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1.
EMBO J ; 37(14)2018 07 13.
Artículo en Inglés | MEDLINE | ID: mdl-29875130

RESUMEN

Cisplatin is the most widely used chemotherapeutic agent, and resistance of neoplastic cells against this cytoxicant poses a major problem in clinical oncology. Here, we explored potential metabolic vulnerabilities of cisplatin-resistant non-small human cell lung cancer and ovarian cancer cell lines. Cisplatin-resistant clones were more sensitive to killing by nutrient deprivation in vitro and in vivo than their parental cisplatin-sensitive controls. The susceptibility of cisplatin-resistant cells to starvation could be explained by a particularly strong dependence on glutamine. Glutamine depletion was sufficient to restore cisplatin responses of initially cisplatin-resistant clones, and glutamine supplementation rescued cisplatin-resistant clones from starvation-induced death. Mass spectrometric metabolomics and specific interventions on glutamine metabolism revealed that, in cisplatin-resistant cells, glutamine is mostly required for nucleotide biosynthesis rather than for anaplerotic, bioenergetic or redox reactions. As a result, cisplatin-resistant cancers became exquisitely sensitive to treatment with antimetabolites that target nucleoside metabolism.


Asunto(s)
Antimetabolitos/farmacología , Antineoplásicos/farmacología , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Cisplatino/farmacología , Resistencia a Antineoplásicos , Glutamina/metabolismo , Neoplasias Ováricas/tratamiento farmacológico , Muerte Celular , Línea Celular Tumoral , Metabolismo Energético , Femenino , Humanos , Espectrometría de Masas , Metaboloma , Modelos Biológicos , Nucleótidos/biosíntesis
2.
Cell Mol Neurobiol ; 41(3): 563-587, 2021 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-32430779

RESUMEN

Cisplatin (CDDP) is one of the most effective chemotherapeutic agents, used for the treatment of diverse tumors, including neuroblastoma and glioblastoma. CDDP induces cell death through different apoptotic pathways. Despite its clinical benefits, CDDP causes several side effects and drug resistance.[Pt(O,O'-acac)(γ-acac)(DMS)], namely PtAcacDMS, a new platinum(II) complex containing two acetylacetonate (acac) and a dimethylsulphide (DMS) in the coordination sphere of metal, has been recently synthesized and showed 100 times higher cytotoxicity than CDDP. Additionally, PtAcacDMS was associated to a decreased neurotoxicity in developing rat central nervous system, also displaying great antitumor and antiangiogenic activity both in vivo and in vitro. Thus, based on the knowledge that several chemotherapeutics induce cancer cell death through an aberrant increase in [Ca2+]i, in the present in vitro study we compared CDDP and PtAcacDMS effects on apoptosis and intracellular Ca2+ dynamics in human glioblastoma T98G cells, applying a battery of complementary techniques, i.e., flow cytometry, immunocytochemistry, electron microscopy, Western blotting, qRT-PCR, and epifluorescent Ca2+ imaging. The results confirmed that (i) platinum compounds may induce cell death through an aberrant increase in [Ca2+]i and (ii) PtAcacDMS exerted stronger cytotoxic effect than CDDP, associated to a larger increase in resting [Ca2+]i. These findings corroborate the use of PtAcacDMS as a promising approach to improve Pt-based chemotherapy against gliomas, either by inducing a chemosensitization or reducing chemoresistance in cell lineages resilient to CDDP treatment.


Asunto(s)
Neoplasias Encefálicas/patología , Cisplatino/efectos adversos , Cisplatino/farmacología , Resistencia a Antineoplásicos , Glioma/patología , Compuestos Organoplatinos/farmacología , Apoptosis/efectos de los fármacos , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/ultraestructura , Calcio/metabolismo , Muerte Celular/efectos de los fármacos , Línea Celular Tumoral , Citoesqueleto/efectos de los fármacos , Citoesqueleto/metabolismo , Resistencia a Antineoplásicos/efectos de los fármacos , Retículo Endoplásmico/efectos de los fármacos , Retículo Endoplásmico/metabolismo , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Glioma/genética , Glioma/ultraestructura , Homeostasis/efectos de los fármacos , Humanos , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Proteínas del Tejido Nervioso/metabolismo , Proteína ORAI1/genética , Proteína ORAI1/metabolismo , ATPasas Transportadoras de Calcio de la Membrana Plasmática/metabolismo , Poli(ADP-Ribosa) Polimerasas/metabolismo , ARN Mensajero/genética , ARN Mensajero/metabolismo
4.
J Immunother Cancer ; 9(6)2021 06.
Artículo en Inglés | MEDLINE | ID: mdl-34162714

