Mebendazole targets essential proteins in glucose metabolism leading gastric cancer cells to death.

Gastric cancer (GC) is among the most-diagnosed and deadly malignancies worldwide. Deregulation in cellular bioenergetics is a hallmark of cancer. Based on the importance of metabolic reprogramming for the development and cancer progression, inhibitors of cell metabolism have been studied as potential candidates for chemotherapy in oncology. Mebendazole (MBZ), an antihelminthic approved by FDA, has shown antitumoral activity against cancer cell lines. However, its potential in the modulation of tumoral metabolism remains unclear. Results evidenced that the antitumoral and cytotoxic mechanism of MBZ in GC cells is related to the modulation of the mRNA expression of glycolic targets SLC2A1, HK1, GAPDH, and LDHA. Moreover, in silico analysis has shown that these genes are overexpressed in GC samples, and this increase in expression is related to decreased overall survival rates. Molecular docking revealed that MBZ modifies the protein structure of these targets, which may lead to changes in their protein function. In vitro studies also showed that MBZ induces alterations in glucose uptake, LDH's enzymatic activity, and ATP production. Furthermore, MBZ induced morphologic and intracellular alterations typical of the apoptotic cell death pathway. Thus, this data indicated that the cytotoxic mechanism of MBZ is related to an initial modulation of the tumoral metabolism in the GC cell line. Altogether, our results provide more evidence about the antitumoral mechanism of action of MBZ towards GC cells and reveal metabolic reprogramming as a potential area in the discovery of new pharmacological targets for GC chemotherapy.

Antitumoral effect of novel synthetic 8-hydroxy-2-((4-nitrophenyl)thio)naphthalene-1,4-dione (CNN16) via ROS-mediated DNA damage, apoptosis and anti-migratory effect in colon cancer cell line.

Colorectal cancer (CRC) is estimated as the third most incident cancer and second in mortality worldwide. Moreover, CRC metastasis reduces patients' survival rates. Thus, the study and identification of new compounds with anticancer activity selectively to tumor cells are encouraged in the CRC treatment. Naphtoquinones are compounds with several pharmacologic activities, including antitumoral properties. Therefore, this study aimed to investigate the anticancer mechanism of synthetic 8-Hydroxy-2-(P-Nitrothiophenol)-1,4-Naphthoquinone (CNN16) in colon cancer cell line HCT-116. CNN16 showed an IC50 of 5.32 µM in HCT-116, and 9.36, 10.77, and 24.57 µM in the non-cancerous cells MRC-5, MNP-01, and PMBC, respectively, evaluated by the MTT assay. CNN16 showed an anticlonogenic effect in HCT-116 and induced cell fragmentation identified by flow cytometry analysis. Furthermore, we observed that CNN16 presented genotoxicity and induces reactive oxygen species (ROS) after 3 h of treatment visualized by alkaline comet assay and DCFH-DA dye fluorescence, respectively. Furthermore, CNN16 caused cellular membrane disruption, reduction in the mitochondrial membrane polarization, and the presence of apoptotic bodies and chromatin condensation was visualized by differential stained (HO/FD/PI) in fluorescent microscopy along with PARP1, TP53, BCL-2, and BAX analyzed by RT-qPCR. Results also evidenced inhibition in the migratory process analyzed by wound healing assay. Therefore, CNN16 can be considered as a potential new leader molecule for CRC treatment, although further studies are still necessary to comprehend the effects of CNN16 in in vivo models to evaluate the anti-migratory effect, and toxicology and assure compound safety and selectively.

1,4-Naphthoquinone (CNN1) Induces Apoptosis through DNA Damage and Promotes Upregulation of H2AFX in Leukemia Multidrug Resistant Cell Line.

The multidrug resistance (MDR) phenotype is one of the major obstacles in the treatment of chronic myeloid leukemia (CML) in advantage stages such as blast crisis. In this scenario, more patients develop resistance mechanisms during the course of the disease, making tyrosine kinase inhibitors (TKIs) target therapies ineffective. Therefore, the aim of the study was to examine the pharmacological role of CNN1, a para-naphthoquinone, in a leukemia multidrug resistant cell line. First, the in vitro cytotoxic activity of Imatinib Mesylate (IM) in K-562 and FEPS cell lines was evaluated. Subsequently, membrane integrity and mitochondrial membrane potential assays were performed to assess the cytotoxic effects of CNN1 in K-562 and FEPS cell lines, followed by cell cycle, alkaline comet assay and annexin V-Alexa Fluor® 488/propidium iodide assays (Annexin/PI) using flow cytometry. RT-qPCR was used to evaluate the H2AFX gene expression. The results demonstrate that CNN1 was able to induce apoptosis, cell membrane rupture and mitochondrial membrane depolarization in leukemia cell lines. In addition, CNN1 also induced genotoxic effects and caused DNA fragmentation, cell cycle arrest at the G2/M phase in leukemia cells. No genotoxicity was observed on peripheral blood mononuclear cells (PBMC). Additionally, CNN1 increased mRNA levels of H2AFX. Therefore, CNN1 presented anticancer properties against leukemia multidrug resistant cell line being a potential anticancer agent for the treatment of resistant CML.

