pharmacology , Spermidine/therapeutic use , Spermine/metabolism , Spermine/pharmacology , Spermine/therapeutic use , TOR Serine-Threonine Kinases/therapeutic useABSTRACT
The biogenic aliphatic polyamines (spermine, spermidine, and putrescine) are responsible for numerous cell functions, including cell proliferation, the stabilization of nucleic acid conformations, cell division, homeostasis, gene expression, and protein synthesis in living organisms. The change of polyamine concentrations in the urine or blood is usually related to the presence of malignant tumors and is regarded as a biomarker for the early diagnosis of cancer. Therefore, the detection of polyamine levels in physiological fluids can provide valuable information in terms of cancer diagnosis and in monitoring therapeutic effects. In this review, we summarize the recent advances in fluorescent methods for polyamine detection (supramolecular fluorescent sensing systems, fluorescent probes based on the chromophore reaction, fluorescent small molecules, and fluorescent nanoparticles). In addition, tumor polyamine-suppressing strategies (such as polyamine conjugate, polyamine analogs, combinations that target multiple components, spermine-responsive supramolecular chemotherapy, a combination of polyamine consumption and photodynamic therapy, etc.) are highlighted. We hope that this review promotes the development of more efficient polyamine detection methods and provides a comprehensive understanding of polyamine-based tumor suppressor strategies.
Subject(s)
Neoplasms , Polyamines , Humans , Neoplasms/diagnosis , Neoplasms/drug therapy , Neoplasms/pathology , Polyamines/metabolism , Polyamines/therapeutic use , Putrescine/metabolism , Putrescine/therapeutic use , Spermidine/metabolism , Spermidine/therapeutic use , Spermine/metabolism , Spermine/therapeutic useABSTRACT
Leishmaniasis is a neglected tropical disease widely distributed worldwide, caused by parasitic protozoa of the genus Leishmania. Despite representing a significant public health problem, the therapeutic options are old, with several reported adverse effects, have high costs, with administration mainly by parenteral route, which makes treatment difficult, increasing dropout and, consequently, the emergence of resistant strains. Thus, the research and development of new antileishmanial therapies become necessary. In this field, inhibiting essential targets that affect the parasite's growth, survival, and infectivity represents an attractive therapeutic strategy. With this in mind, this review addresses the main structural, functional characteristics and recent reports of the discovery of promising inhibitors of the enzymes Arginase (ARG) and trypanothione synthase (TryS), which are involved in the biosynthesis of polyamines and trypanothione and Trypanothione Reductase (TR), responsible for the reduction of trypanothione thiol.
Subject(s)
Antiprotozoal Agents , Leishmania , Leishmaniasis , Humans , Leishmaniasis/drug therapy , Leishmaniasis/parasitology , Polyamines/pharmacology , Polyamines/therapeutic use , Antiprotozoal Agents/pharmacology , Antiprotozoal Agents/therapeutic use , Antiprotozoal Agents/chemistry , Drug DiscoveryABSTRACT
Ovarian cancer accounts for 3% of the total cancers in women, yet it is the fifth leading cause of cancer deaths among women. The BRCA1/2 germline and somatic mutations confer a deficiency of the homologous recombination (HR) repair pathway. Inhibitors of poly (ADP-ribose) polymerase (PARP), another important component of DNA damage repair, are somewhat effective in BRCA1/2 mutant tumors. However, ovarian cancers often reacquire functional BRCA and develop resistance to PARP inhibitors. Polyamines have been reported to facilitate the DNA damage repair functions of PARP. Given the elevated levels of polyamines in tumors, we hypothesized that treatment with the polyamine synthesis inhibitor, α-difluoromethylornithine (DFMO), may enhance ovarian tumor sensitivity to the PARP inhibitor, rucaparib. In HR-competent ovarian cancer cell lines with varying sensitivities to rucaparib, we show that co-treatment with DFMO increases the sensitivity of ovarian cancer cells to rucaparib. Immunofluorescence assays demonstrated that, in the presence of hydrogen peroxide-induced DNA damage, DFMO strongly inhibits PARylation, increases DNA damage accumulation, and reduces cell viability in both HR-competent and deficient cell lines. In vitro viability assays show that DFMO and rucaparib cotreatment significantly enhances the cytotoxicity of the chemotherapeutic agent, cisplatin. These results suggest that DFMO may be a useful adjunct chemotherapeutic to improve the anti-tumor efficacy of PARP inhibitors in treating ovarian cancer.