RESUMEN

BACKGROUND: Tumors rewire their metabolism to achieve robust anabolism and resistance against therapeutic interventions like cisplatin treatment. For example, a prolonged exposure to cisplatin causes downregulation of pyridoxal kinase (PDXK), the enzyme that generates the active vitamin B6, and upregulation of poly ADP-ribose (PAR) polymerase-1 (PARP1) activity that requires a supply of nicotinamide (vitamin B3) adenine dinucleotide. We investigated the impact of the levels of PDXK and PAR on the local immunosurveillance (ie, density of the antigen presenting cells and adaptive immune response by CD8 T lymphocytes) in two different tumor types. METHODS: Tumors from patients with locally advanced cervical carcinoma (LACC) and non-small cell lung cancer (NSCLC) were stained for PAR, PDXK, dendritic cell lysosomal associated membrane glycoprotein (DC-LAMP) and CD8 T cell infiltration. Their correlations and prognostic impact were assessed. Cisplatin-resistant NSCLC cell clones isolated from Lewis-lung cancer (LLC) cells were evaluated for PAR levels by immunoblot. Parental (PARlow) and cisplatin-resistant (PARhigh) clones were subcutaneously injected into the flank of C57BL/6 mice. Tumors were harvested to evaluate their immune infiltration by flow cytometry. RESULTS: The infiltration of tumors by CD8 T and DC-LAMP+ cells was associated with a favorable overall survival in patients with LACC (p=0.006 and p=0.008, respectively) and NSCLC (p<0.001 for both CD8 T and DC-LAMP cells). We observed a positive correlation between PDXK expression and the infiltration by DC-LAMP (R=0.44, p=0.02 in LACC, R=0.14, p=0.057 in NSCLC), and a negative correlation between PAR levels and CD8 T lymphocytes (R=-0.39, p=0.034 in LACC, R=-0.18, p=0.017 in NSCLC). PARP1 is constitutively hyperactivated in cisplatin-resistant LLC cells manifesting elevated intracellular levels of poly(ADP-ribosyl)ated proteins (PARhigh). Tumors formed by such cancer cells injected into immunocompetent mice were scarcely infiltrated by CD8 T (p=0.028) and antigen presenting cells (p=0.086). CONCLUSIONS: Oncometabolic features can impact local immunosurveillance, providing new functional links between cisplatin resistance and therapeutic failure.


Asunto(s)
Inmunoterapia/métodos , Monitorización Inmunológica/métodos , Neoplasias/inmunología , Animales , Modelos Animales de Enfermedad , Femenino , Humanos , Ratones , Microambiente Tumoral/inmunología
5.
Life Sci ; 210: 166-176, 2018 Oct 01.
Artículo en Inglés | MEDLINE | ID: mdl-30144454

RESUMEN

AIMS: Neuroblastoma is a rare cancer that affects children, mostly under the age of 5. This type of cancer starts in very early forms of immature nerve cells or developing cells found in embryo or fetus. To date cisplatin represents one of the most potent antitumor agent known, however, the onset of systemic side effects and the induction of drug resistance limit its use in the clinic for long-term treatment. In the present study we have analysed the effects of a new compound of platinum(IV) conjugates, named Pt(IV)Ac-POA, which is able to generate a synergistic antineoplastic action when released along with cisplatin upon intracellular Pt(IV) → Pt(II) reduction. MAIN METHODS: To assess the growth inhibition of the compounds under investigation, a cell viability test, i.e. the resazurin reduction assay was used on the B50 neuroblastoma rat cells. Further analysis on the cell cycle and metabolic alterations were carried out through flow cytometry. Morphological changes and activation of different cell death pathways after treatment, were observed at transmission electron microscope and by immunocytochemistry at fluorescence microscopy. Protein expression was examined by western blot analysis. KEY FINDINGS: This compound bearing bioactive axial ligand, such as the active histone deacetylase inhibitor (HDACi) (2-propynyl)octanoic acid (POA), induced cell death through different pathways at a concentration ten times lower than cisplatin. SIGNIFICANCE: The results showed that Pt(IV)Ac-POA could represent a promising improvement of Pt-based chemotherapy against neuroblastoma.


