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1.
Int J Mol Sci ; 21(10)2020 May 12.
Artículo en Inglés | MEDLINE | ID: mdl-32408513

RESUMEN

The metabolic abnormality observed in tumors is characterized by the dependence of cancer cells on glycolysis for their energy requirements. Cancer cells also exhibit a high level of reactive oxygen species (ROS), largely due to the alteration of cellular bioenergetics. A highly coordinated interplay between tumor energetics and ROS generates a powerful phenotype that provides the tumor cells with proliferative, antiapoptotic, and overall aggressive characteristics. In this review article, we summarize the literature on how ROS impacts energy metabolism by regulating key metabolic enzymes and how metabolic pathways e.g., glycolysis, PPP, and the TCA cycle reciprocally affect the generation and maintenance of ROS homeostasis. Lastly, we discuss how metabolic adaptation in cancer influences the tumor's response to chemotherapeutic drugs. Though attempts of targeting tumor energetics have shown promising preclinical outcomes, the clinical benefits are yet to be fully achieved. A better understanding of the interaction between metabolic abnormalities and involvement of ROS under the chemo-induced stress will help develop new strategies and personalized approaches to improve the therapeutic efficiency in cancer patients.


Asunto(s)
Resistencia a Antineoplásicos , Metabolismo Energético , Glucólisis , Redes y Vías Metabólicas , Neoplasias/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Adaptación Fisiológica , Animales , Homeostasis , Humanos
2.
Toxicol Appl Pharmacol ; 378: 114606, 2019 09 01.
Artículo en Inglés | MEDLINE | ID: mdl-31170415

RESUMEN

Inorganic arsenic is an environmental carcinogen that poses a major global public health risk. A high percentage of drinking water from wells in the U.S. contains higher-than-normal levels of arsenic, suggesting an increased risk of arsenic-induced deleterious effects. In addition to primary preventive measures, therapeutic strategies need to effectively address and integrate multiple molecular mechanisms underlying arsenic-induced carcinogenesis. We previously showed that the loss of miR-199a-5p in arsenic-transformed cells is pivotal to promote arsenic-induced angiogenesis and tumor growth in lung epithelial cells. In this study, we further showed that subacute or chronic exposure to arsenic diminished miR-199a-5p levels largely due to DNA methylation, which was achieved by increased DNA methyltransferase-1 (DNMT1) activity, mediated by the formation of specific protein 1 (Sp1)/DNMT1 complex. In addition to the DNA hypermethylation, arsenic exposure also repressed miR-199a transcription through a transcriptional repressor Sp1. We further identified an association between miR-199a-5p repression and the arsenic-mediated energy metabolic shift, as reflected by mitochondria defects and a switch to glycolysis, in which a glycolytic enzyme pyruvate kinase 2 (PKM2) was a functional target of miR-199a-5p. Taken together, the repression of miR-199a-5p through both Sp1-dependent DNA methylation and Sp1 transcriptional repression promotes an arsenic-mediated metabolic shift from mitochondria respiration to aerobic glycolysis via PKM2.


Asunto(s)
Arsénico/efectos adversos , Metilación de ADN/efectos de los fármacos , MicroARNs/genética , Factor de Transcripción Sp1/genética , Activación Metabólica/efectos de los fármacos , Carcinogénesis/efectos de los fármacos , Línea Celular , Glucólisis/efectos de los fármacos , Humanos
3.
Arch Pharm (Weinheim) ; 350(11)2017 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-29034498

RESUMEN

An efficient synthesis of novel 3-(3-aryl-1-phenyl-1H-pyrazol-4-yl)-5,7-dimethyl-[1,2,4]triazolo[4,3-a]-pyrimidines was accomplished by the oxidation of pyrimidinylhydrazones by using organoiodine(III) reagent. All new triazolopyrimidine derivatives bearing the pyrazole scaffold were screened to evaluate them as a reproductive toxicant in the testicular germ cells of goat (Capra hircus). This study aimed at assessing the cytological and biochemical changes in testicular germ cells after the exposure to triazolopyrimidines in a dose- and time-dependent manner. Histomorphological analysis, fluorescence assays, apoptosis quantification, and terminal deoxynucleotidyl transferase dUTP-mediated nick-end labeling (TUNEL) assays were performed to determine cytological changes, whereas thiobarbituric acid-reactive substance (TBARS) and ferric reducing antioxidant power (FRAP) assays were carried out to measure the oxidative stress in triazolopyrimidines treated germ cells. The parallel use of these methods enabled us to determine the role of triazolopyrimidines in inducing apoptosis as a consequence of cytogenetic damage and oxidative stress generated in testicular germ cells of goat.