Subject(s)
Antineoplastic Agents , Ovarian Neoplasms , Poly(ADP-ribose) Polymerase Inhibitors , Antineoplastic Agents/pharmacology , Antineoplastic Agents/therapeutic use , Eflornithine/pharmacology , Eflornithine/therapeutic use , Female , Humans , Ovarian Neoplasms/drug therapy , Ovarian Neoplasms/genetics , Ovarian Neoplasms/pathology , Poly(ADP-ribose) Polymerase Inhibitors/pharmacology , Poly(ADP-ribose) Polymerase Inhibitors/therapeutic use , Poly(ADP-ribose) Polymerases/metabolism , Polyamines/pharmacology , Polyamines/therapeutic useABSTRACT
Bladder cancer has a high incidence worldwide accompanies by high recurrent rate after treatment. The emergence of primary or acquired chemotherapy resistance leads to poor efficacy in many cases. To explore the underlying mechanisms of drug resistance, we firstly established a drug-resistant cell model T24/THP by repeated exposure of T24 cells to pirarubicin (THP) whose concentration increases gradually. Non-targeted metabolomics was performed to identify metabolic changes and key metabolism pathways variance in T24/THP cells. Pathway enrichment analysis demonstrated that the arginine and proline metabolic pathway was the most significantly changed pathway, where two representative members of polyamine, putrescine and spermidine were remarkably down regulated in T24/THP. Subsequent experiments further confirmed that ornithine decarboxylase (ODC1) and spermidine synthase (SRM), the key enzymes involved in the synthesis of these compounds, also showed a stable low expression in T24/THP. However, knocking down of ODC1 and SRM sensitized cells to chemotherapy treatment while overexpression of these two enzymes enhances chemotherapy resistance. This leaded to the point that ODC1 and SRM themselves are more likely to promote the drug resistance, which appears to contradict their low expression in T24/THP. We hypothesize that their diminished levels were due to the declined activity of genes upstream. According to this line of thought, we found that c-MYC was also down-regulated in T24/THP and its content could be significantly affected by drug administration. In addition, c-MYC could not only regulate the expression levels of ODC1 and SRM but also influence drug resistance in T24/THP. In conclusion, alterations in gene expression of ODC1 and SRM in drug resistance cell line is probably mediated by some upstream regulators rather than antineoplastic agents alone. Exploration of upstream signals and research on detailed regulatory mechanism, thereby understanding the actual role of c-MYC and polyamine in response to chemotherapy, can become a potential field direction to overcome drug resistance in bladder cancer.
Subject(s)
Urinary Bladder Neoplasms , Dicarboxylic Acid Transporters , Drug Resistance, Multiple , Genes, myc , Humans , Metabolomics , Mitochondrial Membrane Transport Proteins , Polyamines/metabolism , Polyamines/therapeutic use , Proto-Oncogene Proteins c-myc , Urinary Bladder Neoplasms/drug therapy , Urinary Bladder Neoplasms/genetics , Urinary Bladder Neoplasms/metabolismABSTRACT
Deregulated polyamine biosynthesis is emerging as a common feature of neuroblastoma and drugs targeting this metabolic pathway such as DFMO are in clinical and preclinical development. The polyamine analog verlindamycin inhibits the polyamine biosynthesis pathway enzymes SMOX and PAOX, as well as the histone demethylase LSD1. Based on our previous research in acute myeloid leukemia (AML), we reasoned verlindamycin may also unblock neuroblastoma differentiation when combined with all-trans-retinoic acid (ATRA). Indeed, co-treatment with verlindamycin and ATRA strongly induced differentiation regardless of MYCN status, but in MYCN-expressing cells, protein levels were strongly diminished. This process was not transcriptionally regulated but was due to increased degradation of MYCN protein, at least in part via ubiquitin-independent, proteasome-dependent destruction. Here we report that verlindamycin effectively induces the expression of functional tumor suppressor-antizyme via ribosomal frameshifting. Consistent with previous results describing the function of antizyme, we found that verlindamycin treatment led to the selective targeting of ornithine decarboxylase (the rate-limiting enzyme for polyamine biosynthesis) as well as key oncoproteins, such as cyclin D and Aurora A kinase. Retinoid-based multimodal differentiation therapy is one of the few interventions that extends relapse-free survival in MYCN-associated high-risk neuroblastoma and these results point toward the potential use of verlindamycin in this regimen.
