Pancreatic ductal adenocarcinoma chemoresistance: From metabolism reprogramming to novel treatment / 中华医学杂志(英文版)

As pancreatic cancer (PC) is highly malignant, its patients tend to develop metastasis at an early stage and show a poor response to conventional chemotherapies. First-line chemotherapies for PC, according to current guidelines, include fluoropyrimidine- and gemcitabine-based regimens. Accumulating research on drug resistance has shown that biochemical metabolic aberrations in PC, especially those involving glycolysis and glutamine metabolism, are highly associated with chemoresistance. Additionally, lipid metabolism is a major factor in chemoresistance. However, emerging compounds that target these key metabolic pathways have the potential to overcome chemoresistance. This review summarizes how PC develops chemoresistance through aberrations in biochemical metabolism and discusses novel critical targets and pathways within cancer metabolism for new drug research.

Synergistic Antitumor Effect of Everolimus Combined with Gemcitabine on Diffuse Large B-Cell Lymphoma / 中国实验血液学杂志

OBJECTIVE@#To investigate the effects of mTOR inhibitors everolimus (EVE) and gemcitabine (GEM) on the proliferation, apoptosis and cell cycle of diffuse large B-cell lymphoma (DLBCL) cell line U2932, and further explore the molecular mechanisms, so as to provide new ideas and experimental basis for the clinical treatment of DLBCL.@*METHODS@#The effect of EVE and GEM on the proliferation of U2932 cells was detected by CCK-8 assay, the IC50 of the two drugs was calculated, and the combination index (CI=) of the two drugs was calculated by CompuSyn software. The effect of EVE and GEM on apoptosis of U2932 cells was detected by flow cytometry with AnnexinV-FITC/PI staining. Flow cytometry with propidium iodide (PI) staining was used to detect the effect of EVE and GEM on the cell cycle of U2932 cells. Western blot assay was used to detect the effects of EVE and GEM on the channel proteins p-mTOR and p-4EBP1, the anti-apoptotic proteins MCL-1 and Survivin, and the cell cycle protein Cyclin D1.@*RESULTS@#Both EVE and GEM could significantly inhitbit the proliferation of U2932 cells in a time- and dose-dependent manner (r=0.465, 0.848; 0.555, 0.796). According to the calculation of CompuSyn software, EVE combined with GEM inhibited the proliferation of U2932 cells at 24, 48 and 72 h with CI=<1, which had a synergistic effect. After treated U2932 cells with 10 nmol/L EVE, 250 nmol/L GEM alone and in combination for 48 h, both EVE and GEM induced apoptosis, and the difference was statistically significant compared with the control group (P<0.05). The apoptosis rate was significantly enhanced after EVE in combination with GEM compared with single-agent (P<0.05). Both EVE and GEM alone and in combination significantly increased the proportion of cells in G1 phase compared with the control group (P<0.05). The proportion of cells in G1 phase was significantly increased when the two drugs were combined (P<0.05). The expression of p-mTOR and effector protein p-4EBP1 was significantly downregulated in the EVE combined with GEM group, the expression of anti-apoptotic proteins MCL-1, Survivin and cell cycle protein cyclin D1 was downregulated too (P<0.05).@*CONCLUSION@#EVE combined with GEM can synergistically inhibit the proliferation of U2932 cells, and the mechanism may be that they can synergistically induce apoptosis by downregulating the expression of MCL-1 and Survivin proteins and block the cell cycle progression by downregulating the expression of Cyclin D1.

Does systemic anticancer gemcitabine compromise oral soft tissue wound healing? / ¿La gemcitabina anticancerígena sistémica compromete la cicatrización de heridas en tejidos blandos orales?