Asunto(s)
Apoptosis/efectos de los fármacos , Estrés Oxidativo/efectos de los fármacos , Pirazoles/farmacología , Pirimidinas/farmacología , Animales , Aberraciones Cromosómicas/inducido químicamente , Relación Dosis-Respuesta a Droga , Cabras , Etiquetado Corte-Fin in Situ , Masculino , Pirazoles/síntesis química , Pirazoles/química , Pirimidinas/síntesis química , Pirimidinas/química , Espermatozoides/efectos de los fármacos , Testículo/citología , Testículo/efectos de los fármacos , Factores de Tiempo
4.
Carcinogenesis ; 37(12): 1161-1169, 2016 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-27655834

RESUMEN

Esophageal adenocarcinoma (EA) is one of the fastest rising tumors in the USA. The major risk factor for EA is gastroesophageal reflux disease (GERD). During GERD, esophageal cells are exposed to refluxate which contains gastric acid frequently mixed with duodenal bile. This may lead to mucosal injury and Barrett's metaplasia (BE) that are important factors contributing to development of EA. In this study, we investigated DNA damage in BE cells exposed to acidic bile salts and explored for potential protective strategies. Exposure of BE cells to acidic bile salts led to significant DNA damage, which in turn, was due to generation of reactive oxygen species (ROS). We found that acidic bile salts induce a rapid increase in superoxide radicals and hydrogen peroxide, which were determined using electron paramagnetic resonance spectroscopy and Amplex Red assay. Analyzing a panel of natural antioxidants, we identified apocynin to be the most effective in protecting esophageal cells from DNA damage induced by acidic bile salts. Mechanistic analyses showed that apocynin inhibited ROS generation and increases the DNA repair capacity of BE cells. We identified BRCA1 and p73 proteins as apocynin targets. Downregulation of p73 inhibited the protective effect of apocynin. Taken together, our results suggest potential application of natural compounds such as apocynin for prevention of reflux-induced DNA damage and GERD-associated tumorigenesis.


Asunto(s)
Acetofenonas/administración & dosificación , Adenocarcinoma/metabolismo , Esófago de Barrett/metabolismo , Neoplasias Esofágicas/metabolismo , Reflujo Gastroesofágico/metabolismo , Ácidos/efectos adversos , Adenocarcinoma/tratamiento farmacológico , Adenocarcinoma/etiología , Adenocarcinoma/patología , Antioxidantes/administración & dosificación , Proteína BRCA1/biosíntesis , Esófago de Barrett/tratamiento farmacológico , Esófago de Barrett/etiología , Esófago de Barrett/patología , Ácidos y Sales Biliares/efectos adversos , Ácidos y Sales Biliares/metabolismo , Línea Celular Tumoral , Daño del ADN/efectos de los fármacos , Reparación del ADN/efectos de los fármacos , Neoplasias Esofágicas/tratamiento farmacológico , Neoplasias Esofágicas/etiología , Neoplasias Esofágicas/patología , Ácido Gástrico/metabolismo , Reflujo Gastroesofágico/complicaciones , Reflujo Gastroesofágico/patología , Humanos , Especies Reactivas de Oxígeno/metabolismo
5.
Genome Res ; 23(9): 1446-61, 2013 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-23796952

RESUMEN

The functional roles of SNPs within the 8q24 gene desert in the cancer phenotype are not yet well understood. Here, we report that CCAT2, a novel long noncoding RNA transcript (lncRNA) encompassing the rs6983267 SNP, is highly overexpressed in microsatellite-stable colorectal cancer and promotes tumor growth, metastasis, and chromosomal instability. We demonstrate that MYC, miR-17-5p, and miR-20a are up-regulated by CCAT2 through TCF7L2-mediated transcriptional regulation. We further identify the physical interaction between CCAT2 and TCF7L2 resulting in an enhancement of WNT signaling activity. We show that CCAT2 is itself a WNT downstream target, which suggests the existence of a feedback loop. Finally, we demonstrate that the SNP status affects CCAT2 expression and the risk allele G produces more CCAT2 transcript. Our results support a new mechanism of MYC and WNT regulation by the novel lncRNA CCAT2 in colorectal cancer pathogenesis, and provide an alternative explanation of the SNP-conferred cancer risk.


