Hypoxia and Proton microbeam: Role of Gap Junction Intercellular Communication in Inducing Bystander Responses on Human Lung Cancer Cells and Normal Cells

Radiation-induced bystander effect (RIBE) has been identified as an important contributing factor to tumor resistance and normal tissue damage. However, the RIBE in cancer and normal cells under hypoxia remain unclear. In this study, confluent A549 cancer and WI-38 normal cells were subjected to condition of hypoxia or normoxia, before exposure to high-LET protons microbeam. After 6 h incubation, cells were harvested and assayed for colony formation, micronucleus formation, chromosome aberration and western blotting. Our results show that there were differences of RIBE in bystander A549 and WI-38 cells under hypoxia and normoxia. The differences were also observed in the roles of HIF-1α expression in bystander A549 and WI-38 cells under both conditions. Furthermore, inhibition of gap junction intercellular communication (GJIC) showed a decrease in toxicity of hypoxia-treated bystander A549 cells, but increased in bystander WI-38 cells. These findings clearly support that GJIC protection of bystander normal cells from toxicity while enhancing in bystander cancer cells. Together, the data show a promising strategy for high-LET radiation in designing an entire new line of drugs, either increase or restore GJIC in bystander cancer cells which in turn leads to enhancement of radiation accuracy for treatment of hypoxic tumors.

Clinical Significance and Regulation of ERK5 Expression and Function in Cancer

Extracellular signal-regulated kinase 5 (ERK5) is a unique kinase among MAPKs family members, given its large structure characterized by the presence of a unique C-terminal domain. Despite increasing data demonstrating the relevance of the ERK5 pathway in the growth, survival, and differentiation of normal cells, ERK5 has recently attracted the attention of several research groups given its relevance in inflammatory disorders and cancer. Accumulating evidence reported its role in tumor initiation and progression. In this review, we explore the gene expression profile of ERK5 among cancers correlated with its clinical impact, as well as the prognostic value of ERK5 and pERK5 expression levels in tumors. We also summarize the importance of ERK5 in the maintenance of a cancer stem-like phenotype and explore the major known contributions of ERK5 in the tumor-associated microenvironment. Moreover, although several questions are still open concerning ERK5 molecular regulation, different ERK5 isoforms derived from the alternative splicing process are also described, highlighting the potential clinical relevance of targeting ERK5 pathways.

Normal and Neoplastic Growth Suppression by The Extended Myc Network

Among the first discovered and most prominent cellular oncogenes is MYC, which encodes a bHLH-ZIP transcription factor (Myc) that both activates and suppresses numerous genes involved in proliferation, energy production, metabolism and translation. Myc belongs to a small group of bHLH-ZIP transcriptional regulators (the Myc Network) that includes its obligate heterodimerization partner Max and six “Mxd proteins” (Mxd1-4, Mnt and Mga) each of which heterodimerizes with Max and largely oppose Myc’s functions. More recently, a second group of bHLH-ZIP proteins (the Mlx Network) has emerged. It is comprised of the Myc-like factors ChREBP and MondoA, which, in association with the Max-like member Mlx, regulate smaller and more functionally restricted sets of target genes, some of which are shared with Myc. Opposing ChREBP and MondoA are heterodimers comprised of Mlx and Mxd1, Mxd4 and Mnt, which also structurally and operationally link the two Networks. We discuss here the functions of these “Extended Myc Network” members with particular emphasis on the roles played by Max, Mlx and Mxd proteins in suppressing normal and neoplastic growth. These roles are complex due to the temporally- and tissue-restricted expression of Extended Myc Network proteins in normal cells, their regulation of both common and unique target genes and, in some cases, their functional redundancy.

The Activation of Mesenchymal Stem Cells by Glioblastoma Microvesicles Alters Their Exosomal Secretion of miR-100-5p, miR-9-5p and let-7d-5p

Glioblastoma (GBM) is the most aggressive brain tumor, and despite initial response to chemo- and radio-therapy, the persistence of glioblastoma stem cells (GSCs) unfortunately always results in tumor recurrence. It is now largely admitted that tumor cells recruit normal cells, including mesenchymal stem cells (MSCs), and components of their environment, to participate in tumor progression, building up what is called the tumor microenvironment (TME). While growth factors and cytokines constitute essential messengers to pass on signals between tumor and TME, recent uncovering of extracellular vesicles (EVs), composed of microvesicles (MVs) and exosomes, opened new perspectives to define the modalities of this communication. In the GBM context particularly, we investigated what could be the nature of the EV exchange between GSCs and MSCs. We show that GSCs MVs can activate MSCs into cancer-associated fibroblasts (CAFs)-like cells, that subsequently increase their secretion of exosomes. Moreover, a significant decrease in anti-tumoral miR-100-5p, miR-9-5p and let-7d-5p was observed in these exosomes. This clearly suggests a miRNA-mediated GBM tumor promotion by MSCs exosomes, after their activation by GBM MVs.

