ABSTRACT
CXCR1/2 biomolecules play vital roles in cancer cell proliferation, tumor inflammation, and angiogenesis, making them attractive drug targets. In clear cell renal cell carcinoma (RCC) and head and neck squamous cell carcinoma (HNSCC), where CXCR1/2 is overexpressed, inhibition studies are limited. Building upon previous research efforts, we investigated new N,N'-diarylurea analogues as ELR+CXCL-CXCR1/2 inhibitors. Evaluations on RCC and HNSCC cell lines and 3D spheroid cultures identified compound 10 as a lead molecule, exhibiting significant inhibition of invasion, migration, and neo-angiogenesis. It demonstrated strong interference with the signaling pathway, with high selectivity toward kinases. In vivo studies on zebrafish embryos and RCC xenografted mice showed notable anticancer, antimetastatic, and antiangiogenic effects after oral administration and minimal toxicity. Compound 10 emerges as a promising candidate for further preclinical development as an oral anticancer and antiangiogenic drug targeting the ELR+CXCL-CXCR1/2 pathway.
ABSTRACT
This work investigated elemental sulfur (S0) biorecovery from Phosphogypsum (PG) using sulfur-oxidizing bacteria in an O2-based membrane biofilm reactor (MBfR). The system was first optimized using synthetic sulfide medium (SSM) as influent, then switched to biogenic sulfide medium (BSM) generated by biological reduction of PG alkaline leachate. The results using SSM had high sulfide-oxidation efficiency (98 %), sulfide to S0 conversion (â¼90 %), and S0 production rate up to 2.7 g S0/(m2.d), when the O2/S ratio was â¼0.5 g O2/g S. With the BSM influent, the system maintained high sulfide-to-S0 conversion rate (97 %), and S0-production rate of 1.6 g S0/(m2.d). Metagenomic analysis revealed that Thauera was the dominant genus in SSM and BSM biofilms. Furthermore, influent composition affected the bacterial community structure and abundances of functional microbial sulfur genes, modifying the sulfur-transformation pathways in the biofilms. Overall, this work shows promise for O2-MBfR usage in S0 biorecovery from PG-leachate and other sulfidogenic effluents.
Subject(s)
Biofilms , Bioreactors , Calcium Sulfate , Oxygen , Phosphorus , Sulfur , Bioreactors/microbiology , Sulfur/metabolism , Oxygen/metabolism , Calcium Sulfate/chemistry , Membranes, Artificial , Metagenomics/methods , Bacteria/metabolism , Bacteria/genetics , Sulfides , Oxidation-ReductionABSTRACT
BACKGROUND: In clear cell renal cell carcinoma (ccRCC), first-line treatment combines nivolumab (anti-PD-1) and ipilimumab (anti-CTLA4), yielding long-term remissions but with only a 40% success rate. Our study explored the potential of enhancing ccRCC treatment by concurrently using CXCR2 inhibitors alongside immunotherapies. METHODS: We analyzed ELR + CXCL levels and their correlation with patient survival during immunotherapy. RCT001, a unique CXCR2 inhibitor, was examined for its mechanism of action, particularly its effects on human primary macrophages. We tested the synergistic impact of RCT001 in combination with immunotherapies in both mouse models of ccRCC and human ccRCC in the presence of human PBMC. RESUTS: Elevated ELR + CXCL cytokine levels were found to correlate with reduced overall survival during immunotherapy. RCT001, our optimized compound, acted as an inverse agonist, effectively inhibiting angiogenesis and reducing viability of primary ccRCC cells. It redirected M2-like macrophages without affecting M1-like macrophage polarization directed against the tumor. In mouse models, RCT001 enhanced the efficacy of anti-CTLA4 + anti-PD1 by inhibiting tumor-associated M2 macrophages and tumor-associated neutrophils. It also impacted the activation of CD4 T lymphocytes, reducing immune-tolerant lymphocytes while increasing activated natural killer and dendritic cells. Similar effectiveness was observed in human RCC tumors when RCT001 was combined with anti-PD-1 treatment. CONCLUSIONS: RCT001, by inhibiting CXCR2 through its unique mechanism, effectively suppresses ccRCC cell proliferation, angiogenesis, and M2 macrophage polarization. This optimization potentiates the efficacy of immunotherapy and holds promise for significantly improving the survival prospects of metastatic ccRCC patients.
