Search

Nowadays, extracellular DNA or circulating cell-free DNA is considered to be a molecule with clinical applications (diagnosis, prognosis, monitoring of treatment responses, or patient follow-up) in diverse pathologies, especially in cancer. Nevertheless, because of its molecular characteristics, it can have many other functions. This review focuses on the participation of extracellular DNA (exDNA) in fundamental processes such as cell signaling, coagulation, immunity, evolution through horizontal transfer of genetic information, and adaptive response to inflammatory processes. A deeper understanding of its role in each of these processes will allow development of better tools to monitor and control pathologies, as well as helping to generate new therapeutic options, beyond the applicability of DNA in liquid biopsy.

Pérez-Cárdenas E, Taja-Chayeb L, Trejo-Becerril C, et al. Onco Targets Ther. 2018;11:8823–8833. The authors have advised that an error during the preparation of the slide images for Figure 2C, on page 8827, led to the inadvertent duplication of features on the HV slide. All the original data was retained and the correct image for the HV treated chamber was used as a replacement. The correct Figure 2 is shown in Download Article. &nbsp

Drug repositioning is a alternative strategy to discover and develop anticancer drugs based on identification of new mechanisms of actions and indications for existing compounds. Ivermectin belongs to the avermectin group of compounds, a series of 16-membered macrocyclic lactone moieties discovered in 1967 and FDA-approved for human use since 1987. Ivermectin has since been used by millions of people worldwide, and have demonstrated a wide margin of clinical safety. Here we summarize the in vitro and in vivo evidence demonstrating ivermectin\'s potential as a multitargeting anticancer drug that exerts antitumor effects against different tumor types. Notably, the in vitro and in vivo antitumor activities of ivermectin are achieved at concentrations that can be clinically achieved based on human pharmacokinetic studies done in the clinical studies. Moreover, repurposed ivermectin safety has been well established recently in clinical studies against COVID-19. Consequently, we believe that ivermectin is an excellent potential candidate drug that can be repurposed for cancer and deserves rigorous evaluation against a variety of cancers in well-designed clinical trials.

Enrique Pérez-Cárdenas,1 Lucía Taja-Chayeb,1 Catalina Trejo-Becerril,1 José Chanona-Vilchis,2 Alma Chávez-Blanco,1 Guadalupe Domínguez-Gómez,1 Elizabeth Langley,1 Alejandro García-Carrancá,3,4 Alfonso Dueñas-González3,4 1Division of Basic Research, Instituto Nacional de Cancerología, Mexico City, Mexico; 2Department of Pathology, Instituto Nacional de Cancerología, Mexico City, Mexico; 3Unit of Biomedical Research on Cancer, Biomedical Research Institute, Universidad Nacional Autonoma de Mexico, Mexico City, Mexico; 4Unit of Biomedical Research on Cancer, Instituto Nacional de Cancerologia, Mexico City, Mexico Introduction: Metastasis involves the accumulation of genetic and epigenetic alterations leading to activation of prometastatic genes and inactivation of antimetastatic genes. Among epigenetic alterations, DNA hypermethylation and histone hypoacetylation are the focus of intense translational research because their pharmacological inhibition has been shown to produce antineoplastic activity in a variety of experimental models. Aims: This study aimed to evaluate the antimetastatic effect of the DNA-methylation inhibitor, hydralazine, and the histone deacetylase inhibitor, valproic acid. Methods: NIH 3T3-Ras murine cells were treated with hydralazine and valproic acid to evaluate their effects upon cell proliferation, cell motility, chemotaxis, gelatinase activity, and gene expression. Lung metastases were developed by intravenous injection of NIH 3T3-Ras cells in BALB/c nu/nu mice and then treated with the drug combination. Results: Treatment induced a growth-inhibitory effect on NIH 3T3-Ras cells, showed a trend toward increased gelatinase activity of MMP2 and MMP9, and inhibited chemotaxis and cell motility. The combination led to a strong antimetastatic effect in lungs of nude mice. Conclusion: Hydralazine and valproic acid, two repositioned drugs as epigenetic agents, exhibit antimetastatic effects in vitro and in vivo and hold potential for cancer treatment. Keywords: hydralazine, valproic acid, epigenetics, metastasis, ras