Asunto(s)
Inestabilidad Cromosómica , Cromosomas Humanos Par 8/genética , Neoplasias del Colon/genética , ARN Largo no Codificante/genética , ARN Largo no Codificante/metabolismo , Animales , Neoplasias de la Mama/genética , Neoplasias de la Mama/metabolismo , Estudios de Casos y Controles , Línea Celular Tumoral , Neoplasias del Colon/metabolismo , Neoplasias del Colon/patología , Femenino , Regulación Neoplásica de la Expresión Génica , Humanos , Masculino , Ratones , MicroARNs/genética , MicroARNs/metabolismo , Metástasis de la Neoplasia/genética , Polimorfismo de Nucleótido Simple , Proteínas Proto-Oncogénicas c-myc/genética , Proteínas Proto-Oncogénicas c-myc/metabolismo , Proteína 1 Similar al Factor de Transcripción 7/genética , Proteína 1 Similar al Factor de Transcripción 7/metabolismo , Transcripción Genética , Vía de Señalización Wnt
6.
Mol Ther ; 22(8): 1494-1503, 2014 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-24791940

RESUMEN

The microRNA (miR)-200s and their negative regulator ZEB1 have been extensively studied in the context of the epithelial-mesenchymal transition. Loss of miR-200s has been shown to enhance cancer aggressiveness and metastasis, whereas replacement of miR-200 miRNAs has been shown to inhibit cell growth in several types of tumors, including lung cancer. Here, we reveal a novel function of miR-200c, a member of the miR-200 family, in regulating intracellular reactive oxygen species signaling and explore a potential application for its use in combination with therapies known to increase oxidative stress such as radiation. We found that miR-200c overexpression increased cellular radiosensitivity by direct regulation of the oxidative stress response genes PRDX2, GAPB/Nrf2, and SESN1 in ways that inhibits DNA double-strand breaks repair, increase levels of reactive oxygen species, and upregulate p21. We used a lung cancer xenograft model to further demonstrate the therapeutic potential of systemic delivery of miR-200c to enhance radiosensitivity in lung cancer. Our findings suggest that the antitumor effects of miR-200c result partially from its regulation of the oxidative stress response; they further suggest that miR-200c, in combination with radiation, could represent a therapeutic strategy in the future.


Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas/terapia , Neoplasias Pulmonares/terapia , MicroARNs/metabolismo , Fármacos Sensibilizantes a Radiaciones/metabolismo , Animales , Línea Celular Tumoral , Regulación Neoplásica de la Expresión Génica , Humanos , Masculino , Ratones , Ratones Desnudos , MicroARNs/genética , Trasplante de Neoplasias , Especies Reactivas de Oxígeno/metabolismo , Transducción de Señal/efectos de los fármacos , Transducción de Señal/efectos de la radiación
7.
Anticancer Drugs ; 25(3): 296-302, 2014 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-24201306

RESUMEN

Pancreatic cancer has dismally low mean survival rates worldwide. Only a few chemotherapeutic agents including gemcitabine have been shown to improve the survival of pancreatic cancer patients. Biochanin A, an isoflavone, is known to exert an anticancer effect on various cancer types. In this study, we examined the anticancer properties of biochanin A on pancreatic cancer cells. The effect of biochanin A on cellular survival, apoptosis, and proliferation was analyzed using MTT, flow cytometry, and colony formation assay. The effect of biochanin A on pancreatic cancer's mitogenic signaling was determined using western blot analysis. Migration assay and zymography were used to determine biochanin A's effect on pancreatic cancer progression. Biochanin A induced dose-dependent toxicity on pancreatic cancer cells (Panc1 and AsPC-1). It reduced colony formation ability of Panc1 cells and induced dose-dependent apoptosis. Activation of Akt and MAPK was inhibited. Furthermore, the migratory and invasive potential of the cancer cells was also reduced. The results suggest that biochanin A is effective in reducing pancreatic cancer cell survival by inhibiting their proliferation and inducing apoptosis. It affects mitogenic, migratory, and invasive processes involved in cancer progression. These findings may lead to novel approaches to treat pancreatic cancer using isoflavones in combination with other therapeutic drugs.