Subject(s)
Biguanides , Neuroblastoma , Biguanides/therapeutic use , Humans , N-Myc Proto-Oncogene Protein/genetics , N-Myc Proto-Oncogene Protein/therapeutic use , Neuroblastoma/drug therapy , Neuroblastoma/metabolism , Ornithine Decarboxylase/metabolism , Ornithine Decarboxylase/therapeutic use , Polyamines/metabolism , Polyamines/therapeutic useABSTRACT
A pharmacophore integration strategy was utilized to develop the first co-donor of formaldehyde and nitric oxide (FANO), composed of urotropine derived nitramine/nitrosamine. FANO simultaneously generated formaldehyde and nitric oxide on-demand, resulting in synergistic anticancer effects. Importantly, liposomal formulation of FANO effectively inhibited tumor growth with minimal side-effects, providing a potent combined nitric oxide therapy for malignancy.
Subject(s)
Antineoplastic Agents/therapeutic use , Formaldehyde/metabolism , Neoplasms/drug therapy , Nitric Oxide Donors/therapeutic use , Nitric Oxide/metabolism , Polyamines/therapeutic use , Animals , Antineoplastic Agents/chemical synthesis , Apoptosis/drug effects , Cell Line, Tumor , Cell Proliferation/drug effects , Dose-Response Relationship, Drug , Drug Carriers/chemistry , Liposomes/chemistry , Methenamine/chemistry , Mice , Nitric Oxide Donors/chemical synthesis , Nitrosamines/chemical synthesis , Nitrosamines/therapeutic use , Polyamines/chemical synthesisABSTRACT
BACKGROUND: Glioblastoma multiforme (GBM) is the most common and fatal type of glioma. Nanoparticles (NPs) are used in new approaches for the delivery of gene therapy in the treatment of GBM. INTRODUCTION: The purpose of this article was to review the efficacy of NPs as the targeted carriers in the gene therapy aimed at apoptosis in GBM. METHODS: The appropriate keywords such as nanoparticle, glioblastoma, gene therapy, apoptosis, and related words were used to search from PubMed, ISI Web of Science, and Scopus for relevant publications up to September 4, 2020, with no language restrictions. The present systematic review was performed based on PRISMA protocol and reviewed the articles evaluating the effects of nanoparticles, carriers of various gene therapies essentials, on GBM cells apoptosis in vitro and in vivo. The selected articles were considered using specific scores on the quality of the articles. Data extraction and quality evaluation were performed by two reviewers. RESULTS: Of 101 articles retrieved, forty-two met the inclusion criteria and were, therefore, subjected to the final deduction. The most widely used NP in GBM gene therapy studies is polyamidoamine (PAMAM). The most common gene therapy approach for apoptosis in GBM is using siRNAs. CONCLUSION: In conclusion, these studies validated that NPs could be a practical choice to enhance the efficiency and specific delivery in gene therapies for GBM cell apoptosis. However, the choice of NP type and gene therapy mechanism affect the GBM cell apoptotic efficiency.
Subject(s)
Apoptosis , Genetic Therapy/methods , Glioblastoma/therapy , Nanoparticles/therapeutic use , Polyamines/therapeutic use , RNA, Small Interfering/therapeutic use , Animals , Humans , Treatment OutcomeABSTRACT
Diffuse intrinsic pontine glioma (DIPG) is an incurable malignant childhood brain tumor, with no active systemic therapies and a 5-year survival of less than 1%. Polyamines are small organic polycations that are essential for DNA replication, translation and cell proliferation. Ornithine decarboxylase 1 (ODC1), the rate-limiting enzyme in polyamine synthesis, is irreversibly inhibited by difluoromethylornithine (DFMO). Herein we show that polyamine synthesis is upregulated in DIPG, leading to sensitivity to DFMO. DIPG cells compensate for ODC1 inhibition by upregulation of the polyamine transporter SLC3A2. Treatment with the polyamine transporter inhibitor AMXT 1501 reduces uptake of polyamines in DIPG cells, and co-administration of AMXT 1501 and DFMO leads to potent in vitro activity, and significant extension of survival in three aggressive DIPG orthotopic animal models. Collectively, these results demonstrate the potential of dual targeting of polyamine synthesis and uptake as a therapeutic strategy for incurable DIPG.