The malignant energetic demands are satisfied through glycolysis, glutaminolysis and de novo synthesis of fatty acids, while the host curses with a state of catabolism and systemic inflammation. The concurrent inhibition of both, tumor anabolism and host catabolism, and their effect upon tumor growth and whole animal metabolism, have not been evaluated. We aimed to evaluate in colon cancer cells a combination of six agents directed to block the tumor anabolism (orlistat + lonidamine + DON) and the host catabolism (growth hormone + insulin + indomethacin). Treatment reduced cellular viability, clonogenic capacity and cell cycle progression. These effects were associated with decreased glycolysis and oxidative phosphorylation, leading to a quiescent energetic phenotype, and with an aberrant transcriptomic landscape showing dysregulation in multiple metabolic pathways. The in vivo evaluation revealed a significant tumor volume inhibition, without damage to normal tissues. The six-drug combination preserved lean tissue and decreased fat loss, while the energy expenditure got decreased. Finally, a reduction in gene expression associated with thermogenesis was observed. Our findings demonstrate that the simultaneous use of this six-drug combination has anticancer effects by inducing a quiescent energetic phenotype of cultured cancer cells. Besides, the treatment is well-tolerated in mice and reduces whole animal energetic expenditure and fat loss.

Background Novel prognostic factors in patients with diffuse large B-cell lymphoma (DLBCL) are required in the era of Rituximab. Objective The objective of the study was to study the prognostic impact of exon-16 enhancer-of-zeste homolog-2 (EZH2) mutations in patients with DLBCL. Methods In a cohort of patients with DLBCL treated between 2015 and 2017, we analyzed the presence of EZH2 mutations and their association with clinical response (CR), relapse, progression-free survival (PFS), and overall survival (OS). Results A total of 198 patients were included; of them, 30 (15.2%) had mutations at codon 641, in exon 16 of EZH2. Response was achieved in 151 patients (76.3%), and 43 (21.7%) relapsed or progressed during follow-up. EZH2 mutations were associated with relapse/progression (risk ratio [RR] 1.18; 95% confidence interval [CI] 0.98-1.42; p = 0.031), while a trend for not achieving a complete response was observed (RR: 0.876; 95%CI 0.74-1.038; p = 0.071). Of note, Tyr641His and Tyr641Ser EZH2 mutations were associated with shorter PFS (hazard ratio 3.234; 95% CI 1.149-9.1; p = 0.026). Conclusion The presence of EZH2 mutations was negatively associated with relapse/progression and showed a trend for lack of complete response. Further studies are needed to define better the prognostic significance of these mutations in Mexican-Mestizo DLBCL patients.

Background: Diffuse large B-cell lymphoma (DLBCL) is the most frequent non-Hodgkin lymphoma worldwide. The current standard of care is chemoimmunotherapy with an R-CHOP regimen. We aim to review the role of this regimen after two decades of being the standard of care. Methods: A comprehensive literature review of DLBCL, including the epidemiology, trials defining R-CHOP as the standard of care, as well as dose intensification and dose reduction schemes. Additionally, we briefly review the development of rituximab biosimilars and the addition of targeted drugs to R-CHOP in clinical trials. Discussion: R-CHOP cures approximately 70% of DLBCL patients. Dose-dense regimens do not show a benefit in response and increase toxicity. Dose reduction, particularly in elderly patients or with comorbidities, may be a treatment option. DLBCL constitutes a group of diseases that activate different biological pathways. Matching specific treatments to a defined genetic alteration is under development. Rituximab biosimilars have become available to a broader population, particularly in developing countries, where access to treatment is limited because of economic resources. Conclusion: DLBCL landscape is heterogeneous. R-CHOP immunochemotherapy has been a standard of care for two decades and cures approximately 70% of cases. Molecular characterization of patients is evolving and may have critical therapeutic implications.