Asunto(s)
Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Neuroblastoma/patología , Compuestos Organoplatinos/farmacología , Profármacos/farmacología , Animales , Ciclo Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Neuroblastoma/tratamiento farmacológico , Neuroblastoma/metabolismo , Ratas , Células Tumorales Cultivadas
6.
Arch Med Res ; 48(2): 156-161, 2017 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-28625318

RESUMEN

Aldosterone synthase (CYP11B2) is as an 9-exon gene on chromosome 8q22 and exists as a common single nucleotide polymorphism C-T transition for position -344. The aim of this study was to assess the -344T/C polymorphism of the aldosterone synthase promoter in a European continental ancestry congestive heart failure (CHF) population. METHODS: Patients discharged after an acute decompensation were enrolled and underwent echocardiography, determination of BNP, evaluation of non-invasive cardiac outputs and determination of -344 T/C SNP in the aldosterone synthase gene. RESULTS: 175 patients (137 male; age 69.9 ± 10.2 years) were enrolled. The genotype distribution of -344 T/C SNP demonstrated a TT genotype in 61 patients (34.9%), CT in 80 (45.7%) and finally CC in 34 (19.4%) CHF patients. According to presence of C allele, CHF patients were divided into C group (-CT/CC genotype, 114 subjects) and T Group (-TT genotype, 61 subjects). The two groups did not differ in term of age, non-invasive cardiac output at rest, creatinine level or end-systolic or diastolic left ventricle diameter, LVEF and BNP. In group C patients in comparison than in group T a higher degree of disability (Barthel Index p = 0.004), NYHA class (p = 0.02) and a lower cardiac index (p = 0.01) emerged. Moreover, the two groups showed a similar clinical outcome (death for any cause/hospital readmission for CHF) at 48 month follow-up (p = 0.16; log-rank 1.99). CONCLUSIONS: In European continental ancestry patients the C allele (CC or CT) at -344T/C SNP in the aldosterone synthase gene does not significantly influence clinical prognosis of CHF.


Asunto(s)
Citocromo P-450 CYP11B2/genética , Insuficiencia Cardíaca/genética , Anciano , Femenino , Frecuencia de los Genes , Genotipo , Insuficiencia Cardíaca/etnología , Humanos , Masculino , Persona de Mediana Edad , Polimorfismo de Nucleótido Simple , Pronóstico , Regiones Promotoras Genéticas , Estudios Prospectivos , Población Blanca
7.
Int J Biol Markers ; 31(2): 0, 2016.
Artículo en Inglés | MEDLINE | ID: mdl-27040135

RESUMEN

PURPOSE: HPV-related locally advanced head and neck cancers (LA-HNCs) show a good prognosis. This study aimed to investigate the HPV prevalence in LA-HNCs and compare the prognostic value of E1, E6 and L1 genomic viral fragments and p16, individually and in combination, in order to find the best prognosticator in terms of overall survival (OS) and progression-free survival (PFS). PATIENTS AND METHODS: HPV16 was searched in 255 LA-HNC formalin-fixed paraffin-embedded tumor tissues, 89 oropharyngeal cancers (OPCs), and 166 non-OPCs by DNA-PCR with 3 primer pairs. p16 was analyzed by immunohistochemistry in 235 patients. RESULTS: The prevalence of positive samples decreased constantly from E6 to L1 and E1 in both OPCs and non-OPCs. Each LA-HNC patient highlighted variable positivity for each fragment. OPCs showed a higher prevalence of positive samples compared to non-OPCs.Positive coexistence of all the fragments was more common in OPCs (31.5%) than non-OPCs (4.2%), and E1 detection was always associated with E6 and L1. E1-positive OPCs showed improved OS (p = 0.012) and PFS (p = 0.036), while L1- or E6-positive ones did not. p16-positive patients were more prevalent in the OPC (29.8%) than the non-OPC group (7.3%) (p<0.0001) and its prognostic value was not superior to that of E1. However, the multivariate Cox analysis which included E1, L1, E6 status and p16 expression did not show a significant p value. CONCLUSIONS: Though HPV16 positivity measured by DNA-PCR was higher for L1 and E6, they performed weakly as prognosticators; E1 might become a strong prognostic marker for OS and PFS in OPCs.