Subject(s)
Carcinoma, Renal Cell , Kidney Neoplasms , Animals , Mice , Humans , Carcinoma, Renal Cell/drug therapy , Kidney Neoplasms/drug therapy , Kidney Neoplasms/pathology , Drug Inverse Agonism , Leukocytes, Mononuclear/pathology , ImmunotherapyABSTRACT
Phosphogypsum (PG) is an industrial by-product of the transformation of phosphate rocks. For decades, PG has been a source of environmental concern due to the massive amount produced thus far, i.e., 7 billion tons, with a current production rate of 200-280 million tons per year. Phosphate minerals contain various impurities that precipitate and concentrate within PG. These impurities hinder PG usability in various sectors. This paper aims to purify PG using an innovative process based on staged valorization of PG. Initially, PG dissociation by ethylenediaminetetraacetic acid (EDTA) was optimized. After screening of different parameters and monitoring the ionic conductivity of solutions, it was disclosed that a pH-dependent solubilization process in the presence of EDTA resulted in high solubility of PG, up to 11.82 g/100 mL at pH > 11. Subsequently, a recovery of the purified PG by selective precipitation of calcium sulfate dihydrate (CSD) from obtained filtrate through pH adjustment to 3.5 were investigated. An abatement of 99.34% Cr, 97.15% Cd, 95.73% P2O5, 92.75% Cu, 92.38% Al2O3, 91.16% Ni, 74.58% Zn, 72.75% F, 61.43% MgO, 58.8% Fe2O3, 56.97% K2O, and 55.41% Ba was achieved. The process relied on the variation of EDTA chelation properties towards monovalent, divalent, and trivalent cations at different pHs. According to the findings of this study, a staged purification process in the presence of EDTA is an effective method for removing impurities from the industrial PG.
Subject(s)
Calcium Sulfate , Phosphorus , Calcium Sulfate/chemistry , Edetic Acid , Phosphorus/chemistry , PhosphatesABSTRACT
Amidinoureas are an understudied class of molecules with unique structural properties and biological activities. A simple methodology has been developed for the synthesis of aliphatic substituted amidinoureas via unexpected cycle opening of benzothiazolo-1,3,5-triazine-2-ones and transamination reaction of N-(N-(benzo[d]thiazol-2-yl)carbamimidoyl)aniline-1-carboxamide in good yields. A novel series of amidinoureas derivatives was designed, synthesized, and evaluated for its antiproliferative activity on an aggressive metastatic melanoma A375â cell line model. This evaluation reveals antiproliferative activities in the low micromolar range and establishes a first structure-activity relationship. In addition, analogues selected for their structural diversity were assayed on a panel of cancer cell lines through the DTP-NCI60, on which they showed effectiveness on various cancer types, with promising activities on melanoma cells for two hit compounds. This work paves the way for further optimization of this family of compounds towards the development of potent antimelanoma agents.
Subject(s)
Antineoplastic Agents , Guanidine/analogs & derivatives , Melanoma , Urea/analogs & derivatives , Humans , Cell Line, Tumor , Antineoplastic Agents/chemistry , Triazines/chemistry , Structure-Activity Relationship , Cell Proliferation , Drug Screening Assays, Antitumor , Molecular StructureABSTRACT
The therapeutic management of age-related macular degeneration (AMD) is a major public health issue. One of its two late forms, neovascular AMD, is currently treated by intravitreal injections of pharmaceutical active ingredients. Although it is very effective in treating pathologies of the posterior segment of the eye, the intravitreal route is not an ideal option for the long-term management of a chronic disease such as AMD. Indeed, in the literature, some authors even call it a "burden" for the practitioners, the patients and the healthcare system. Thus, consideration should be given to less invasive routes. Among the possible administration routes to reach the posterior segment of the eye, the most suitable for the patient with the least risk of systemic adverse effects is the topical route. Several research teams have attempted to formulate molecules for topical administration in the treatment of atrophic or neovascular AMD. In this review, we emphasize the importance of the pharmaceutical formulation to meet the challenge of targeting the posterior segment of the eye by a topical route.