Cervical cancer (CC) is one of the most common gynecological tumors and an important health problem, especially in developing countries. The vast majority of patients in early stages are cured of the disease with surgical treatment and with concomitant chemoradiotherapy in locally advanced stages. However, in patients with recurrent, persistent, or metastatic cervical CC, the effectiveness of treatment is limited, except for the combination of chemotherapy based on platinum doublets plus bevacizumab, the treatment that has achieved the best results to date. Programmed cell death-1/PD ligand-1 (PD-1/PD-L1) inhibitors could be a novel and cutting-edge therapeutic option to improve clinical outcomes in this group of patients. Thus far, there are a few Phase I/II clinical trials that have assessed the usefulness of pembrolizumab and nivolumab in this group of patients; these include the KEYNOTE 028, KEYNOTE 158, and CHECKMATE 358 trials, in which clinical benefit has been proven with PD-1/PD-L1 inhibitors in recurrent, persistent, or metastatic CC, as second-line treatment. There are also some ongoing trials that could provide further evidence on the PD-1/PD-L1 pathway as a therapeutic target in CC. In this review, we will focus on the usefulness of these PD-1/PDL1 inhibitors in CC, as well as on trials that are still in the recruitment phase, to confirm their effectiveness in this clinical setting.

Background The increasing survival of patients with non-Hodgkin lymphoma has allowed the diagnosis of long-term com- plications, including late-onset hematological toxicity (LOHT), transitory cytopenias, or therapy-related myeloid neoplasm (t-MDS/t-AML). Objective The objective of the study was to determine the frequency and clinical evolution of LOHT in patients with lymphoproliferative malignancies. Materials and methods Two cohorts of patients B-cell lymphomas were reviewed. Patients who achieved full hematologic recovery at the end of treatment, and thereafter developed any degree of cytopenia were included in the study. Clinical and biochemical parameters were compared between patients with and without cytopenias with X2 test. Bi-and multivariate analyses were performed to evaluate factors associated with the development of late-onset cytopenias. Results Of 758 patients enrolled, 19 developed cytopenias (2.5%). Transitory cytopenia was documented in 6 cases, 3 developed ICUS, 8 t-MDS, and 2 t-AML. In patients with FL, only hemoglobin 6 nodal areas (p = 0.037) at diagnosis were factors statistically significant for the development of cytopenia. During cytopenias, 55% of patients died. Conclusions LOHT constitutes a cause of morbidity and mortality in 2.5% of lymphoma patients treated with different therapy regimens.

