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1.
Swiss Med Wkly ; 151: w30053, 2021 Oct 11.
Artigo em Inglês | MEDLINE | ID: mdl-34694105

RESUMO

Transthyretin amyloidosis (ATTR amyloidosis) is a disease caused by deposition of transthyretin fibrils in organs and tissues, which causes their dysfunction. The clinical heterogeneity of ATTR amyloidosis and the variable presentation of symptoms at early disease stages, historically meant treatment delays. Diagnostic tools and therapy options of ATTR amyloidosis have markedly improved in recent years. The first Swiss Amyloidosis Network (SAN) meeting (Zurich, Switzerland, January 2020) aimed to define a consensus statement regarding the diagnostic work-up and treatment for systemic amyloidosis, tailored to the Swiss healthcare system. A consortium of 45 clinicians and researchers from all Swiss regions and universities was selected by the SAN committee to represent all sub-specialty groups involved in care of patients with amyloidosis. A steering committee conducted the literature search and analysis, wrote the critical synthesis and elaborated a list of statements that were evaluated by all the participants. These recommendations will improve outcomes and quality of life for patients with ATTR amyloidosis. A global review of these guidelines is planned every 3 years with a formal meeting of all the involved experts.

2.
Front Med (Lausanne) ; 8: 747612, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34676229

RESUMO

Rare diseases (RDs) are complicated health conditions that are difficult to be managed at several levels. The scarcity of available data chiefly determines an intricate scenario even for experts and specialized clinicians, which in turn leads to the so called "diagnostic odyssey" for the patient. This situation calls for innovative solutions to support the decision process via quantitative and automated tools. Machine learning brings to the stage a wealth of powerful inference methods; however, matching the health conditions with advanced statistical techniques raises methodological, technological, and even ethical issues. In this contribution, we critically point to the specificities of the dialog of rare diseases with machine learning techniques concentrating on the key steps and challenges that may hamper or create actionable knowledge and value for the patient together with some on-field methodological suggestions and considerations.

3.
J Med Chem ; 64(18): 13439-13450, 2021 Sep 23.
Artigo em Inglês | MEDLINE | ID: mdl-34510899

RESUMO

During inflammatory reactions, the production and release of chemotactic factors guide the recruitment of selective leukocyte subpopulations. The alarmin HMGB1 and the chemokine CXCL12, both released in the microenvironment, can form a heterocomplex, which exclusively acts on the chemokine receptor CXCR4, enhancing cell migration, and in some pathological conditions such as rheumatoid arthritis exacerbates the immune response. An excessive cell influx at the inflammatory site can be diminished by disrupting the heterocomplex. Here, we report the computationally driven identification of the first peptide (HBP08) binding HMGB1 and selectively inhibiting the activity of the CXCL12/HMGB1 heterocomplex. Furthermore, HBP08 binds HMGB1 with the highest affinity reported so far (Kd of 0.8 ± 0.4 µM). The identification of this peptide represents an important step toward the development of innovative pharmacological tools for the treatment of severe chronic inflammatory conditions characterized by an uncontrolled immune response.

4.
Clin Immunol ; 231: 108837, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34455097

RESUMO

RAS-associated autoimmune leukoproliferative disease (RALD) is a rare immune dysregulation syndrome caused by somatic gain-of-function mutations of either NRAS or KRAS gene in hematopoietic cells. We describe a 27-year-old patient presenting at 5 months of age with recurrent infections and generalized lymphadenopathy who developed a complex multi-organ autoimmune syndrome with hypogammaglobulinemia, partially controlled with oral steroids, hydroxichloroquine, mofetil mycophenolate and IVIG prophylaxis. Activation of type I interferon pathway was observed in peripheral blood. Since 18 years of age, the patient developed regenerative nodular hyperplasia of the liver evolving into hepatopulmonary syndrome. Whole exome sequencing analysis of the peripheral blood DNA showed the NRAS p.Gly13Asp mutation validated as somatic. Our report highlights the possibility of detecting somatic NRAS gene mutations in patients with inflammatory immune dysregulation and type I interferon activation.