Title: Traitement topique de la dégénérescence maculaire liée à l'âge - Où en sommes-nous ? Abstract: La prise en charge thérapeutique de la dégénérescence maculaire liée à l'âge (DMLA) est un enjeu majeur de santé publique. L'une de ses deux formes tardives, la DMLA néovasculaire, est actuellement traitée par injection intravitréenne de molécules anti-angiogéniques. Bien qu'elle soit très efficace pour traiter les atteintes du segment postérieur de l'Åil, la voie intravitréenne n'est pas une option idéale pour la prise en charge au long cours d'une maladie chronique telle que la DMLA. L'administration topique de molécules actives contre cette maladie, plus confortable pour le patient et moins coûteuse pour la société, représente un vrai défi.
Subject(s)
Angiogenesis Inhibitors , Wet Macular Degeneration , Humans , Vascular Endothelial Growth Factor A , Visual Acuity , Administration, TopicalABSTRACT
The search for new classes of antibiotics is a real concern of public health due to the emergence of multi-resistant bacteria strains. We report herein the synthesis and characterization of a new series of 13 molecules combining isoxazoline/isoxazole sulfonamides and hydrazides motives. These molecules were obtained according to a costless eco-friendly procedure, and a one-pot three-step cascade synthesis under ultrasonic cavitation. All the synthesized compounds were fully characterized by HRMS, 1H NMR, 13C NMR spectroscopy and HPLC analysis. These new molecules have been evaluated against the major human opportunistic pathogen Pseudomonas aeruginosa to determine their potential to affect its growth and biofilm formation or dispersion. Two derivatives (5a and 6a) demonstrated their ability to destabilize a mature biofilm by about 50 % within 24 h. This may pave the way to the development of a new class of compounds affecting biofilm, which are easy to synthesize according to green chemistry processes.
Subject(s)
Biofilms , Pseudomonas aeruginosa , Humans , Anti-Bacterial Agents/pharmacology , Anti-Bacterial Agents/chemistry , Sulfanilamide , Sulfonamides/pharmacologyABSTRACT
Phosphogypsum (PG), a by-product of the phosphate industry, is high in sulfate, (SO42-), which makes it an excellent substrate for sulfate-reducing bacteria (SRB) to produce hydrogen sulfide. This work aimed to optimize SO42- leaching from PG to achieve a high biological reduction of SO42- and generate high sulfide concentrations for subsequent use in the biological recovery of elemental sulfur. Five SRB consortia were isolated and enriched from: IS (Industrial sludges), MS (Marine sediments), WC (Winogradsky column), SNV (petroleum industry sediments) and PG (stored Phosphogypsum). The five consortia showed reduction activity when using PG leachate (with water) as source of SO42- and lactate, acetate, or glucose as the electron donor. The highest reduction rate (81.5 %) was registered using lactate and the IS consortium (81.5 %) followed by MS (79 %) and PG (71 %). To enhance the concentration of leached SO42- from PG for future utilization with the isolated consortia, PG was treated with NaOH solutions (2 % and 5 %). SO42- release of 97 % was achieved with a 5 % concentration and the resulting leachate was further diluted to target a SO42- concentration of 12.4 g·L-1 for utilization with the isolated consortia. Compared to water leachate, a significantly higher reduction rate was registered (2 g·L-1 of SO42) using the IS consortium, demonstrating limited inhibition effect of sulfide- concentration on SRB functionalities. Moreover, metagenomic analysis of the consortia revealed that using PG as a source of SO42- increased the abundance of Deltaproteobacteria, including known SRB like Desulfovibrio, Desulfomicrobium, and Desulfosporosinus, as well as novel SRB genera (Cupidesulfovibrio, Desulfocurvus, Desulfococcus) that showed, for the first time, significant potential as novel sulfate-reducers using PG as a SO42- source.