Objetivo: Utilizamos ultrasonidos tridimensionales con power-doppler transabdominal para determinar la evolución vascular placentaria en embarazos normales (NP- normal pregnancies) y gestaciones insulinodependientes (GDP- gestacional diabetes pregnancies). Material y métodos: Se obtuvieron 473 medidas de 43 NP, entre las semanas 20-40 de gestación, y 122 medidas de 70 madres con diabetes gestacional, entre las semanas 22-40. La estandarización se consiguió grabando 3 volúmenes vasculares placentarios sucesivos, analizando el volumen esférico entre las placas coriónica y basal, siempre debajo o cerca de la inserción del cordón umbilical. Los parámetros analizados fueron una media de la intensidad del flujo sanguíneo (índice de flujo, FI); porcentaje del área ocupada por los vasos (índice de vascularización, VI); y la intensidad del flujo sanguíneo en el volumen ocupado por los vasos (índice vascularización-flujo, VFI). Resultados: en NP, el FI aumentó a lo largo del embarazo desde el comienzo y disminuyó antes del parto, y guarda relación con los parámetros fetales. Por el contrario, en GDP, FI se presentaba alto desde el comienzo, teniendo relación con los parámetros maternos, y tenía un valor límite diagnóstico de 45 (que sólo fue encontrado en un 7% de las muestras en NP al final del embarazo). VI fue variable y tenía un bajo valor diagnóstico, probablemente relacionado con los parámetros maternos; los valores de VI fueron significativamente bajos en NP (17.4±7.4%) que en GDP (21±12%) con un límite diagnóstico de 31%. En NP, el valor más alto lo encontramos a las 32 semanas, dos semanas después el valor del VI, mientras que el VFI no mostró diferencias significativas. Conclusión: el flujo sanguíneo placentario (FI) se relacionó con la circulación fetal, mientras que el porcentaje de vasos por volumen (VI) lo está probablemente con la circulación materna. 3D-US power doppler nos indica el diagnóstico de GDP cuando el FI>45 y VI>30% Purpose: We used three-dimensional ultrasound with trans-abdominal Power-Doppler (3D-US PD) to determine placental vascular evolution in normal pregnancies (NP) and in insulin-dependient gestational diabetes pregnancies (GDP). Material and methods: We obtained 473 measurements from 43 NP at 20-40 weeks gestation and 122 measurements from 70 insulin-dependent GDP at 22-40 weeks. Standardization was achieved recording three succesive placental vascular tree volumes, measuring the spherical volume between the chorionic and basal plates, always under or near funicular insertion. Parameters analysed were mean intensity of blood flow (flow index, FI); percentage of area occupied by vessels (vascularization index, VI); and intensity of blood flow in the volume occupied by vessels (vascularization-flow index, VFI). Results: In NP, FI increased throughout early pregnancy and decreased before delivery, and correlated with fetal parameters. In contrast, in GDP, FI was high from onset, correlated better with maternal placental parameters, and had a diagnostic cutoff value of 45, which was only found in 7% of NP at the end of pregnancy. VI was variable and had low diagnostic value, probably being related to maternal parameters; VI values were significantly lower in NP (17.4±7.4%) than in GDP (21±12%) with a diagnostic cutoff of 31%. In NP, peak FI was at 32 weeks, 2 weeks after peak VI, while VFI showed no significant differences. Conclusion: Placental blood flow (FI) was related to fetal circulation, while the percentage of vessels per volume (VI) was probably related to maternal circulation. 3D-US PD indicated a diagnosis of GDP when FI >45 and VI >30%. We also found that change in VI values predicted change in fetal FI.

Treacher Collins Syndrome is an autosomal dominant craniofacial malformation (CTS) that occurs when the TCOF1 gene (5q32-q33.1) suffers a mutation. Its incidence is estimated at 1/50,000 births and it presents manifestations in soft and hard tissues. Methods: Six individuals diagnosed with CTS, were referred from the Asociación Treacher Collins México AC, for pre-surgical imaging studies. Objective: To describe the clinical, radiographic, and morphometric characteristics of individuals with this condition. Results: There are not enough studies in which specific patterns are determined in the same individual, and even when they are compared with each other, so it is necessary to establish protocols for their management. Conclusions: The clinical characteristics of the individual with CTS vary according to the severity of genetic expression, which can be corroborated with photographs, radiographic images, and morphometric measurements that will guide us in the management and planning of treatment. El Síndrome de Treacher Collins es una malformación craneofacial autosómica dominante (STC) que se presenta cuando el gen TCOF1 (5q32-q33.1) sufre una mutación. Su incidencia se estimaen 1/50,000 nacidos y presenta manifestacionesen tejidos blandos y duros.Métodos: Seis individuos diagnosticadoscon STC, remitidos de la Asociación Treacher Collins México AC, para la realización de estudios imagenológicos prequirúrgicos. Objetivo: Describir las características clínicas, radiográficas y morfométricas de individuos con esta condición. Resultados: No existen suficientes estudios en los cuales se determinen patrones específicos en un mismo individuo, e incluso cuando se comparan entre sí, por lo que es necesario establecer protocolos para su manejo. Conclusiones: Las característicasclínicas del individuo con STC varían deacuerdo con la severidad de expresióngenética, las cuales se pueden corroborarcon fotografías, imágenes radiográficasy medidas morfométricas quenos orientaran en el manejo y planeacióndel tratamiento.