5.
Nat Commun ; 12(1): 4662, 2021 08 02.
Artigo em Inglês | MEDLINE | ID: mdl-34341345

RESUMO

Impaired cellular cholesterol efflux is a key factor in the progression of renal, cardiovascular, and autoimmune diseases. Here we describe a class of 5-arylnicotinamide compounds, identified through phenotypic drug discovery, that upregulate ABCA1-dependent cholesterol efflux by targeting Oxysterol Binding Protein Like 7 (OSBPL7). OSBPL7 was identified as the molecular target of these compounds through a chemical biology approach, employing a photoactivatable 5-arylnicotinamide derivative in a cellular cross-linking/immunoprecipitation assay. Further evaluation of two compounds (Cpd A and Cpd G) showed that they induced ABCA1 and cholesterol efflux from podocytes in vitro and normalized proteinuria and prevented renal function decline in mouse models of proteinuric kidney disease: Adriamycin-induced nephropathy and Alport Syndrome. In conclusion, we show that small molecule drugs targeting OSBPL7 reveal an alternative mechanism to upregulate ABCA1, and may represent a promising new therapeutic strategy for the treatment of renal diseases and other disorders of cellular cholesterol homeostasis.


Assuntos
Transportador 1 de Cassete de Ligação de ATP/metabolismo , Colesterol/metabolismo , Nefropatias Diabéticas/metabolismo , Compostos Orgânicos/farmacologia , Podócitos/metabolismo , Proteinúria/metabolismo , Receptores de Esteroides/antagonistas & inibidores , Transportador 1 de Cassete de Ligação de ATP/genética , Animais , Transporte Biológico/efeitos dos fármacos , Células Cultivadas , Modelos Animais de Doenças , Células HEK293 , Humanos , Rim/efeitos dos fármacos , Rim/metabolismo , Rim/patologia , Camundongos da Linhagem 129 , Camundongos Knockout , Estrutura Molecular , Niacinamida/química , Niacinamida/farmacologia , Compostos Orgânicos/síntese química , Compostos Orgânicos/química , Podócitos/citologia , Interferência de RNA , Receptores de Esteroides/genética , Receptores de Esteroides/metabolismo , Células THP-1
6.
Int J Mol Sci ; 22(16)2021 Aug 23.
Artigo em Inglês | MEDLINE | ID: mdl-34445804

RESUMO

Protein kinases (PKs) have been recognized as central nervous system (CNS)-disease-relevant targets due to their master regulatory role in different signal transduction cascades in the neuroscience space. Among them, GSK-3ß, FYN, and DYRK1A play a crucial role in the neurodegeneration context, and the deregulation of all three PKs has been linked to different CNS disorders with unmet medical needs, including Alzheimer's disease (AD), Parkinson's disease (PD), frontotemporal lobar degeneration (FTLD), and several neuromuscular disorders. The multifactorial nature of these diseases, along with the failure of many advanced CNS clinical trials, and the lengthy approval process of a novel CNS drug have strongly limited the CNS drug discovery. However, in the near-decade from 2010 to 2020, several computer-assisted drug design strategies have been combined with synthetic efforts to develop potent and selective GSK-3ß, FYN, and DYRK1A inhibitors as disease-modifying agents. In this review, we described both structural and functional aspects of GSK-3ß, FYN, and DYRK1A and their involvement and crosstalk in different CNS pathological signaling pathways. Moreover, we outlined attractive medicinal chemistry approaches including multi-target drug design strategies applied to overcome some limitations of known PKs inhibitors and discover improved modulators with suitable blood-brain barrier (BBB) permeability and drug-like properties.


Assuntos
Glicogênio Sintase Quinase 3 beta/metabolismo , Doenças Neurodegenerativas/metabolismo , Proteínas Tirosina Quinases/metabolismo , Proteínas Proto-Oncogênicas c-fyn/metabolismo , Transdução de Sinais/fisiologia , Animais , Humanos
7.
Nat Commun ; 12(1): 4147, 2021 07 06.
Artigo em Inglês | MEDLINE | ID: mdl-34230470

RESUMO

The TMPRSS2-ERG gene fusion is the most frequent alteration observed in human prostate cancer. However, its role in disease progression is still unclear. In this study, we uncover an important mechanism promoting ERG oncogenic activity. We show that ERG is methylated by Enhancer of zest homolog 2 (EZH2) at a specific lysine residue (K362) located within the internal auto-inhibitory domain. Mechanistically, K362 methylation modifies intra-domain interactions, favors DNA binding and enhances ERG transcriptional activity. In a genetically engineered mouse model of ERG fusion-positive prostate cancer (Pb-Cre4 Pten flox/flox Rosa26-ERG, ERG/PTEN), ERG K362 methylation is associated with PTEN loss and progression to invasive adenocarcinomas. In both ERG positive VCaP cells and ERG/PTEN mice, PTEN loss results in AKT activation and EZH2 phosphorylation at serine 21 that favors ERG methylation. We find that ERG and EZH2 interact and co-occupy several sites in the genome forming trans-activating complexes. Consistently, ERG/EZH2 co-regulated target genes are deregulated preferentially in tumors with concomitant ERG gain and PTEN loss and in castration-resistant prostate cancers. Collectively, these findings identify ERG methylation as a post-translational modification sustaining disease progression in ERG-positive prostate cancers.