Subject(s)
Desulfovibrio , Sulfates , Sulfates/chemistry , Anaerobiosis , Bacteria , Water , Sulfides , Lactates , Oxidation-ReductionABSTRACT
The role of metrology in the industrial and manufacturing sectors is of paramount importance to ensure informed decision-making whether for product quality control, process monitoring and R&D activities. However, to guarantee the quality and reliability of analytical measurements, the development and use of appropriate reference materials (CRMs) is essential. In particular, certified reference materials (CRMs) are extensively used to validate analytical methods in a multitude of applications, measure uncertainty, improve the accuracy of measurement data, as well as to establish the meteorological traceability of analytical results. In this paper, we report the improvement of the characterization uncertainty of an in-house matrix reference material by direct determination of the concentration of fluorosilicic acid recovered from the fertilizers production industry. The certified reference material was characterized by the potentiometric method as a novel and direct approach for the determination of H2SiF6 concentration and the results were compared against a reference measurement procedure based on molecular absorption spectrophotometry (UV-VIS). The approach adopted in the work resulted in the improvement of the uncertainty of the CRM by decreasing the characterization uncertainty, which constitutes the major contribution to the overall uncertainty. The newly obtained characterization combined standard uncertainty was 2.0 g.kg-1, which gives an expanded uncertainty (k = 2 with a confidence interval of 95%) of the CRM of 6.3 g.kg-1 instead of 11.7 g.kg-1 reported in previous works. This improved CRM can be used to improve the uncertainty of the analytical methods used for the determination of H2SiF6 mass fraction and, therefore, to improve the accuracy of measurement data.
ABSTRACT
The recent advancement in the human glycome and progress in the development of an inclusive network of glycosylation pathways allow the incorporation of suitable machinery for protein modification in non-natural hosts and explore novel opportunities for constructing next-generation tailored glycans and glycoconjugates. Fortunately, the emerging field of bacterial metabolic engineering has enabled the production of tailored biopolymers by harnessing living microbial factories (prokaryotes) as whole-cell biocatalysts. Microbial catalysts offer sophisticated means to develop a variety of valuable polysaccharides in bulk quantities for practical clinical applications. Glycans production through this technique is highly efficient and cost-effective, as it does not involve expensive initial materials. Metabolic glycoengineering primarily focuses on utilizing small metabolite molecules to alter biosynthetic pathways, optimization of cellular processes for glycan and glycoconjugate production, characteristic to a specific organism to produce interest tailored glycans in microbes, using preferably cheap and simple substrate. However, metabolic engineering faces one of the unique challenges, such as the need for an enzyme to catalyze desired substrate conversion when natural native substrates are already present. So, in metabolic engineering, such challenges are evaluated, and different strategies have been developed to overcome them. The generation of glycans and glycoconjugates via metabolic intermediate pathways can still be supported by glycol modeling achieved through metabolic engineering. It is evident that modern glycans engineering requires adoption of improved strain engineering strategies for creating competent glycoprotein expression platforms in bacterial hosts, in the future. These strategies include logically designing and introducing orthogonal glycosylation pathways, identifying metabolic engineering targets at the genome level, and strategically improving pathway performance (for example, through genetic modification of pathway enzymes). Here, we highlight current strategies, applications, and recent progress in metabolic engineering for producing high-value tailored glycans and their applications in biotherapeutics and diagnostics.
Subject(s)
Biological Products , Humans , Biological Products/metabolism , Polysaccharides/chemistry , Glycosylation , Glycoconjugates/genetics , Glycoconjugates/metabolism , Metabolic Engineering/methods , Bacteria/geneticsABSTRACT
Targeted therapies have revolutionized cancer chemotherapy. Unfortunately, most patients develop multifocal resistance to these drugs within a matter of months. Here, we used a high-throughput phenotypic small molecule screen to identify MCB-613 as a compound that selectively targets EGFR-mutant, EGFR inhibitor-resistant non-small cell lung cancer (NSCLC) cells harboring diverse resistance mechanisms. Subsequent proteomic and functional genomic screens involving MCB-613 identified its target in this context to be KEAP1, revealing that this gene is selectively essential in the setting of EGFR inhibitor resistance. In-depth molecular characterization demonstrated that (1) MCB-613 binds KEAP1 covalently; (2) a single molecule of MCB-613 is capable of bridging two KEAP1 monomers together; and, (3) this modification interferes with the degradation of canonical KEAP1 substrates such as NRF2. Surprisingly, NRF2 knockout sensitizes cells to MCB-613, suggesting that the drug functions through modulation of an alternative KEAP1 substrate. Together, these findings advance MCB-613 as a new tool for exploiting the selective essentiality of KEAP1 in drug-resistant, EGFR-mutant NSCLC cells.