Asunto(s)
Neoplasias de Cabeza y Cuello/virología , Proteínas Oncogénicas Virales/análisis , Neoplasias Orofaríngeas/virología , Papillomaviridae/aislamiento & purificación , Infecciones por Papillomavirus/virología , Adulto , Anciano , Anciano de 80 o más Años , Biomarcadores de Tumor/análisis , Femenino , Humanos , Masculino , Persona de Mediana Edad , Papillomaviridae/genética , Pronóstico , Estudios Retrospectivos , Adulto Joven
8.
Anticancer Res ; 36(5): 2211-5, 2016 May.
Artículo en Inglés | MEDLINE | ID: mdl-27127125

RESUMEN

BACKGROUND/AIM: Head and neck cancer (HNC) is characterized by epidermal growth factor receptor (EGFR) overexpression and radiotherapy (RT) resistance. Cancer cells are able to survive and proliferate in hypoxic conditions. Hypoxia can be transiently interrupted by phases of reoxygenation. This work aimed to analyze the reoxygenation effect on proliferation in response to radiation in HNC cells. MATERIALS AND METHODS: HNC cell lines CAL33 and CAL166 were subjected to an 8-Gy radiation dose in hypoxia and/or after reoxygenation. Cell proliferation and molecular factors involved in response to treatments were studied. RESULTS: Cytotoxicity test confirmed radioresistance in hypoxia and highlighted that reoxygenation before RT restores sensitivity in both cell lines. Our results showed a similar proliferation inhibition effect and EGFR modulation but a different cell death mechanism in the two cell lines after treatment. CONCLUSION: Reoxygenation before RT rescued radiosensitivity in HNC cells.


Asunto(s)
Carcinoma de Células Escamosas/patología , Hipoxia de la Célula/efectos de los fármacos , Neoplasias de Cabeza y Cuello/patología , Oxígeno/farmacología , Tolerancia a Radiación/efectos de los fármacos , Apoptosis/efectos de los fármacos , División Celular/efectos de los fármacos , Línea Celular Tumoral , Inhibidor p21 de las Quinasas Dependientes de la Ciclina/biosíntesis , Inhibidor p21 de las Quinasas Dependientes de la Ciclina/genética , Inhibidor p27 de las Quinasas Dependientes de la Ciclina/biosíntesis , Inhibidor p27 de las Quinasas Dependientes de la Ciclina/genética , Proteínas de Unión al ADN/biosíntesis , Proteínas de Unión al ADN/genética , Endonucleasas/biosíntesis , Endonucleasas/genética , Receptores ErbB/biosíntesis , Receptores ErbB/fisiología , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Genes erbB-1/efectos de los fármacos , Humanos , Subunidad alfa del Factor 1 Inducible por Hipoxia/biosíntesis , Subunidad alfa del Factor 1 Inducible por Hipoxia/genética , Proteínas de Neoplasias/biosíntesis , Proteínas de Neoplasias/genética
9.
Int J Biol Markers ; 31(2): e183-92, 2016 May 28.
Artículo en Inglés | MEDLINE | ID: mdl-26916894

RESUMEN

PURPOSE: Adequate biomarkers are still required to optimize therapy in patients with locally advanced head and neck squamous carcinomas (HNSCC) treated with chemoradiotherapy (CRT). METHODS: We updated the follow-up of 66 HNSCC patients treated with CRT we described more than 10 years ago, focusing on SNP Arg/Pro (R/P) at codon 72 and somatic mutations in TP53 and on SNP309 in the MDM2 gene. RESULTS: In wild-type TP53 cases, overall survival (OS) was longer in 72RR and less favorable in 72PP (p = 0.005); when TP53 was mutated, OS was longest in 72PP and less favorable in 72RR and 72RP (p = 0.058). Median OS was significantly shorter in patients with MDM2 SNP309 GG or GT genotypes compared with the TT genotype (p = 0.002). CONCLUSIONS: TP53 SNP72 may be useful in selecting patients for CRT, but has to be related to somatic TP53 mutations. The MDM2 SNP309, easily determined in peripheral blood, might be more convenient as a predictive biomarker.


Asunto(s)
Biomarcadores de Tumor/genética , Carcinoma de Células Escamosas/tratamiento farmacológico , Carcinoma de Células Escamosas/genética , Neoplasias de Cabeza y Cuello/tratamiento farmacológico , Neoplasias de Cabeza y Cuello/genética , Proteínas Proto-Oncogénicas c-mdm2/genética , Proteína p53 Supresora de Tumor/genética , Adulto , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Carcinoma de Células Escamosas/patología , Femenino , Estudios de Seguimiento , Genotipo , Neoplasias de Cabeza y Cuello/patología , Humanos , Masculino , Persona de Mediana Edad , Mutación Missense , Estadificación de Neoplasias , Compuestos Organoplatinos/administración & dosificación , Polimorfismo de Nucleótido Simple , Carcinoma de Células Escamosas de Cabeza y Cuello
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