Assuntos
Proteína Potenciadora do Homólogo 2 de Zeste/metabolismo , Lisina/metabolismo , Proteínas de Fusão Oncogênica/metabolismo , Proteínas Oncogênicas/metabolismo , Neoplasias da Próstata/metabolismo , Serina Endopeptidases/metabolismo , Regulador Transcricional ERG/metabolismo , Adenocarcinoma/genética , Animais , Proteína Potenciadora do Homólogo 2 de Zeste/genética , Regulação Neoplásica da Expressão Gênica , Técnicas de Silenciamento de Genes , Masculino , Camundongos , Camundongos Knockout , Proteínas Oncogênicas/genética , Proteínas de Fusão Oncogênica/genética , Neoplasias da Próstata/genética , Conformação Proteica , Processamento de Proteína Pós-Traducional , Alinhamento de Sequência , Serina Endopeptidases/genética , Transativadores/metabolismo , Fatores de Transcrição/genética , Regulador Transcricional ERG/genética
8.
J Chem Theory Comput ; 17(8): 5287-5300, 2021 Aug 10.
Artigo em Inglês | MEDLINE | ID: mdl-34260233

RESUMO

Computational capabilities are rapidly increasing, primarily because of the availability of GPU-based architectures. This creates unprecedented simulative possibilities for the systematic and robust computation of thermodynamic observables, including the free energy of a drug binding to a target. In contrast to calculations of relative binding free energy, which are nowadays widely exploited for drug discovery, we here push the boundary of computing the binding free energy and the potential of mean force. We introduce a novel protocol that leverages enhanced sampling, machine learning, and ad hoc algorithms to limit human intervention, computing time, and free parameters in free energy calculations. We first validate the method on a host-guest system, and then we apply the protocol to glycogen synthase kinase 3 beta, a protein kinase of pharmacological interest. Overall, we obtain a good correlation with experimental values in relative and absolute terms. While we focus on protein-ligand binding, the strategy is of broad applicability to any complex event that can be described with a path collective variable. We systematically discuss key details that influence the final result. The parameters and simulation settings are available at PLUMED-NEST to allow full reproducibility.


Assuntos
Aprendizado de Máquina , Hidrocarbonetos Aromáticos com Pontes/química , Hidrocarbonetos Aromáticos com Pontes/metabolismo , Glicogênio Sintase Quinase 3 beta/química , Glicogênio Sintase Quinase 3 beta/metabolismo , Imidazóis/química , Imidazóis/metabolismo , Ligantes , Simulação de Dinâmica Molecular , Ligação Proteica , Termodinâmica
9.
J Phys Chem Lett ; 12(23): 5616-5622, 2021 Jun 17.
Artigo em Inglês | MEDLINE | ID: mdl-34110174

RESUMO

Ligand shell-protected gold nanoparticles can form nanoreceptors that recognize and bind to specific molecules in solution, with numerous potential innovative applications in science and industry. At this stage, the challenge is to rationally design such nanoreceptors to optimize their performance and boost their further development. Toward this aim, we have developed a new computational tool, Nanotron. This allows the analysis of molecular dynamics simulations of ligand shell-protected nanoparticles to define their exact surface morphology and pocket fingerprints of binding cavities in the coating monolayer. Importantly, from dissecting the well-characterized pairing formed by the guest salicylate molecule and specific host nanoreceptors, our work reveals that guest binding at such nanoreceptors occurs via preformed deep pockets in the host. Upon the interaction with the guest, such pockets undergo an induced-fit-like structural optimization for best host-guest fitting. Our findings and methodological advancement will accelerate the rational design of new-generation nanoreceptors.