Asunto(s)
Antineoplásicos/farmacología , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Genisteína/farmacología , Neoplasias Pancreáticas/patología , Apoptosis/efectos de los fármacos , Línea Celular Tumoral/efectos de los fármacos , Humanos , Invasividad Neoplásica , Transducción de Señal
8.
Cancer ; 119(10): 1768-75, 2013 May 15.
Artículo en Inglés | MEDLINE | ID: mdl-23423860

RESUMEN

The c-Met/hepatocyte growth factor receptor and its family members are known to promote cancer cell migration and invasion. Signaling within and beyond this pathway contributes to the systemic spread of metastases through induction of the epithelial-mesenchymal transition, a process also implicated in mediating resistance to current anticancer therapies, including radiation. Induction of c-Met has also been observed after irradiation, suggesting that c-Met participates in radiation-induced disease progression through the epithelial-mesenchymal transition. Therefore, c-Met inhibition is an attractive target for potentially mitigating radiation resistance. This article summarizes key findings regarding crosstalk between radiotherapy and c-Met and discusses studies performed to date in which c-Met inhibition was used as a strategy to increase cellular radiosensitivity.


Asunto(s)
Antineoplásicos/farmacología , Neoplasias/metabolismo , Proteínas Proto-Oncogénicas c-met/antagonistas & inhibidores , Proteínas Proto-Oncogénicas c-met/metabolismo , Transducción de Señal/efectos de la radiación , Anilidas/farmacología , Animales , Anticuerpos Monoclonales/farmacología , Anticuerpos Monoclonales Humanizados , Movimiento Celular/efectos de la radiación , Daño del ADN/efectos de la radiación , Transición Epitelial-Mesenquimal/efectos de los fármacos , Transición Epitelial-Mesenquimal/efectos de la radiación , Clorhidrato de Erlotinib , Regulación Neoplásica de la Expresión Génica , Humanos , Invasividad Neoplásica , Neovascularización Patológica , Piridinas/farmacología , Pirrolidinonas/farmacología , Quinazolinas/farmacología , Quinolinas/farmacología , Tolerancia a Radiación , Transducción de Señal/efectos de los fármacos , Regulación hacia Arriba
9.
Indian J Orthop ; 57(6): 868-875, 2023 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-37214364

RESUMEN

Aim: To evaluate the efficacy of combined use of pre-operative oral and post-operative intravenous (IV) tranexamic acid (TXA) as an effective blood conserving regimen in total knee arthroplasty (TKA) and compare its outcome with other modes of TXA administration. Patients and Methods: A prospective observational study was conducted on 25 patients with osteoarthritis knee undergoing TKA. Patients were given 1950 mg of oral TXA pre-operatively and 15 mg/kg of IV TXA post-operatively before tourniquet deflation. The outcome of the study in terms of peri-operative (intra-operative and post-operative) blood loss estimation, drain output, percentage fall in haemoglobin, and knee HSS scores pre-operatively and on subsequent follow-up were compared with the outcome of previous studies conducted in the same institution with intra-operative topical TXA administration, pre-operative oral TXA administration and without TXA administration. Results: The mean drain volume was 307.30 ± 148.00 ml and 22 (88%) patients had a drain volume less than 500 ml. The mean post-operative haemoglobin value was 10.53 ± 1.75 g/dl. It was observed that 18 (72%) of patients had up to 15% fall in haemoglobin. The mean percentage fall was 11.92%. In this study, 22 (88%) patients did not require any blood transfusion. Mean blood loss was 369.6 ± 159.96 ml. Maximum patients had less than 500 ml blood loss. No incidence of implant loosening, infection or wound gaping, clinically evident DVT/pulmonary thromboembolism was observed in the present study. We analysed total modified HSS knee score from pre-operative to 6 months follow-up using multi-group repeated measures analysis of variance (ANOVA), the difference in total modified HSS knee score between all the duration was observed to be highly significant (p < 0.001). Discussion: Combined administration of pre-operative oral and post-operative IV TXA is a safe and effective blood-conserving strategy in patients undergoing TKA along with the use of tourniquet. The outcome in terms of post-operative blood loss and drain output and the knee HSS score is comparable to the other modes of administration. Supplementary Information: The online version contains supplementary material available at 10.1007/s43465-023-00875-w.