Cancer upregulates glycolysis, glutaminolysis and lipogenesis, and induces a catabolic state in patients. The concurrent inhibition of both tumor anabolism and host catabolism, and the energetic consequences of such an approach, have not previously been fully investigated. In the present study, CT26.WT murine colon cancer cells were treated with the combination of anti-anabolic drugs orlistat, lonidamine and 6-diazo-5-oxo-L-norleucine (DON; OLD scheme), which are inhibitors of the de novo synthesis of fatty acids, glycolysis and glutaminolysis, respectively. In addition, the effects of OLD scheme sumplemented with the combination of anti-catabolic compounds, namely growth hormone, insulin and indomethacin (GII scheme), were also evaluated. The effects of the compounds used in combination on CT26.WT cell viability, clonogenicity and energetic metabolism were assessed in vitro. The results demonstrated that the anti-anabolic approach reduced cell viability, clonogenicity and cell cycle progression, and increased apoptosis. These effects were associated with decreased oxidative phosphorylation, glycolysis and fuel flexibility. Furthermore, the anti-catabolic scheme, alone or supplemented with anti-anabolic compounds, did not favor tumor growth. These findings indicated that the simultaneous pharmacological inhibition of tumor anabolism and host catabolism exhibits antitumor effects that should be further evaluated.

Cervical cancer is the fourth most common cancer in women with 85% of the mortality burden occurring in less-developed regions of the world. The Cervix Cancer Research Network (CCRN) was founded by the Gynecologic Cancer InterGroup (GCIG) with a mission to improve outcomes in cervix cancer by increasing access to high-quality clinical trials worldwide, with particular attention to less-developed, underrepresented sites. The CCRN held its second international educational symposium in Mexico City with ninety participants from fifteen Latin America countries in January 2017. The purpose of this symposium was to advance knowledge in cervix cancer therapy, promote recruitment to CCRN clinical trials, and to identify relevant future CCRN clinical trial concepts that could improve global care standards for women with cervical cancer., Highlights • Cervix cancer is the fourth most common cancer in women worldwide with up to an 18-fold disparity in mortality rates. • The Cervix Cancer Research Network (CCRN) aims to increase access to clinical trials in order to improve outcomes for women. • The 2nd CCRN international symposium was held in Mexico City including 90 participants from 15 Latin American countries. • CCRN clinical trials were discussed, including new trials proposed of hypofractionation and HPV targeted therapy.

Cancer continues to be a worldwide health problem. Certain macrocyclic molecules have become attractive therapeutic alternatives for this disease because of their efficacy and, frequently, their novel mechanisms of action. Herein, we report the synthesis of a series of 20-, 21-, and 22-membered macrocycles containing triazole and bis(aryl ether) moieties. The compounds were prepared by a multicomponent approach from readily available commercial substrates. Notably, some of the compounds displayed interesting cytotoxicity against cancer (PC-3) and breast (MCF-7) cell lines, especially those bearing an aliphatic or a trifluoromethyl substituent on the N-phenyl moiety (IC50

Lonidamine, 6-Diazo-5-oxo-L-norleucine (DON) and orlistat are well known inhibitors of glycolysis, glutaminolysis and of de novo fatty acid synthesis, respectively. Although their antitumor effects have been explored in detail, the potential inhibition of the malignant metabolic phenotype and its influence on the expression of chemokines and growth factors involved in colon cancer, have not been previously reported to the best of our knowledge. In the present study, dose-response curves with orlistat, lonidamine or DON were generated from cell viability assays conducted in SW480 colon cancer cells. In addition, the synergistic effect of these compounds was evaluated in SW480 human colon cancer cells. The determination of the doses used for maximum synergistic efficacy led to the exploration of the mRNA levels of the target genes hexokinase-2 (HK2), glutaminase-1 (GLS-1) and fatty acid synthase (FASN) in human SW480 and murine CT26.WT colon cancer cells. The cell viability was evaluated following transfection with small interfering (si)RNA targeting these genes and was assessed with trypan blue. The expression levels of chemokines and growth factors were quantified in the supernatant of SW480 cells with LEGENDplex™. The combination of lonidamine, DON and orlistat resulted in a synergistic cytotoxic effect and induced the transcription of the corresponding gene targets but their corresponding proteins were actually downregulated. The downregulation of the expression levels of HK2, GLS-1 and FASN following transfection of the cells with the corresponding siRNA sequences decreased their viability. The treatment significantly reduced the expression levels of 9 chemokines [interleukin-9, C-X-C motif chemokine ligand (CXCL) 10, eotaxin, chemokine ligand (CCL) 9, CXCL5, CCL20, CXCL1, CXCL11 and CCCL4] and one growth factor (stem cell factor). These changes were associated with decreased phosphorylated-nuclear factor κB-p65. The data demonstrate that lonidamine, DON and orlistat in combination reduce the expression levels of chemokines and growth factors in colon cancer cells. Additional research is required to investigate the exact way by which both tumor and stromal cells regulate the expression levels of chemokines and growth factors.