Background: Numerous types of cancer are of substantial medical and social concern, posing a major challenge to modern medicine. Chemotherapeutic drugs include the use of nucleosides, which are composed of nucleic acid and sugar. Objective: This study aims to assess the impact of systemic chemotherapeutic drugs at a therapeutic dose on the wound healing process of the oral mucosa. Material and Methods: 30 healthy rats were randomly divided into two main groups based on the study material, 15 rats in each group. Group A (control) was given a single dose of normal saline (1ml/kg, intraperitoneal), and Group B (study) a single injection of gemcitabine (50 mg /Kg, intraperitoneal). After anesthesia, a full-thickness soft tissue incision (0.5 cm length) on the right side of the buccal mucosa was made in the animals of both groups. Each group was subdivided according to the time of sacrifice into 3, 7, 14 days after surgery, at the end of the experimental periods, specimens were collected for histopathological study, and samples of blood were obtained from retro-orbital venous plexus and collected in microfuge tubes and levels of antioxidant enzymes were measured by ELISA. The data were analyzed statistically at a 0.05 level of significance. Results: Gemcitabine delayed the onset of wound cascade (inflammation and re-epithelization) which lead to worsening healing of the oral tissue; it also resulted in a decrease of the antioxidant activity of glutathione peroxidase and catalase, as well as activated caspase 3, which induces cell apoptosis. Conclusion: Gemcitabine showed negative feedback on oral tissue wound healing through delayed wound healing cascade and by inducing apoptosis.

Antecedentes: numerosos tipos de cáncer son motivo de gran preocupación médica y social, lo que representa un gran desafío para la medicina moderna. Los fármacos quimioterapéuticos incluyen el uso de nucleósidos, que están compuestos de ácido nucleico y azúcar. Objetivo: Este estudio tiene como objetivo evaluar el impacto de los fármacos quimioterapéuticos sistémicos a una dosis terapéutica en el proceso de cicatrización de heridas de la mucosa oral. Material y Métodos: 30 ratas sanas se dividieron aleatoriamente en dos grupos principales según el material de estudio, 15 ratas en cada grupo. Al grupo A (control) se le administró una dosis única de solución salina normal (1 ml/kg, intraperitoneal) y al grupo B (estudio) una inyección única de gemcitabina (50 mg/kg, intraperitoneal). Después de la anestesia, se realizó una incisión de tejido blando de espesor total (0,5 cm de longitud) en el lado derecho de la mucosa bucal en los animales de ambos grupos. Cada grupo se subdividió de acuerdo al tiempo de sacrificio en 3, 7, 14 días después de la cirugía, al final de los períodos experimentales se colectaron especímenes para estudio histopatológico, se obtuvieron muestras de sangre del plexo venoso retroorbitario y se recolectaron en tubos de microcentrífuga y los niveles de enzimas antioxidantes se midieron por ELISA. Los datos se analizaron estadísticamente a un nivel de significación de 0,05. Resultados: La gemcitabina retrasó el inicio de la cascada de heridas (inflamación y reepitelización) que condujo a un empeoramiento de la cicatrización del tejido oral; también resultó en una disminución de la actividad antioxidante de la glutatión peroxidasa y la catalasa, así como de la caspasa 3 activada, que induce la apoptosis celular. Conclusión: La gemcitabina mostró retroalimentación negativa sobre la cicatrización de heridas del tejido oral a través de una cascada de cicatrización retardada y mediante la inducción de apoptosis.

Índice pronóstico nutricional en pacientes con cáncer de páncreas avanzado tratados con nimotuzumab combinado a quimioterapia / Nutritional prognostic index in patients with advanced pancreatic cancer treated with nimotuzumab combined with chemotherapy

Introducción: El índice pronóstico nutricional es un marcador inmuno-nutricional que puede ser útil como factor pronóstico en tumores gastrointestinales. Objetivo: Evaluar supervivencia de pacientes con adenocarcinoma pancreático avanzado tratados con quimioinmunoterapia según índice pronóstico nutricional, según parámetros clínico-patológicos y tratamiento. Métodos: Se realizó estudio retrospectivo y observacional en pacientes que recibieron quimioterapia gemcitabina-oxaliplatino combinado a nimotuzumab (n=118), en el Hospital Ameijeiras, entre 2014 y 2019. Se evaluó supervivencia por método Kaplan-Meier, y regresión de Cox, para determinar los factores pronósticos independientes de supervivencia. Resultados: El punto de corte seleccionado fue 40 (sensibilidad 52,9 por ciento y especificidad 85,7 por ciento (p = 0,019), con área bajo la curva de 0,693. Para pacientes con índice menor de 40, la supervivencia fue más baja respecto a los pacientes con índice ≥ 40 (11,4 meses frente a 16,0 meses; p=0,001), con un HR de 1,7 (1,13-2,60; p=0,011). Las variables mayormente asociadas con índice pronóstico nutricional altos son pacientes con sesenta años o menos; ECOG cero, índice de masa corporal ≥25 Kg/m2 y albúmina sérica >3,5g/dL (x² < 0,05). Los pacientes con índice ≥ 40 tienen medianas de supervivencia más altas que pacientes con índice < 40 en las variables seleccionadas con p < 0,05, excepto el índice de masa corporal. Conclusiones: Este trabajo constituye el primer reporte nacional de utilización del índice pronóstico nutricional como pronóstico de supervivencia en pacientes con cáncer de páncreas avanzado(AU)