Assuntos
Ouro/análise , Nanopartículas Metálicas/análise , Simulação de Dinâmica Molecular , Mapeamento de Peptídeos/métodos , Biologia Computacional/métodos , Ouro/química , Nanopartículas Metálicas/química , Propriedades de Superfície
10.
Nat Commun ; 12(1): 3532, 2021 06 10.
Artigo em Inglês | MEDLINE | ID: mdl-34112780

RESUMO

In systemic light chain amyloidosis (AL), pathogenic monoclonal immunoglobulin light chains (LC) form toxic aggregates and amyloid fibrils in target organs. Prompt diagnosis is crucial to avoid permanent organ damage, but delayed diagnosis is common because symptoms usually appear only after strong organ involvement. Here we present LICTOR, a machine learning approach predicting LC toxicity in AL, based on the distribution of somatic mutations acquired during clonal selection. LICTOR achieves a specificity and a sensitivity of 0.82 and 0.76, respectively, with an area under the receiver operating characteristic curve (AUC) of 0.87. Tested on an independent set of 12 LCs sequences with known clinical phenotypes, LICTOR achieves a prediction accuracy of 83%. Furthermore, we are able to abolish the toxic phenotype of an LC by in silico reverting two germline-specific somatic mutations identified by LICTOR, and by experimentally assessing the loss of in vivo toxicity in a Caenorhabditis elegans model. Therefore, LICTOR represents a promising strategy for AL diagnosis and reducing high mortality rates in AL.


Assuntos
Caenorhabditis elegans/metabolismo , Cadeias Leves de Imunoglobulina/genética , Cadeias Leves de Imunoglobulina/toxicidade , Amiloidose de Cadeia Leve de Imunoglobulina/diagnóstico , Amiloidose de Cadeia Leve de Imunoglobulina/genética , Aprendizado de Máquina , Algoritmos , Sequência de Aminoácidos , Animais , Anticorpos/genética , Caenorhabditis elegans/genética , Bases de Dados Genéticas , Expressão Gênica , Humanos , Cadeias Leves de Imunoglobulina/química , Modelos Moleculares , Mutação , Proteínas Recombinantes
11.
Angew Chem Int Ed Engl ; 60(24): 13331-13342, 2021 06 07.
Artigo em Inglês | MEDLINE | ID: mdl-33951246

RESUMO

Tubulin plays essential roles in vital cellular activities and is the target of a wide range of proteins and ligands. Here, using a combined computational and crystallographic fragment screening approach, we addressed the question of how many binding sites exist in tubulin. We identified 27 distinct sites, of which 11 have not been described previously, and analyzed their relationship to known tubulin-protein and tubulin-ligand interactions. We further observed an intricate pocket communication network and identified 56 chemically diverse fragments that bound to 10 distinct tubulin sites. Our results offer a unique structural basis for the development of novel small molecules for use as tubulin modulators in basic research applications or as drugs. Furthermore, our method lays down a framework that may help to discover new pockets in other pharmaceutically important targets and characterize them in terms of chemical tractability and allosteric modulation.


Assuntos
Ligantes , Tubulina (Proteína)/metabolismo , Regulação Alostérica , Sítios de Ligação , Cristalografia por Raios X , Simulação de Dinâmica Molecular , Ligação Proteica , Tubulina (Proteína)/química , Moduladores de Tubulina/química , Moduladores de Tubulina/metabolismo
12.
J Chem Inf Model ; 61(6): 3091-3108, 2021 06 28.
Artigo em Inglês | MEDLINE | ID: mdl-33998810

RESUMO

Janus kinases (JAKs) are a family of proinflammatory enzymes able to mediate the immune responses and the inflammatory cascade by modulating multiple cytokine expressions as well as various growth factors. In the present study, the inhibition of the JAK-signal transducer and activator of transcription (STAT) signaling pathway is explored as a potential strategy for treating autoimmune and inflammatory disorders. A computationally driven approach aimed at identifying novel JAK inhibitors based on molecular topology, docking, and molecular dynamics simulations was carried out. For the best candidates selected, the inhibitory activity against JAK2 was evaluated in vitro. Two hit compounds with a novel chemical scaffold, 4 (IC50 = 0.81 µM) and 7 (IC50 = 0.64 µM), showed promising results when compared with the reference drug Tofacitinib (IC50 = 0.031 µM).