10.
Int Orthop ; 36(2): 271-6, 2012 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-21735206

RESUMEN

PURPOSE: The World Health Organisation has declared tuberculosis (TB) a global emergency and spinal tuberculosis is one of the most common forms. There is still controversy regarding optimum duration of treatment in osteoarticular tuberculosis due to the lack of well-defined criteria for the end point of treatment. Emergence of multi drug resistant tuberculosis, primarily due to use of poor drug regimens, further illustrates the need of newer and more effective diagnostic methods, particularly in developing countries. METHODS: This prospective clinical study to evaluate the role of technetium ((99m)Tc)-ciprofloxacin scan as a tool to assess disease activity involved in 15 cases of TB spine with a mean age of 32.2 years (range 21-72). Following a clinico-radiological diagnosis, all patients were treated with standard anti tubercular treatment and a scan was done at zero, three and six months of treatment with tracer activity being recorded and compared in sequential scans along with a parallel evaluation of clinical and radiological profile at regular intervals. RESULTS: Out of 15 cases, nine had an initially positive bone scan. Two patients (22%) converted to negative scans at three months, whereas the remaining seven (78%) turned negative at six months. The end of six months treatment was also accompanied by clinico-radiological resolution in all cases. CONCLUSION: In conclusion, technetium ((99m)Tc)-ciprofloxacin scan could be a promising tool for monitoring disease activity in selected cases of tuberculosis spine as an alternative for therapeutic drug monitoring; however, due to the small sample size, studies with a large number of patients might be of help in defining these cases in a better way.


Asunto(s)
Ciprofloxacina/análogos & derivados , Compuestos de Organotecnecio , Tiocarbamatos , Tuberculosis de la Columna Vertebral/diagnóstico por imagen , Adulto , Anciano , Comorbilidad , Diabetes Mellitus/epidemiología , Femenino , Humanos , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Cintigrafía , Tuberculosis de la Columna Vertebral/diagnóstico , Tuberculosis de la Columna Vertebral/epidemiología
11.
J Foot Ankle Surg ; 51(4): 479-81, 2012.
Artículo en Inglés | MEDLINE | ID: mdl-22342606

RESUMEN

Muscle abscess presenting as nerve palsy is rare and has not been previously reported in the common peroneal nerve (CPN). The objective of this case report is to describe the diagnosis and treatment of an uncommon presentation of peroneal abscess in the leg of an otherwise healthy man. We present a case of CPN palsy in a 50-year-old immunocompetent man with no other comorbid medical condition secondary to peroneus longus abscess. The diagnosis was suggested by magnetic resonance imaging examination and confirmed by intraoperative findings. After surgical drainage of the abscess, the patient made a complete recovery. A review of the literature confirms that peroneus longus abscess giving rise to CPN palsy has not been described. Early diagnosis and surgical drainage of the compressing abscess can produce a favorable outcome.


Asunto(s)
Absceso/complicaciones , Pierna , Enfermedades Musculares/complicaciones , Neuropatías Peroneas/etiología , Absceso/diagnóstico , Absceso/cirugía , Humanos , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Enfermedades Musculares/diagnóstico , Enfermedades Musculares/cirugía
12.
Med Oncol ; 39(12): 227, 2022 Sep 29.
Artículo en Inglés | MEDLINE | ID: mdl-36175776

RESUMEN

Metabolic reprogramming wherein the cancer cells exhibit altered energetics is a hallmark of cancer. Although recent discoveries have enhanced our understanding of tumor metabolism, the therapeutic utility of targeting tumor metabolism is not yet realized. Glutamine, a non-essential amino acid, plays a critical role in regulating tumor metabolism and provides an alternative tumor energy source. In this study, we investigate the molecular mechanism regulated by glutamine and elucidate if targeting glutamine metabolism would enhance the efficacy of cancer chemotherapy. Using clonogenic and cell cycle analysis, we found that deprivation of glutamine suppress the growth of cancer cells. Mechanistically we demonstrate that glutamine stabilizes myc by preventing its ubiquitination through alpha-ketoglutarate. Inhibition of glutamine metabolism enhanced the sensitivity of tumor cells to chemotherapeutic agent paclitaxel. Our results delineate the mechanism behind glutamine-induced myc stabilization, and they provide a viable strategy to target cancer with a glutamine metabolism inhibitor in the clinic.