Solid Tumors and Kinase Inhibition: Management and Therapy Efficacy Evolution.

The increasing numbers of cancer cases worldwide and the exceedingly high mortality rates of some tumor subtypes raise the question about if the current protocols for cancer management are effective and what has been done to improve upon oncologic patients' prognoses. The traditional chemo-immunotherapy options for cancer treatment focus on the use of cytotoxic agents that are able to overcome neoplastic clones' survival mechanisms and induce apoptosis, as well as on the ability to capacitate the host's immune system to hinder the continuous growth of malignant cells. The need to avert the highly toxic profiles of conventional chemo-immunotherapy and to overcome the emerging cases of tumor multidrug resistance has fueled a growing interest in the field of precision medicine and targeted molecular therapies in the last couple of decades, although relatively new alternatives in oncologic practices, the increased specificity, and the positive clinical outcomes achieved through targeted molecular therapies have already consolidated them as promising prospects for the future of cancer management. In recent years, the development and application of targeted drugs as tyrosine kinase inhibitors have enabled cancer treatment to enter the era of specificity. In addition, the combined use of targeted therapy, immunotherapy, and traditional chemotherapy has innovated the standard treatment for many malignancies, bringing new light to patients with recurrent tumors. This article comprises a series of clinical trials that, in the past 5 years, utilized kinase inhibitors (KIs) as a monotherapy or in combination with other cytotoxic agents to treat patients afflicted with solid tumors. The results, with varying degrees of efficacy, are reported.

Three dimensional reconstruction of skin with melanoma: A model for study of invasion in vitro.

Melanoma is a type of tumor skin with high metastatic potential. Reconstructed human skin, development for pre-clinic assay, are make using primary human cells, but with same limitations. The aim this study was to characterize a cell culture model, with structure similar to human skin containing melanoma cells entirely from cell lines. Reconstructed skin with melanoma were development using human fibroblasts (MRC5), human epidermal keratinocytes (HaCat), and human melanoma (SK-MEL-28) embedded in collagen type I. The structure was characterized by hematoxylin-eosin stained, as well as points of melanoma cell invasion, which was associated with activity of MMPs (MMP-2 and MMP-9) by zymographic method. Then, the gene expression of the target molecular mechanisms involved in melanoma progression were evaluated. Here, the model development showed a region epidermis organized and separated from the dermis, with fibroblast cells confined and melanoma cells form delimited area invasion. MMP-2 and MMP-9 were identified during of cell culture and gene expression of BRAF, NRAS, and Vimentin was confirmed. The proposed model provides one more opportunity to study in vitro tumor biology of melanoma and also to allows the study of new drugs with more reliable results then whats we would find in vivo.

In silico analysis of ACE2 from different animal species provides new insights into SARS-CoV-2 species spillover.

Aim: This study aimed to analyze the phylogenetic relationships between the ACE2 of humans and other animals and investigate the potential interaction between SARS-CoV-2 RBD and ACE2 of different species. Materials & methods: The phylogenetic construction and molecular interactions were assessed using computational models. Results & conclusion: Despite the evolutionary distance, 11 species had a perfect fit for the interaction between their ACE2 and SARS-CoV-2 RBD (Chinchilla lanigera, Neovison vison, Rhinolophus sinicus, Emballonura alecto, Saccopteryx bilineata, Numida meleagris). Among them, the avian N. meleagris was reported for the first time in this study as a probable SARS-CoV-2 host due to the strong molecular interactions. Therefore, predicting potential hosts for SARS-CoV-2 for understanding the epidemiological cycle and proposal of surveillance strategies.

Here, computational analysis was employed to predict the interaction between the Spike protein from SARS-COV-2 with the ACE2 receptor with animals that could serve as a reservoir for SARS-CoV-2 spillover. Our results reported for the first time that N. meleagris could act as a possible host for SARS-CoV-2.

PARP1 Characterization as a Potential Biomarker for BCR::ABL1 p190+ Acute Lymphoblastic Leukemia.