Background: The nutritional prognostic index is an immuno-nutritional marker that can be useful as a prognostic factor in gastrointestinal tumors. Aim: To evaluate the survival of patients with advanced pancreatic adenocarcinoma treated with chemoimmunotherapy according to the nutritional prognostic index, according to clinical-pathological parameters and treatment. Methods: A retrospective and observational study was carried out in patients who received gemcitabine-oxaliplatin chemotherapy combined with nimotuzumab (n=118), at the Ameijeiras Hospital, between 2014 and 2019. Survival was evaluated by the Kaplan-Meier method, and Cox regression, for determine independent prognostic factors for survival. Results: The selected cut-off point was 40 (52.9 percent sensitivity and 85.7 percent specificity) (p=0,019), with an area under the curve of 0,693. For patients with an index less than 40, survival was lower compared to patients with index ≥ 40 (11, 4 months vs. 16, 0 months; p=0,001), with a HR of 1, 7 (1, 13-2, 60; p=0,011). The variables mostly associated with nutritional prognostic index patients with 60 years or less, ECOG 0, body mass index ≥ 25 kg/m2 and serum albumin >3,5g/dL (x2 < 0, 05). Patients with index ≥ 40 have higher median survival than patients with index < 40 in the selected variables with p < 0, 05, except body mass index. Conclusions: This work constitutes the first national report on the use of the nutritional prognostic index as a prognosis of survival in patients with advanced pancreatic cancer(AU)

14-3-3ζ protein mediates gemcitabine resistance in NK/T-cell lymphoma / 中华血液学杂志

Objective: To explore the molecular mechanisms of 14-3-3ζ in gemcitabine resistance in extranodal NK/T-cell lymphoma, nasal type (ENKTL) . Methods: The effects of cell proliferation and invasion were detected by cell counting kit-8 (CCK-8) assay and transwell assay. YTS cells were exposed to gradually increased concentrations of gemcitabine to establish gemcitabine-resistant YTS cells (YTS-gem) in vitro. 14-3-3ζ specific siRNA lentiviral vector was transfected into YTS and YTS-gem cells to downregulate 14-3-3ζ expression, and stable transfected cell clones were screened. The protein expression was determined by Western blot. Results: ①14-3-3ζ expression was significantly up-regulated in gemcitabine resistant YTS-gem cells, comparing with that of YTS cells (P<0.05) . ②The results of CCK-8 and transwell assay showed that downregulation of 14-3-3ζ significantly reduced the cell proliferation and invasion abilities (P<0.05) . ③Downregulation of 14-3-3ζ could restore gemcitabine sensitivity in gemcitabine resistant YTS-gem cells (P<0.05) . ④Western blotting results showed that knockdown of 14-3-3ζ significantly upregulated pro-apoptotic Bax, and downregulated anti-apoptotic Bcl-2, Caspase-3, cleaved caspase-3, Cyclin D1 in gemcitabine-resistant YTS-gem cells (P<0.05) . There was no significant difference in p53 ang P-gp expression levels. Conclusions: 14-3-3ζ was upregulated in gemcitabine resistant YTS cells. Overexpression of 14-3-3ζ promoted cell proliferation and enhanced cell migration. 14-3-3ζ contributed to gemcitabine resistance to ENKTL through anti-apoptosis.