Asunto(s)
Glutamina , Ácidos Cetoglutáricos , Instituciones de Atención Ambulatoria , Aminoácidos , Humanos , Ácidos Cetoglutáricos/farmacología , Paclitaxel/farmacología
13.
Int Orthop ; 35(12): 1869-74, 2011 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-21116818

RESUMEN

In the evidence-based medicine era, objective treatment guidelines have been laid down for pulmonary tuberculosis, but the same is not true for osteoarticular tuberculosis. This has led to demands for standardising the treatment protocol and to a lack of consensus between doctors regarding the composition and duration of treatment. Twenty-five patients with extraspinal osteoarticular tuberculosis were evaluated prospectively. Following the diagnosis, patients were given standard directly observed treatment short course (DOTS) regimen and were monitored for disease activity at zero, three and six months with the help of technetium-99m-labelled ciprofloxacin ((99m)Tc) scan. Tracer activity at the site was recorded and compared on sequential scans. Clinical and radiological profile of all the patients were also recorded at regular intervals and compared. All 25 cases had a positive (99m)Tc bone scan initially. Four patients (16%) converted to negative scans at three months, whereas the remaining 21 patients (84%) showed negative scans at six months. The end of six months therapy also coincided with resolution of clinical and radiological parameters in all cases. In conclusion, (99m)Tc scan is a promising tool for monitoring drug response in osteoarticular tuberculosis; however, due to the small sample size, studies with a large number of patients might be of help.


Asunto(s)
Antituberculosos/uso terapéutico , Ciprofloxacina/análogos & derivados , Monitoreo de Drogas/métodos , Compuestos de Organotecnecio , Radiofármacos , Tuberculosis Osteoarticular/diagnóstico por imagen , Tuberculosis Osteoarticular/tratamiento farmacológico , Adolescente , Adulto , Anciano , Niño , Preescolar , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Cintigrafía , Factores de Tiempo , Resultado del Tratamiento , Adulto Joven
14.
World J Gastroenterol ; 27(39): 6527-6550, 2021 Oct 21.
Artículo en Inglés | MEDLINE | ID: mdl-34754151

RESUMEN

Pancreatic ductal adenocarcinoma (PDAC) is the third leading cause of cancer-related deaths in the United States. Although chemotherapeutic regimens such as gemcitabine+ nab-paclitaxel and FOLFIRINOX (FOLinic acid, 5-Fluroruracil, IRINotecan, and Oxaliplatin) significantly improve patient survival, the prevalence of therapy resistance remains a major roadblock in the success of these agents. This review discusses the molecular mechanisms that play a crucial role in PDAC therapy resistance and how a better understanding of these mechanisms has shaped clinical trials for pancreatic cancer chemotherapy. Specifically, we have discussed the metabolic alterations and DNA repair mechanisms observed in PDAC and current approaches in targeting these mechanisms. Our discussion also includes the lessons learned following the failure of immunotherapy in PDAC and current approaches underway to improve tumor's immunological response.


Asunto(s)
Carcinoma Ductal Pancreático , Neoplasias Pancreáticas , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Carcinoma Ductal Pancreático/tratamiento farmacológico , Resistencia a Antineoplásicos , Humanos , Inmunoterapia , Neoplasias Pancreáticas/tratamiento farmacológico
15.
Cancer Metab ; 8: 19, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-32974013