Automated Detection Model in Classification of B-Lymphoblast Cells from Normal B-Lymphoid Precursors in Blood Smear Microscopic Images Based on the Majority Voting Technique

Introduction. Acute lymphoblastic leukemia (ALL) is the most common type of leukemia, a deadly white blood cell disease that impacts the human bone marrow. ALL detection in its early stages has always been riddled with complexity and difficulty. Peripheral blood smear (PBS) examination, a common method applied at the outset of ALL diagnosis, is a time-consuming and tedious process that largely depends on the specialist’s experience. Materials and Methods. Herein, a fast, efficient, and comprehensive model based on deep learning (DL) was proposed by implementing eight well-known convolutional neural network (CNN) models for feature extraction on all images and classification of B-ALL lymphoblast and normal cells. After evaluating their performance, four best-performing CNN models were selected to compose an ensemble classifier by combining each classifier’s pretrained model capabilities. Results. Due to the close similarity of the nuclei of cancerous and normal cells, CNN models alone had low sensitivity and poor performance in diagnosing these two classes. The proposed model based on the majority voting technique was adopted to combine the CNN models. The resulting model achieved a sensitivity of 99.4, specificity of 96.7, AUC of 98.3, and accuracy of 98.5. Conclusion. In classifying cancerous blood cells from normal cells, the proposed method can achieve high accuracy without the operator’s intervention in cell feature determination. It can thus be recommended as an extraordinary tool for the analysis of blood samples in digital laboratory equipment to assist laboratory specialists.

O Impacto dos Sintomas Orais Gerados por Quimioterapia e Radioterapia / The Impact of Oral Symptoms Generated by Chemotherapy and Radiotherapy

Os primeiros efeitos da radioterapia e da quimioterapia antineoplásica acontecem sobre as células do epitélio oral, as quais sofrem rápida proliferação. O tamanho destes efeitos depende de muitos fatores ligados ao tratamento, ao paciente e ao tumor. No que se trata do paciente, interferem nesse processo o seu estado geral de saúde, presença de comorbidades, sexo, estado nutricional, idade, fatores sociais e psicológicos, além de hábitos deletérios e patologias orofaciais preexistentes. Esses adoecimentos na integridade bucal devem-se a veracidade de que a radioterapia e quimioterapia não são capazes de destruir as células tumorais sem lesionar células normais. O tratamento oncológico pode provocar reações adversas na cavidade oral, e é comum, em pacientes oncológicos submetidos ao tratamento antineoplásico, o desenvolvimento de agravamentos orais agudos ou tardios.---The first effects of radiotherapy and antineoplastic chemotherapy happen on the cells of the oral epithelium, which quickly notice proliferation. The size of these effects depends on many factors related to the treatment, the patient, and the tumor. With regard to the patient, this process interferes with their general health status, presence of comorbidities, gender, nutritional status, age, social and psychological factors, in addition to deleterious habits and pre-existing orofacial pathologies. These illnesses in the oral integrity are due to the veracity that radiotherapy and chemotherapy are not capable of destroying tumor cells without normal cells. Oncological treatment can cause adverse reactions in the oral cavity, and it is common, in cancer patients, to antineoplastic treatment, to develop acute or late oral aggravations.

In Vitro Anticancer Activity and Mechanism of Action of an Aziridinyl Galactopyranoside

We recently screened a series of new aziridines β-D-galactopyranoside derivatives for selective anticancer activity and identified 2-methyl-2,3-[N-(4-methylbenzenesulfonyl)imino]propyl 2,3-di-O-benzyl-4,6-O-(S)-benzylidene-β-D-galactopyranoside (AzGalp) as the most promising compound. In this article, we explore the possible mechanisms involved in the cytotoxicity of this aziridine and evaluate its selective anticancer activity using cancer cells and normal cells from a variety of tissues. Our data show that AzGalp induces DNA damage (comet assay). Cells deficient in the nucleotide excision repair (NER) pathway were hypersensitive to the cytotoxicity of this compound. These results suggest that AzGalp induces bulky DNA adducts, and that cancer cells lacking a functional NER pathway may be particularly vulnerable to the anticancer effects of this aziridine. Several experiments revealed that neither the generation of oxidative stress nor the inhibition of glycolysis played a significant role in the cytotoxicity of AzGalp. Combinations of AzGalp with oxaliplatin or 5-fluorouracil slightly improved the ability of both anticancer drugs to selectively kill cancer cells. AzGalp also showed selective cytotoxicity against a panel of malignant cells versus normal cells; the highest selectivity was observed for two acute promyelocytic leukemia cell lines. Additional preclinical studies are necessary to evaluate the anticancer potential of AzGalp.