Algunas de las variables que tratan de representar el medio ambiente son de difícil medida, por lo que suelen estimarse en función de otras mediante modelos, propa- gando el error de los datos de origen. El presente artículo es una recopilación bibliográfica de los aspectos más importantes a considerar al analizar la propagación del error en modelos con datos de entradas espaciales y salidas discretas sobre vari- ables medioambientales. Debido a que estos modelos suelen tener datos de entrada en forma de variables discretas, también se aborda la influencia de sus fuentes de error en su propagación por los modelos cartográficos. Las fuentes de error más importantes en los datos de entrada de este tipo son la adecuada determinación de las clases, la identificación de la categoría —error temático y conceptual—, la localización de sus bordes —precisión y exactitud cartográfica— y la escala, considerándose como variables en los análisis de propagación de errores. Una vez conocida la fuente del error, posteriormente se analizan diferentes tra- bajos de análisis de sensibilidad de algunos modelos que pueden servir como refe- rencia para el estudio de otras variables medioambientales discretas. Monte Carlo se muestra como un método idóneo para el análisis de propagación de errores para variables discretas, aunque no se ha encontrado bibliografía que compare diferentes métodos para un mismo juego de datos ni modelo. Se analizan ciertas particularida- des de cada modelo de datos —raster y vectorial— y su influencia en el resultado.

Epigenetic alterations are associated with cancer and their targeting is a promising approach for treatment of this disease. Among current epigenetic drugs, histone deacetylase (HDAC) inhibitors induce changes in gene expression that can lead to cell death in tumors. Valproic acid (VPA) is a HDAC inhibitor that has antitumor activity at mM range. However, it is known that VPA is a hepatotoxic drug. Therefore, the aim of this study was to design a set of VPA derivatives adding the arylamine core of the suberoylanilide hydroxamic acid (SAHA) with different substituents at its carboxyl group. These derivatives were submitted to docking simulations to select the most promising compound. The compound 2 (N-(2-hydroxyphenyl)-2-propylpentanamide) was the best candidate to be synthesized and evaluated in vitro as an anti-cancer agent against HeLa, rhabdomyosarcoma and breast cancer cell lines. Compound 2 showed a better IC50 (μM range) than VPA (mM range) on these cancer cells. And also, 2 was particularly effective on triple negative breast cancer cells. In conclusion, 2 is an example of drugs designed in silico that show biological properties against human cancer difficult to treat as triple negative breast cancer.

Background. Cell-free DNA circulates in cancer patients and induces in vivo cell transformation and cancer progression in susceptible cells. Based on this, we hypothesized that depletion of circulating DNA with DNAse I and a protease mix could have antitumor effects. Study design. The study aimed to demonstrate that DNAse I and a protease mix can degrade in vitro DNA and proteins from the serum of healthy individuals and cancer patients, and in vivo in serum of Wistar rats,. Moreover, the antitumor effect of the systemically administered enzyme mix treatmentwas evaluated in nude mice subcutaneously grafted with the human colon cancer cell line SW480. Results. The serum DNA of cancer patients or healthy individuals was almost completely degraded in vitro by the enzymatic treatment, but no degradation was found with the enzymes given separately. The intravenous administration of the enzymes led to significant decreases in DNA and proteins from rat serum. No antitumor effect was observed in immunodeficient mice treated with the enzymes given separately. In contrast, the animals that received both enzymes exhibited a marked growth inhibition of tumors, 40% of them having pathological complete response. Conclusion. This study demonstrated that systemic treatment with DNAse I and a protease mix in rats decreases DNA and proteins from serum and that this treatment has antitumor effects. Our results support the hypothesis that circulating DNA could have a role in tumor progression, which can be offset by depleting it. Further studies are needed to prove this concept.