Subject(s)
Biological Transport/drug effects , Brain Stem Neoplasms/drug therapy , Diffuse Intrinsic Pontine Glioma/drug therapy , Polyamines/metabolism , Polyamines/pharmacology , Animals , Cell Death/drug effects , Cell Line, Tumor , Cell Proliferation/drug effects , DNA Replication/drug effects , Dicarboxylic Acid Transporters , Disease Models, Animal , Eflornithine/pharmacology , Eflornithine/therapeutic use , Female , Gene Expression Regulation, Neoplastic/drug effects , Humans , Mice , Mice, Inbred BALB C , Mice, Nude , Mitochondrial Membrane Transport Proteins , Ornithine Decarboxylase/drug effects , Ornithine Decarboxylase/metabolism , Polyamines/therapeutic useABSTRACT
BRAF mutations are present in over half of all melanoma tumors. Although BRAF inhibitors significantly improve survival of patients with metastatic melanoma, recurrences occur within several months. We previously reported that BRAF mutant melanoma cells are more sensitive to a novel arylmethyl-polyamine (AP) compound that exploits their increased polyamine uptake compared to that of BRAF wildtype cells. Using an animal model of BRAF inhibitor-resistant melanoma, we show that co-treatment with the BRAF inhibitor, PLX4720, and AP significantly delays the recurrence of PLX4720-resistant melanoma tumors and decreases tumor-promoting macrophages. Development of BRAF inhibitor-resistance enriches for metastatic cancer stem cells (CSC) and increases tumor-promoting macrophages. In vitro studies demonstrated that CD304+, CXCR4+ spheroid cultures of BRAF mutant melanoma cells are resistant to PLX4720 but are more sensitive to AP compared to monolayer cultures of the same cells. AP significantly inhibited YUMM1.7 melanoma cell invasiveness across a Matrigel-coated filter using the CXCR4 ligand, SDF-1α, as the chemoattractant. AP also blocked the chemotactic effect of SDF-1α on CXCR4+ macrophages and inhibited M2 polarization of macrophages. In melanoma-macrophage co-cultures, AP prevented the PLX4720-induced release of pro-tumorigenic growth factors, such as VEGF, from macrophages and prevented the macrophage rescue of BRAF mutant melanoma cells treated with PLX4720. Our study offers a novel therapy (AP) to treat chemo-resistant melanoma. AP is unique because it targets the polyamine transport system in BRAF inhibitor-resistant CSCs and also blocks CXCR4 signaling in invasive melanoma cells and pro-tumorigenic macrophages.
Subject(s)
Drug Resistance, Neoplasm/genetics , Melanoma/genetics , Polyamines/therapeutic use , Proto-Oncogene Proteins B-raf/metabolism , Animals , Disease Models, Animal , Humans , Mice , Mutation , Polyamines/pharmacologyABSTRACT
A series consisting of new polyaminoisoprenyl derivatives were prepared in moderate to good chemical yields varying from 32 to 64% according to two synthetic pathways: (1) using a titanium-reductive amination reaction affording a 50/50 mixture of cis and trans isomers and (2) a direct nucleophilic substitution leading to a stereoselective synthesis of the compounds of interest. These compounds were then successfully evaluated for their in vitro antibiotic enhancer properties against resistant Gram-negative bacteria of four antibiotics belonging to four different families. The mechanism of action against Enterobacter aerogenes of one of the most efficient of these chemosensitizing agents was precisely evaluated by using fluorescent dyes to measure outer-membrane permeability and to determine membrane depolarization. The weak cytotoxicity encountered led us to perform an in vivo experiment dealing with the treatment of mice infected with Salmonella typhimurium and affording preliminary promising results in terms of tolerance and efficiency of the polyaminoisoprenyl derivative 5r/doxycycline combination.