Assuntos
Janus Quinases , Inibidores de Proteínas Quinases , Janus Quinases/metabolismo , Ligantes , Inibidores de Proteínas Quinases/farmacologia , Transdução de Sinais , Transdutores
13.
Front Med (Lausanne) ; 8: 650231, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33981715

RESUMO

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-associated coronavirus disease 2019 (COVID-19) pandemic has been the subject of a large number of studies in recent times. Here, starting from the evidence that in Italy, the areas with the lowest number of COVID-19 cases were those with the highest incidence of malaria in the early 1900's, we explore possible inverse relationships between malaria and COVID-19. Indeed, some genetic variants, which have been demonstrated to give an advantage against malaria, can also play a role in the incidence and severity of SARS-CoV-2 infections (e.g., the ACE2 receptor). To verify this scientific hypothesis, we here use public data from whole-genome sequencing (WGS) experiments to extrapolate the genetic information of 46 world populations with matched COVID-19 data. In particular, we focus on 47 genes, including ACE2 and genes which have previously been reported to play a role in malaria. Only common variants (>5%) in at least 30% of the selected populations were considered, and, for this subset, we correlate the intra-population allele frequency with the COVID-19 data (cases/million inhabitants), eventually pinpointing meaningful variants in 6 genes. This study allows us to distinguish between positive and negative correlations, i.e., variants whose frequency significantly increases with increasing or decreasing COVID-19 cases. Finally, we discuss the possible molecular mechanisms associated with these variants and advance potential therapeutic options, which may help fight and/or prevent COVID-19.

14.
Front Mol Biosci ; 8: 666626, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33996911

RESUMO

Camostat, nafamostat, and bromhexine are inhibitors of the transmembrane serine protease TMPRSS2. The inhibition of TMPRSS2 has been shown to prevent the viral infection of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and other viruses. However, while camostat and nafamostat inhibit TMPRSS2 by forming a covalent adduct, the mode of action of bromhexine remains unclear. TMPRSS2 is autocatalytically activated from its inactive form, zymogen, through a proteolytic cleavage that promotes the binding of Ile256 to a putative allosteric pocket (A-pocket). Computer simulations, reported here, indicate that Ile256 binding induces a conformational change in the catalytic site, thus providing the atomistic rationale to the activation process of the enzyme. Furthermore, computational docking and molecular dynamics simulations indicate that bromhexine competes with the N-terminal Ile256 for the same binding site, making it a potential allosteric inhibitor. Taken together, these findings provide the atomistic basis for the development of more selective and potent TMPRSS2 inhibitors.

15.
Cells ; 10(3)2021 03 09.
Artigo em Inglês | MEDLINE | ID: mdl-33803230

RESUMO

Macrophages are involved in tissue homeostasis. They participate in inflammatory episodes and are involved in tissue repair. Macrophages are characterized by a phenotypic heterogeneity and a profound cell plasticity. In the kidney, and more particularly within glomeruli, macrophages are thought to play a maintenance role that is potentially critical for preserving a normal glomerular structure. Literature on the glomerular macrophage role in human crescentic glomerulonephritis and renal transplantation rejection with glomerulitis, is sparse. Evidence from preclinical models indicates that macrophages profoundly modulate disease progression, both in terms of number-where depletion has resulted in a reduced glomerular lesion-and sub-phenotype-M1 being more profoundly detrimental than M2. This evidence is corroborated by better outcomes in patients with a lower number of glomerular macrophages. However, due to the very limited biopsy sample size, the type and role of macrophage subpopulations involved in human proliferative lesions is more difficult to precisely define and synthesize. Therefore, specific biomarkers of macrophage activation may enhance our ability to assess their role, potentially enabling improved monitoring of drug activity and ultimately allowing the development of novel therapeutic strategies to target these elusive cellular players.


Assuntos
Glomerulonefrite/imunologia , Glomerulonefrite/patologia , Glomérulos Renais/patologia , Macrófagos/patologia , Animais , Modelos Animais de Doenças , Rejeição de Enxerto/patologia , Humanos , Fenótipo
18.
Molecules ; 26(2)2021 Jan 07.
Artigo em Inglês | MEDLINE | ID: mdl-33430231

RESUMO

In the present, proof-of-concept paper, we explore the potential of one common solid support for blood microsampling (dried blood spot, DBS) and a device (volumetric absorptive microsampling, VAMS) developed for the untargeted lipidomic profiling of human whole blood, performed by high-resolution LC-MS/MS. Dried blood microsamples obtained by means of DBS and VAMS were extracted with different solvent compositions and compared with fluid blood to evaluate their efficiency in profiling the lipid chemical space in the most broad way. Although more effort is needed to better characterize this approach, our results indicate that VAMS is a viable option for untargeted studies and its use will bring all the corresponding known advantages in the field of lipidomics, such as haematocrit independence.