Ribavirin exhibits inhibitory effects on the epigenetic enzyme enhancer of zeste homolog 2 (EZH2), which participates in lymphomagenesis. Additionally, preclinical and clinical studies have demonstrated the anti‑lymphoma activity of this drug. To further investigate the potential of ribavirin as an anticancer treatment for lymphoma, the tumor‑suppressive effects of ribavirin were analyzed in lymphoma cell lines. The effects of ribavirin on the viability and clonogenicity of the B‑cell lymphoma cell line Pfeiffer (EZH2‑mutant), Toledo (EZH2 wild‑type) and cutaneous T‑cell lymphoma Hut78 cell line were assessed. Expression of EZH2 and trimethylation status of histone 3, lysine 27 trimethylated (H3K27m3) was also determined in response to ribavirin. The transcriptional effects of ribavirin on Hut78 cells were analyzed by microarray expression and the results were validated by reverse transcription‑quantitative polymerase chain reaction, western blotting and knockout of signal transducer and activator of transcription 1 (STAT1). The results of the present study demonstrated that ribavirin suppressed the growth and clonogenicity of cells in a dose‑dependent manner. Ribavirin did not affect the expression of EZH2 nor altered its activity as evaluated by H3K27 trimethylation status. Furthermore, the results of transcriptome analysis indicated that the majority of the canonical pathways affected by ribavirin were associated with the immune system, including 'antigen presentation', 'communication between innate and adaptive immune cells' and 'cross‑talk between dendritic and natural killer cells'. The results of gene expression analysis were confirmed, by demonstrating at the RNA and protein levels, downregulation of stearoyl‑CoA desaturase and upregulation of STAT1. Depletion of STAT1, which was proposed as a key regulator of the aforementioned pathways, exerted growth inhibitory effects almost to the same extent as ribavirin. In conclusion, ribavirin was proposed to exert growth inhibitory effects on lymphoma cell lines, particularly Hut78 cells, a cutaneous T‑cell lymphoma cell line. Of note, these effects may depend on, at least in part, the activation of canonical immune pathways regulated by the key factors STAT1 and interferon‑γ. Our results provide insight into the anti‑lymphoma potential of ribavirin; however, further investigations in preclinical and clinical studies are required to determine the effectiveness of ribavirin as a therapeutic agent for treating lymphoma.

Cancer patients are particularly susceptible to undernourishment so associated weight loss is frequent. Approximately 15% of patients lose >10% of their usual body weight, 40-80% become undernourished, and about 20% die as a result. Well-nourished patients have a higher survival rate when compared with patients at risk of undernourishment (19.9 vs. 3.7 months); hence, nutritional intervention is pivotal. Undernourishment negatively influences the patient's prognosis, and its prevalence depends on the tumor type and location, disease stage, treatment, and the applied nutritional evaluation tool. During abdominopelvic radiotherapy, up to 90% of patients experience symptoms of varying severity; weight loss during radiotherapy is an early indicator of nutritional deterioration, and he the use of radiation is associated with a higher likelihood of undernourishment. In patients with gynecological malignancies, 12.5-54% are malnourished before receiving oncological treatment, worsening after treatment in 35.8-82% of cases. There is also deterioration of the nutritional status in patients with colorectal cancer once pelvic radiotherapy is initiated, whereby 50% of cases are malnourished at the beginning of treatment, and 66.7% are so when it ends. Although there are notable differences in the impact of radiotherapy on weight according to the radiated region, 88% patients receiving abdominal radiotherapy were found to lose weight compared to 38% of patients whose treatment was limited to the pelvis.