Subject(s)
Anti-Bacterial Agents/therapeutic use , Enterobacter/drug effects , Polyamines/therapeutic use , Salmonella Infections, Animal/drug therapy , Salmonella/drug effects , Terpenes/therapeutic use , Animals , Anti-Bacterial Agents/chemical synthesis , Anti-Bacterial Agents/toxicity , Cell Membrane/drug effects , Cell Membrane Permeability/drug effects , Drug Resistance, Multiple, Bacterial/drug effects , Mice , Microbial Sensitivity Tests , Polyamines/chemical synthesis , Polyamines/toxicity , Terpenes/chemical synthesis , Terpenes/toxicityABSTRACT
Retinal ganglion cell (RGC) loss and optic neuropathy, both hallmarks of glaucoma, have been shown to involve N-methyl-D-aspartate receptor (NMDAR)-mediated excitotoxicity. This study investigated the neuroprotective effects of Philanthotoxin (PhTX)-343 in NMDA-induced retinal injury to alleviate ensuing visual impairments. Sprague-Dawley rats were divided into three; Group I was intravitreally injected with phosphate buffer saline as the control, Group II was injected with NMDA (160 nM) to induce retinal excitotoxic injury, while Group III was injected with PhTX-343 (160 nM) 24 h prior to excitotoxicity induction with NMDA. Rats were subjected to visual behaviour tests seven days post-treatment and subsequently euthanized. Rat retinas and optic nerves were subjected to H&E and toluidine blue staining, respectively. Histological assessments showed that NMDA exposure resulted in significant loss of retinal cell nuclei and thinning of ganglion cell layer (GCL). PhTX-343 pre-treatment prevented NMDA-induced changes where the RGC layer morphology is similar to the control. The numbers of nuclei in the NMDA group were markedly lower compared to the control (p<0.05). PhTX-343 group had significantly higher numbers of nuclei within 100 µm length and 100 µm2 area of GCL (2.9- and 1.7-fold, respectively) compared to NMDA group (p<0.05). PhTX-343 group also displayed lesser optic nerve fibres degeneration compared to NMDA group which showed vacuolation in all sections. In the visual behaviour test, the NMDA group recorded higher total distance travelled, and lower total immobile time and episodes compared to the control and PhTX-343 groups (p<0.05). Object recognition tests showed that the rats in PhTX-343 group could recognize objects better, whereas the same objects were identified as novel by NMDA rats despite multiple exposures (p<0.05). Visual performances in the PhTX-343 group were all comparable with the control (p>0.05). These findings suggested that PhTX-343 inhibit retinal cell loss, optic nerve damage, and visual impairments in NMDA-induced rats.
Subject(s)
Neuroprotective Agents , Optic Nerve Injuries/drug therapy , Optic Nerve/drug effects , Phenols , Polyamines , Retinal Ganglion Cells/drug effects , Animals , Male , N-Methylaspartate/toxicity , Neuroprotective Agents/pharmacology , Neuroprotective Agents/therapeutic use , Optic Nerve/pathology , Optic Nerve Injuries/chemically induced , Phenols/pharmacology , Phenols/therapeutic use , Polyamines/pharmacology , Polyamines/therapeutic use , Rats , Rats, Sprague-Dawley , Retinal Ganglion Cells/pathology , Vision, Ocular/drug effectsABSTRACT
Treatment of triple-negative breast carcinoma (TNBC) remains an unmet medical need with no targeted therapy available to date. Accounting for 10-30% of all human breast cancer tumors, this mammary carcinoma subtype has a particularly poor prognosis owing to its high metastatic potential, aggressive biology and limited pharmacological treatment options. Platinum chemotherapeutics are the mainstay therapy in patients with TNBC but their clinical use is limited by severe toxicity and acquired resistance. Palladium-based complexes are appealing alternative metal-based drugs because of significant similarities regarding structure and coordination chemistry with the platinum agents. This review summarizes the knowledge gathered so far on 121 Pd(II) complexes, emphasizing their anticancer activity and putative pharmacological targets toward TNBC.