ABSTRACT
Medulloblastoma (MB) is the most common and aggressive paediatric brain tumour. Although the cure rate can be as high as 70%, current treatments (surgery, radio- and chemotherapy) excessively affect the patients' quality of life. Relapses cannot be controlled by conventional or targeted treatments and are usually fatal. The strong heterogeneity of the disease (four subgroups and several subtypes) is related to innate or acquired resistance to reference treatments. Therefore, more efficient and less-toxic therapies are needed. Here, we demonstrated the efficacy of a novel inhibitor (C29) of CXCR1/2 receptors for ELR+CXCL cytokines for the treatment of childhood MB. The correlation between ELR+CXCL/CXCR1/2 expression and patient survival was determined using the R2: Genomics Analysis and Visualization platform. In vitro efficacy of C29 was evaluated by its ability to inhibit proliferation, migration, invasion, and pseudo-vessel formation of MB cell lines sensitive or resistant to radiotherapy. The growth of experimental MB obtained by MB spheroids on organotypic mouse cerebellar slices was also assayed. ELR+CXCL/CXCR1/2 levels correlated with shorter survival. C29 inhibited proliferation, clone formation, CXCL8/CXCR1/2-dependent migration, invasion, and pseudo-vessel formation by sensitive and radioresistant MB cells. C29 reduced experimental growth of MB in the ex vivo organotypic mouse model and crossed the blood-brain barrier. Targeting CXCR1/2 represents a promising therapeutic strategy for the treatment of paediatric MB in first-line treatment or after relapse following conventional therapy.
Subject(s)
Cerebellar Neoplasms , Medulloblastoma , Animals , Mice , Cerebellar Neoplasms/drug therapy , Medulloblastoma/drug therapy , Neoplasm Recurrence, Local , Quality of Life , Receptors, Interleukin-8A/metabolism , Humans , ChildABSTRACT
Age-related macular degeneration (AMD) was described for the first time in the 1840s and is currently the leading cause of blindness for patients over 65 years in Western Countries. This disease impacts the eye's posterior segment and damages the macula, a retina section with high levels of photoreceptor cells and responsible for the central vision. Advanced AMD stages are divided into the atrophic (dry) form and the exudative (wet) form. Atrophic AMD consists in the progressive atrophy of the retinal pigment epithelium (RPE) and the outer retinal layers, while the exudative form results in the anarchic invasion by choroidal neo-vessels of RPE and the retina. This invasion is responsible for fluid accumulation in the intra/sub-retinal spaces and for a progressive dysfunction of the photoreceptor cells. To date, the few existing anti-AMD therapies may only delay or suspend its progression, without providing cure to patients. However, in the last decade, an outstanding number of research programs targeting its different aspects have been initiated by academics and industrials. This review aims to bring together the most recent advances and insights into the mechanisms underlying AMD pathogenicity and disease evolution, and to highlight the current hypotheses towards the development of new treatments, i.e., symptomatic vs. curative. The therapeutic options and drugs proposed to tackle these mechanisms are analyzed and critically compared. A particular emphasis has been given to the therapeutic agents currently tested in clinical trials, whose results have been carefully collected and discussed whenever possible.