Antiangiogenic Compound Axitinib Demonstrates Low Toxicity and Antitumoral Effects against Medulloblastoma

Background: Despite the improvement of medulloblastoma (MB) treatments, survivors face severe long-term adverse effects and associated morbidity following multimodal treatments. Moreover, relapses are fatal within a few months. Therefore, chemotherapies inducing fewer adverse effects and/or improving survival at relapse are key for MB patients. Our purpose was to evaluate the last-generation antiangiogenic drugs for their relevance in the therapeutic arsenal of MB. Methods: We screened three EMA- and FDA-approved antiangiogenic compounds (axitinib, cabozantinib and sunitinib) for their ability to reduce cell viability of five MB cell lines and their low toxicity towards two normal cell lines in vitro. Based on this screening, single-agent and combination therapies were designed for in vivo validation. Results: Axitinib, cabozantinib and sunitinib decreased viability of all the tested tumor cells. Although sunitinib was the most efficient in tumor cells, it also impacted normal cells. Therefore, axitinib showed the highest selectivity index for MB cells as compared to normal cells. The compound did not lead to acute toxicity in juvenile rats and crossed the blood–brain barrier. Moreover, axitinib efficiently reduced the growth rate of experimental brain tumors. Analysis of public databases showed that high expression of axitinib targets correlates with poor prognosis. Conclusion: Our results suggest that axitinib is a compelling candidate for MB treatment.

REVIEW OF DESIGN APPROACHES AND CLINICAL PROGRESS OF MDM2 INHIBITORS

Activation of the oncogenes and inhibition of the apoptotic function of the p53 protein is a gateway for the cancer genesis. Interaction of the MDM2 protein with p53 protein is responsible for the inhibition of the p53 function. Inhibiting the p53-MDM2 interaction by drug will lead to the p53 release in the cancer cells. And can restart the apoptosis in the cancer cell. Computational methods successfully used for the design and development of the new, potent MDM2 inhibitors. Researchers and pharma companies used rational approach like target-based drug design or ligand-based drug design to develop the novel MDM2 inhibitors. The number of MDM2 inhibitors, has been designed by the computer-aided drug design and in-silico studies. In clinical studies, MDM2 inhibitors are led by RG7112. RG7112 completed its phase-1 trials in 2016, and recently it is under phase-2 trials. Along with RG7112, the number of potent MDM2 inhibitors entered the clinical trials successfully. It indicates the successful development of this class (MDM2 inhibitors). MDM2 inhibitors were found very effective in various studies for the treatment of various kinds of cancers. They have good selectivity for the tumor cells over the normal cells. It induced the dose dependent cell cycle arrest only; in the normal cells. In studies, MDM2 inhibitors successfully detached the p53 protein from the MDM2 protein. And restart the cell-killing function of the p53 protein in the cancer cells. Hence, MDM2 inhibitors can selectively kill the cancer cells over the normal cells.

Highly Active Thermophilic L-Asparaginase from Melioribacter roseus Represents a Novel Large Group of Type II Bacterial L-Asparaginases from Chlorobi-Ignavibacteriae-Bacteroidetes Clade

L-asparaginase (L-ASNase) is a biotechnologically relevant enzyme for the pharmaceutical, biosensor and food industries. Efforts to discover new promising L-ASNases for different fields of biotechnology have turned this group of enzymes into a growing family with amazing diversity. Here, we report that thermophile Melioribacter roseus from Ignavibacteriae of the Bacteroidetes/Chlorobi group possesses two L-ASNases—bacterial type II (MrAII) and plant-type (MrAIII). The current study is focused on a novel L-ASNase MrAII that was expressed in Escherichia coli, purified and characterized. The enzyme is optimally active at 70 °C and pH 9.3, with a high L-asparaginase activity of 1530 U/mg and L-glutaminase activity ~19% of the activity compared with L-asparagine. The kinetic parameters KM and Vmax for the enzyme were 1.4 mM and 5573 µM/min, respectively. The change in MrAII activity was not significant in the presence of 10 mM Ni2+, Mg2+ or EDTA, but increased with the addition of Cu2+ and Ca2+ by 56% and 77%, respectively, and was completely inhibited by Zn2+, Fe3+ or urea solutions 2–8 M. MrAII displays differential cytotoxic activity: cancer cell lines K562, Jurkat, LnCap, and SCOV-3 were more sensitive to MrAII treatment, compared with normal cells. MrAII represents the first described enzyme of a large group of uncharacterized counterparts from the Chlorobi-Ignavibacteriae-Bacteroidetes clade.