Assuntos
Lipidômica/métodos , Cromatografia Líquida , Análise de Dados , Teste em Amostras de Sangue Seco/métodos , Humanos , Lipídeos/sangue , Solventes , Espectrometria de Massas em Tandem
19.
Br J Neurosurg ; 35(3): 334-340, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32870049

RESUMO

OBJECTIVES: (1) Describe presentation, management and outcomes of a single-centre series of patients with pituitary apoplexy. (2) Compare early and long-term outcomes of conservative and surgical management. (3) Identify predictive factors for visual recovery. METHODS: Retrospective analysis of patients acutely managed by Sheffield's Neurosurgery over a 9-years period. Outcome comparison was made between 2 groups ('conservative' versus 'emergency') at early FU and 3 groups ('conservative' versus 'elective' versus 'emergency') at long-term FU. RESULTS: Data from 30 patients (M:F = 2.8:1; mean age: 54 years; median FU: 31.5 months) were collected. 86,7% patients presented with visual disturbances (70% acuity, 50% field, 50% diploplia). 10 (33%) patients underwent emergency surgery and further 8 underwent delayed elective surgery.At early FU, resolution rates of VA (33% versus 38%), VF (40% versus 50%) and CN deficits (71% versus 40%) were not significantly different between groups.At long-term FU, resolution of VA (80% versus 20% versus 75%) and CN deficits (67% versus 50% versus 80%) was not significantly different between groups. Most patients who underwent surgery presented with severe VA deficit (20% versus 40% versus 63%) but severity of initial deficit wasn't correlated with long-term resolution.VF recovery rates showed significant difference between groups (p = 0.027): 67% versus 0% versus 88%.Endocrine outcomes were generally poor, regardless of the management strategy.Regarding possible predictive factors, age and tumour size correlated with visual outcomes. Especially in patients treated conservatively in the acute phase, no cases of complete resolution of VA or VF deficit were recorded when tumour was higher than 35 mm. CONCLUSIONS: Good results are possible with conservative management in selected cases. Emergency surgery provides better visual outcomes. Decision-making process should be tailored to every single patient. We believe that a tumour vertical diameter >35 mm should tip the balance in favour of surgical management in presence of visual deficit.


Assuntos
Apoplexia Hipofisária , Neoplasias Hipofisárias , Tratamento Conservador , Humanos , Pessoa de Meia-Idade , Apoplexia Hipofisária/cirurgia , Neoplasias Hipofisárias/cirurgia , Estudos Retrospectivos , Resultado do Tratamento , Reino Unido
20.
Biochim Biophys Acta Gen Subj ; 1865(1): 129760, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33035602

RESUMO

BACKGROUND: Cancer cells show highly increased glucose utilization which, among other cancer-essential functions, was found to facilitate DNA repair. Lactate dehydrogenase (LDH) activity is pivotal for supporting the high glycolytic flux of cancer cells; to our knowledge, a direct contribution of this enzyme in the control of DNA integrity was never investigated. In this paper, we looked into a possible LDH-mediated regulation of homologous recombination (HR) repair. METHODS: We identified two cancer cell lines with different assets in energy metabolism: either based on glycolytic ATP or on oxidative reactions. In cells with inhibited LDH, we assessed HR function by applying four different procedures. RESULTS: Our findings revealed an LDH-mediated control of HR, which was observed independently of cell metabolic asset. Since HR inhibition is known to make cancer cells responsive to PARP inhibitors, in both the cellular models we finally explored the effects of a combined inhibition of LDH and PARP. CONCLUSIONS: The obtained results suggest for LDH a central role in cancer cell biology, not merely linked to the control of energy metabolism. The involvement of LDH in the DNA damage response could suggest new drug combinations to obtain improved antineoplastic effects. GENERAL SIGNIFICANCE: Several evidences have correlated the metabolic features of cancer cells with drug resistance and LDH inhibition has been repeatedly shown to increase the antineoplastic power of chemotherapeutics. By shedding light on the processes linking cell metabolism to the control of DNA integrity, our findings also give a mechanistic explanation to these data.


Assuntos
Antineoplásicos/farmacologia , Inibidores Enzimáticos/farmacologia , L-Lactato Desidrogenase/antagonistas & inibidores , Neoplasias/tratamento farmacológico , Ftalazinas/farmacologia , Piperazinas/farmacologia , Reparo de DNA por Recombinação/efeitos dos fármacos , Linhagem Celular Tumoral , Glicólise/efeitos dos fármacos , Humanos , L-Lactato Desidrogenase/metabolismo , Neoplasias/genética , Neoplasias/metabolismo , Inibidores de Poli(ADP-Ribose) Polimerases/farmacologia
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