Subject(s)
Aging , Macular Degeneration , Aged , Humans , Macular Degeneration/drug therapy , Photoreceptor Cells , Retina , Retinal Pigment EpitheliumABSTRACT
Bis(trichlorosilyl)phosphine (HP(SiCl3)2, 1) was prepared from [TBA][P(SiCl3)2] ([TBA]2, TBA = tetra-n-butylammonium) and triflic acid in 36% yield. Phosphine 1 is an efficient reagent for hydrophosphination of unactivated terminal olefins under UV irradiation (15-60 min) and gives rise to bis(trichlorosilyl)alkylphosphines (RP(SiCl3)2, R = (CH2)5CH3, 88%; (CH2)7CH3, 98%; (CH2)2C(CH3)3, 76%; CH2Cy, 93%; (CH2)2Cy, 95%; CH2CH(CH3)(CH2)2CH3, 82%; (CH2)3O(CH2)3CH3, 95%; (CH2)3Cl, 83%; (CH2)2SiMe3, 92%; (CH2)5C(H)CH2, 44%) in excellent yields. The products require no further purification beyond filtration and removal of volatile material under reduced pressure. The P-Si bonds of prototypical products RP(SiCl3)2 (R = -(CH2)5CH3, -(CH2)7CH3) are readily functionalized to give further phosphorus-containing products: H3C(CH2)7PCl2 (56%), [H3C(CH2)5P(CH2Ph)3]Br (84%), H3C(CH2)7PH2 (61%), H3C(CH2)5P(O)(H)(OH) (81%), and H3C(CH2)5P(O)(OH)2 (55%). Experimental mechanistic investigations, accompanied by quantum chemical calculations, point toward a radical-chain mechanism. Phosphine 1 enables the fast, high-yielding, and atom-efficient preparation of compounds that contain phosphorus-carbon bonds in procedures that bypass white phosphorus (P4), a toxic and high-energy intermediate of the phosphorus industry.
ABSTRACT
In the present study, following a one-pot two-step protocol, we have synthesized novel sulfonamides-isoxazolines hybrids (3a-r) via a highly regioselective 1,3-dipolar cycloaddition. The present methodology capitalized on trichloroisocyanuric acid (TCCA) as a safe and ecological oxidant and chlorinating agent for the in-situ conversion of aldehydes to nitrile oxides in the presence of hydroxylamine hydrochloride, under ultrasound activation. These nitrile oxides could be engaged in 1,3-dipolar cycloaddition reactions with various alkene to afford the targeted sulfonamides-isoxazolines hybrids (3a-r). The latter were assessed for their antineoplastic activity against model leukemia cell lines (Chronic Myeloid Leukemia, K562 and Promyelocytic Leukemia, HL-60).
Subject(s)
Hematologic Neoplasms , Humans , Isoxazoles , Leukemia , Nitriles , Oxides , SulfonamidesABSTRACT
The chemokine receptors CXCR1/2 play a key role in the aggressiveness of several types of cancers including head and neck squamous cell carcinomas (HNSCCs). In HNSCCs, CXCR1/2 signaling promotes cell proliferation and angiogenesis leading to tumor growth and metastasis. The competitive inhibitor of CXCR1/2, C29, inhibits the growth of experimental HNSCCs in mice. However, a non-invasive tool to monitor treatment response is essential to implement the use of C29 in clinical practices. 18F-FDG PET/CT is a gold-standard tool for the staging and the post-therapy follow-up of HNSCCs patients. Our study aimed to perform the first in vivo monitoring of C29 efficacy by non-invasive 18F-FDG PET/CT imaging. Mice bearing experimental HNSCCs (CAL33) were injected with 18F-FDG (T0) and thereafter treated (n = 7 mice, 9 tumors, 50 mg/kg by gavage) or not (n = 7 mice, 10 tumors) with C29 for 4 consecutive days. Final 18F-FDG-tumor uptake was determined at day 4 (TF). The average relative change (TF-T0) in 18F-FDG tumor uptake was +25.85 ± 10.93 % in the control group vs -5.72 ± 10.07 % in the C29-treated group (p < 0.01). These results were consistent with the decrease of the tumor burden and with the decrease of tumor proliferating Ki67+ cells. These results paved the way for the use of 18F-FDG to monitor tumor response following C29 treatment.
ABSTRACT
The coronavirus pandemic, which appeared in Wuhan, China, in December 2019, rapidly spread all over the world in only a few weeks. Faster testing techniques requiring less resources are key in managing the pandemic, either to enable larger scale testing or even just provide developing countries with limited resources, particularly in Africa, means to perform tests to manage the crisis. Here, we report an unprecedented, rapid, reagent-free and easy-to-use screening spectroscopic method for the detection of SARS-CoV-2 on RNA extracts. This method, validated on clinical samples collected from 280 patients with quantitative predictive scores on both positive and negative samples, is based on a multivariate analysis of FTIR spectra of RNA extracts. This technique, in agreement with RT-PCR, achieves 97.8% accuracy, 97% sensitivity and 98.3% specificity while reducing the testing time post RNA extraction from hours to minutes. Furthermore, this technique can be used in several laboratories with limited resources.