The aim of the present study was to demonstrate that ivermectin preferentially inhibited cancer stem‑like cells (CSC) in breast cancer cells and downregulated the expression of 'stemness' genes. Computational searching of DrugBank, a database of approved drugs, was performed using the principles of two‑dimensional similarity searching; the chemical structure of salinomycin was used as a query. Growth inhibition of the breast cancer cell lin e MDA‑MB‑231 by ivermectin was investigated in the total cell population, in cell spheroids and in sorted cells that expressed cluster of differentiation (CD)44+/CD24‑. The effects of ivermectin treatment on the expression of pluripotency and self‑renewal transcription factors, such as homeobox protein nanog (nanog), octamer‑binding protein 4 (oct‑4) and SRY‑box 2 (sox‑2), were evaluated by reverse transcription‑quantitative polymerase chain reaction and western blotting. Ivermectin exhibited a similarity value of 0.78 in reference to salinomycin. Ivermectin demonstrated an inhibitory effect upon the growth of MDA‑MB‑231 cells in the range of 0.2‑8 µM. Ivermectin preferentially inhibits the viability of CSC‑enriched populations (CD44+/CD24‑ and cells growing in spheroids) compared with the total cell population. The opposite pattern was observed with paclitaxel treatment. Ivermectin exposure reduced the expression of nanog, oct‑4 and sox‑2 at the mRNA and protein levels. Ivermectin preferentially inhibited the CSC subpopulation in the MDA‑MB‑231 cells and downregulated the expression of genes involved in the maintenance of pluripotency and self‑renewal.

There is a strong rationale for targeting the metabolic alterations of cancer cells. The most studied of these are the higher rates of glycolysis, glutaminolysis and de novo synthesis of fatty acids (FAs). Despite the availability of pharmacological inhibitors of these pathways, no preclinical studies targeting them simultaneously have been performed. In the present study it was determined whether three key enzymes for glycolysis, glutaminolysis and de novo synthesis of FAs, hexokinase-2, glutaminase and fatty acid synthase, respectively, were overexpressed as compared to primary fibroblasts. In addition, we showed that at clinically relevant concentrations lonidamine, 6-diazo-5-oxo-L-norleucine and orlistat, known inhibitors of the mentioned enzymes, exerted a cell viability inhibitory effect. Genetic downregulation of the three enzymes also reduced cell viability. The three drugs were highly synergistic when administered as a triple combination. Of note, the cytotoxicity of the triple combination was low in primary fibroblasts and was well tolerated when administered into healthy BALB/c mice. The results suggest the feasibility and potential clinical utility of the triple metabolic targeting which merits to be further studied by using either repositioned old drugs or newer, more selective inhibitors.

Nimotuzumab is a humanized IgG1 monoclonal antibody against the EGFR extracellular domain that has been evaluated in solid tumors as a single agent or in combination with chemotherapy and radiation. Cervical cancer patients who are refractory or progressive to first-line chemotherapy have a dismal prognosis, and no second- or third-line chemotherapy is considered standard. This pilot trial aimed to evaluate the efficacy and safety of nimotuzumab in 17 patients with pre-treated advanced refractory or progressive cervical cancer. Nimotuzumab was administered weekly at 200 mg/m(2) as single agent for 4 weeks (induction phase), then concurrent with 6 21-day cycles of gemcitabine (800 mg/m(2)) or cisplatin (50 mg/m(2)) for 18 weeks (concurrent phase) and then once every 2 weeks (maintenance phase). Nimotuzumab could be continued beyond disease progression. Seventeen patients were accrued and evaluated for safety and efficacy. The median number of nimotuzumab applications was 20 (5-96). The median number of chemotherapy cycles administered was 6 (1-6). No toxicity occurred during induction and maintenance phases (single agent nimotuzumab). In the concurrent phase, grade 3 toxicity events observed were leucopenia, anemia and diarrhea in 11.7%, 5.8% and 11.7% respectively. No complete or partial responses were observed. The stable disease (SD) rate was 35%. The median PFS and OS rates were 163 days (95% CI, 104 to 222), and 299 days (95% IC, 177 to 421) respectively. Nimotuzumab is well tolerated and may have a role in the treatment of advanced cervical cancer.