RESUMEN

Pancreatic ductal adenocarcinoma (PDAC) is one of the most malignant forms of cancer. Lack of effective treatment options and drug resistance contributes to the low survival among PDAC patients. In this study, we investigated the metabolic alterations in pancreatic cancer cells that do not respond to the EGFR inhibitor erlotinib. We selected erlotinib-resistant pancreatic cancer cells from MiaPaCa2 and AsPC1 cell lines. Metabolic profiling of erlotinib-resistant cells revealed a significant downregulation of glycolytic activity and reduced level of glycolytic metabolites compared to the sensitive cells. The resistant cells displayed elevated expression of the pentose phosphate pathway (PPP) enzymes involved in ROS regulation and nucleotide biosynthesis. The enhanced PPP elevated cellular NADPH/NADP+ ratio and protected the cells from reactive oxygen species (ROS)-induced damage. Inhibition of PPP using 6-aminonicotinamide (6AN) elevated ROS levels, induced G1 cell cycle arrest, and sensitized resistant cells to erlotinib. Genetic studies identified elevated PPP enzyme glucose-6-phosphate dehydrogenase (G6PD) as an important contributor to erlotinib resistance. Mechanistically, our data showed that upregulation of inhibitor of differentiation (ID1) regulates G6PD expression in resistant cells thus contributing to altered metabolic phenotype and reduced response to erlotinib. Together, our results highlight an underlying role of tumor metabolism in PDAC drug response and identify G6PD as a target to overcome drug resistance.

16.
Oncogene ; 39(49): 7181-7195, 2020 12.
Artículo en Inglés | MEDLINE | ID: mdl-33037411

RESUMEN

The development of resistance to EGFR Tyrosine kinase inhibitors (TKIs) in NSCLC with activating EGFR mutations is a critical limitation of this therapy. In addition to genetic alterations such as EGFR secondary mutation causing EGFR-TKI resistance, compensatory activation of signaling pathways without interruption of genome integrity remains to be defined. In this study, we identified S6K1/MDM2 signaling axis as a novel bypass mechanism for the development of EGFR-TKI resistance. The observation of S6K1 as a candidate mechanism for resistance to EGFR TKI therapy was investigated by interrogation of public databases and a clinical cohort to establish S6K1 expression as a prognostic/predictive biomarker. The role of S6K1 in TKI resistance was determined in in vitro gain-and-loss of function studies and confirmed in subcutaneous and orthotopic mouse lung cancer models. Blockade of S6K1 by a specific inhibitor PF-4708671 synergistically enhanced the efficacy of TKI without showing toxicity. The mechanistic study showed the inhibition of EGFR caused nuclear translocation of S6K1 for binding with MDM2 in resistant cells. MDM2 is a downstream effector of S6K1-mediated TKI resistance. Taken together, we present evidence for the reversal of resistance to EGFR TKI by the addition of small molecule S6K1/MDM2 antagonists that could have clinical benefit.


Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas/patología , Resistencia a Antineoplásicos/efectos de los fármacos , Neoplasias Pulmonares/patología , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Quinasas S6 Ribosómicas 70-kDa/antagonistas & inhibidores , Adulto , Animales , Línea Celular Tumoral , Transformación Celular Neoplásica , Receptores ErbB/antagonistas & inhibidores , Humanos , Masculino , Ratones , Mutación , Pronóstico , Proteínas Proto-Oncogénicas c-mdm2/metabolismo , Proteínas Quinasas S6 Ribosómicas 70-kDa/metabolismo , Transducción de Señal/efectos de los fármacos , Regulación hacia Arriba/efectos de los fármacos
17.
J Biomed Res ; 36(1): 68-69, 2022 Jan 13.
Artículo en Inglés | MEDLINE | ID: mdl-35403613
18.
Sci Rep ; 7(1): 9956, 2017 08 30.
Artículo en Inglés | MEDLINE | ID: mdl-28855537

RESUMEN

Gastroesophageal reflux disease (GERD) is the strongest known risk factor for esophageal adenocarcinoma. In the center of tumorigenic events caused by GERD is repeated damage of esophageal tissues by the refluxate. In this study, we focused on a genotoxic aspect of exposure of esophageal cells to acidic bile reflux (BA/A). Analyzing cells generated from patients with Barrett's esophagus and human esophageal specimens, we found that BA/A cause significant DNA damage that is mediated by reactive-oxygen species. ROS originate from mitochondria and NADPH oxidases. We specifically identified NOX1 and NOX2 enzymes to be responsible for ROS generation. Inhibition of NOX2 and NOX1 with siRNA or chemical inhibitors significantly suppresses ROS production and DNA damage induced by BA/A. Mechanistically, our data showed that exposure of esophageal cells to acidic bile salts induces phosphorylation of the p47phox subunit of NOX2 and its translocation to the cellular membrane. This process is mediated by protein kinase C, which is activated by BA/A. Taken together, our studies suggest that inhibition of ROS induced by reflux can be a useful strategy for preventing DNA damage and decreasing the risk of tumorigenic transformation caused by GERD.