Subject(s)
COVID-19 Testing/methods , RNA, Viral/analysis , Spectroscopy, Fourier Transform Infrared , Humans , RNA, Viral/chemistry , RNA, Viral/isolation & purification , Time FactorsABSTRACT
Biguanides have attracted much attention a century ago and showed resurgent interest in recent years after a long period of dormancy. They constitute an important class of therapeutic agents suitable for the treatment of a wide spectrum of diseases. Therapeutic indications of biguanides include antidiabetic, antimalarial, antiviral, antiplaque, and bactericidal applications. This review presents an extensive overview of the biological activity of biguanides and different mechanisms of action of currently marketed biguanide-containing drugs, as well as their pharmacological properties when applicable. We highlight the recent developments in research on biguanide compounds, with a primary focus on studies on metformin in the field of oncology. We aim to provide a critical overview of all main bioactive biguanide compounds and discuss future perspectives for the design of new drugs based on the biguanide fragment.
Subject(s)
Biguanides/therapeutic use , Drug Discovery/methods , Hypoglycemic Agents/therapeutic use , Biguanides/pharmacology , Humans , Hypoglycemic Agents/pharmacology , Molecular StructureABSTRACT
Overcoming acquired drug resistance is a primary challenge in cancer treatment. Notably, more than 50% of patients with BRAFV600E cutaneous metastatic melanoma (CMM) eventually develop resistance to BRAF inhibitors. Resistant cells undergo metabolic reprogramming that profoundly influences therapeutic response and promotes tumor progression. Uncovering metabolic vulnerabilities could help suppress CMM tumor growth and overcome drug resistance. Here we identified a drug, HA344, that concomitantly targets two distinct metabolic hubs in cancer cells. HA344 inhibited the final and rate-limiting step of glycolysis through its covalent binding to the pyruvate kinase M2 (PKM2) enzyme, and it concurrently blocked the activity of inosine monophosphate dehydrogenase, the rate-limiting enzyme of de novo guanylate synthesis. As a consequence, HA344 efficiently targeted vemurafenib-sensitive and vemurafenib-resistant CMM cells and impaired CMM xenograft tumor growth in mice. In addition, HA344 acted synergistically with BRAF inhibitors on CMM cell lines in vitro. Thus, the mechanism of action of HA344 provides potential therapeutic avenues for patients with CMM and a broad range of different cancers. SIGNIFICANCE: Glycolytic and purine synthesis pathways are often deregulated in therapy-resistant tumors and can be targeted by the covalent inhibitor described in this study, suggesting its broad application for overcoming resistance in cancer.
Subject(s)
Aminoimidazole Carboxamide/analogs & derivatives , Carrier Proteins/antagonists & inhibitors , IMP Dehydrogenase/antagonists & inhibitors , Melanoma/drug therapy , Membrane Proteins/antagonists & inhibitors , Ribonucleotides/pharmacology , Skin Neoplasms/drug therapy , Aged , Aminoimidazole Carboxamide/pharmacology , Animals , Cell Line, Tumor , Female , HEK293 Cells , Humans , Melanoma/enzymology , Melanoma/pathology , Mice , Mice, Nude , Random Allocation , Skin Neoplasms/enzymology , Skin Neoplasms/pathology , Thyroid Hormones , Xenograft Model Antitumor Assays , Thyroid Hormone-Binding Proteins , Melanoma, Cutaneous MalignantABSTRACT
Background: In line with our recent discovery of an efficient anticancer thiazolebenzenesulfonamide framework HA15 (1) based on a remarkable endoplasmic reticulum stress inducement mode of action, we report herein a series of innovative constrained HA15 analogs, featuring four types of bicylic derivatives. Results: The structure-activity relationship analysis, using a cell line assay, led us to identify a novel version of HA15: a new benzothiazole derivative (10b) exhibiting important anti-melanoma effect against sensitive and resistant melanoma cells. Meanwhile, compound 10b induced a significant tumor growth inhibition in vivo with no apparent signs of toxicity. Conclusion: These results consistently open new directions to improve and develop more powerful anticancer therapeutics harboring this type of fused framework.