Asunto(s)
Esófago de Barrett/patología , Daño del ADN , Células Epiteliales/patología , NADPH Oxidasa 1/metabolismo , NADPH Oxidasa 2/metabolismo , Ácidos y Sales Biliares/toxicidad , Células Cultivadas , Humanos , Especies Reactivas de Oxígeno/toxicidad
19.
Oncotarget ; 6(3): 1531-43, 2015 Jan 30.
Artículo en Inglés | MEDLINE | ID: mdl-25605238

RESUMEN

H. pylori infection is the strongest known risk factor for gastric cancer. Inhibition of host tumor suppressor mechanisms by the bacteria underlies the development of this disease. Among the tumor suppressors affected by H. pylori are p53 and E-cadherin, which inhibition has been shown to increase the risk of gastric cancer. In this report, we investigated the interaction between E-cadherin and p53 in H. pylori-infected cells. We found that downregulation of E-cadherin leads to cellular stress and activation of p53. In the setting of H. pylori infection, this mechanism, however, is disrupted. We found that although co-culture of gastric epithelial cells with H. pylori led to downregulation of E-cadherin and cellular stress, it resulted in inhibition of p53, which is mediated by intracellular Erk kinases and HDM2 protein induced by H. pylori. Experimental inhibition of HDM2/p53 interactions restored p53 activity, and decreased survival of infected cells. Collectively, our results revealed that regulation of p53 and E-cadherin is tightly linked through the p53 stress response mechanism that is inhibited by H. pylori via activation of Erk1/2-HDM2-p53 pathway leading to survival of damaged cells. This might be advantageous to the bacteria but may increase the cancer risk.


Asunto(s)
Infecciones por Helicobacter/microbiología , Helicobacter pylori/fisiología , Sistema de Señalización de MAP Quinasas , Proteínas Proto-Oncogénicas c-mdm2/metabolismo , Neoplasias Gástricas/microbiología , Proteína p53 Supresora de Tumor/metabolismo , Animales , Línea Celular Tumoral , Gerbillinae , Infecciones por Helicobacter/metabolismo , Infecciones por Helicobacter/patología , Humanos , Neoplasias Gástricas/metabolismo , Neoplasias Gástricas/patología , Transfección
20.
Eur J Med Chem ; 39(12): 1073-7, 2004 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-15571869

RESUMEN

Synthesis of some new 3-aryl/hetryl-5,7-dimethyl-1,2,4-triazolo[4,3-a]pyrimidines (3a-k) has been accomplished by the oxidation of 4,6-dimethyl-2-pyrimidinylhydrazones of various aldehydes with iodobenzene diacetate in dichloromethane. Nine new compounds (3b-g and 3i-k) were tested in vitro for their antibacterial activity. Two compounds, namely 3-(4'-pyridyl)-5,7-dimethyl-1,2,4-triazolo[4,3-a]pyrimidine (3k) and 3-(3',4'-dimethoxyphenyl)-5,7-dimethyl-1,2,4-triazolo[4,3-a]pyrimidine (3f), were associated with substantially higher antibacterial activity than some commercial antibiotics against Bacillus subtilis, Escherichia coli, Staphylococcus aureus and Salmonella typhi at MIC (minimum inhibitory concentration) i.e. 10 microg/ml.


Asunto(s)
Antibacterianos/síntesis química , Yodobencenos/química , Pirimidinas/síntesis química , Antibacterianos/farmacología , Bacillus subtilis/efectos de los fármacos , Catálisis , Escherichia coli/efectos de los fármacos , Pirimidinas/farmacología , Salmonella typhi/efectos de los fármacos , Staphylococcus aureus/efectos de los fármacos , Triazoles/síntesis química , Triazoles/farmacología
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