Detection of t(9;22), and consequent BCR::ABL1 fusion, is still a marker of worse prognosis for acute lymphoblastic leukemia (ALL), with resistance to tyrosine-kinase inhibitor therapy being a major obstacle in the clinical practice for this subset of patients. In this study, we investigated the effectiveness of targeting poly-ADP-ribose polymerase (PARP) in a model of BCR::ABL1 p190+ ALL, the most common isoform to afflict ALL patients, and demonstrated the use of experimental PARP inhibitor (PARPi), AZD2461, as a therapeutic option with cytotoxic capabilities similar to that of imatinib, the current gold standard in medical care. We characterized cytostatic profiles, induced cell death, and biomarker expression modulation utilizing cell models, also providing a comprehensive genome-wide analysis through an aCGH of the model used, and further validated PARP1 differential expression in samples of ALL p190+ patients from local healthcare institutions, as well as in larger cohorts of online and readily available datasets. Overall, we demonstrate the effectiveness of PARPi in the treatment of BCR::ABL1 p190+ ALL cell models and that PARP1 is differentially expressed in patient samples. We hope our findings help expand the characterization of molecular profiles in ALL settings and guide future investigations into novel biomarker detection and pharmacological choices in clinical practice.

Differences in glucose concentration shows new perspectives in gastric cancer metabolism.

Gastric cancer (GC) is among the deadliest cancers worldwide despite available therapies, highlighting the need for novel therapies and pharmacological agents. Metabolic deregulation is a potential study area for new anticancer targets, but the in vitro metabolic studies are controversial, as different ranges of glucose used in the culture media can influence results. In this study, we evaluated cellular viability, glucose uptake, and LDH activity in gastric cancer cell lines when exposed to different glucose concentrations: high (HG, 25mM), low (LG, 5.5mM), and free (FG, 0mM) glucose media. Moreover, we evaluated how glucose variations may influence cellular phenotype and the expression of genes related to epithelial-mesenchymal transition (EMT), metabolism, and cancer development in metastatic GC cells (AGP-01). Results showed that metastatic cells exposed to FG medium evidenced higher alterations when compared to other cell lines. Most phenotypic assays did not show difference when exposed to either HG or LG media. However, gene expression profile of cells exposed to LG revealed differences in mRNA levels of metabolism-related genes when compared to HG medium. According to our results, we recommend using LG medium for metabolic studies since the glucose concentration is closer to physiological levels. These findings point out new relevant targets in metabolic reprogramming that can be alternatives to current chemotherapies in patients with metastatic GC.

A fingerprint of plasma proteome alteration after local tissue damage induced by Bothrops leucurus snake venom in mice.

Bothrops spp. is responsible for about 70% of snakebites in Brazil, causing a diverse and complex pathophysiological condition. Bothrops leucurus is the main species of medical relevance found in the Atlantic coast in the Brazilian Northeast region. The pathophysiological effects involved B. leucurus snakebite as well as the organism's reaction in response to this envenoming, it has not been explored yet. Thus, edema was induced in mice paw using 1.2, 2.5, and 5.0 µg of B. leucurus venom, the percentage of edema was measured 30 min after injection and the blood plasma was collected and analyzed by shotgun proteomic strategy. We identified 80 common plasma proteins with differential abundance among the experimental groups and we can understand the early aspects of this snake envenomation, regardless of the suggestive severity of an ophidian accident. The results showed B. leucurus venom triggers a thromboinflammation scenario where family's proteins of the Serpins, Apolipoproteins, Complement factors and Component subunits, Cathepsins, Kinases, Oxidoreductases, Proteases inhibitors, Proteases, Collagens, Growth factors are related to inflammation, complement and coagulation systems, modulators platelets and neutrophils, lipid and retinoid metabolism, oxidative stress and tissue repair. Our findings set precedents for future studies in the area of early diagnosis and/or treatment of snakebites. SIGNIFICANCE: The physiopathological effects that the snake venoms can cause have been investigated through classical and reductionist tools, which allowed, so far, the identification of action mechanisms of individual components associated with specific tissue damage. The currently incomplete limitations of this knowledge must be expanded through new approaches, such as proteomics, which may represent a big leap in understanding the venom-modulated pathological process. The exploration of the complete protein set that suffer modifications by the simultaneous action of multiple toxins, provides a map of the establishment of physiopathological phenotypes, which favors the identification of multiple toxin targets, that may or may not act in synergy, as well as favoring the discovery of biomarkers and therapeutic targets for manifestations that are not neutralized by the antivenom.

Anticancer potential of mebendazole against chronic myeloid leukemia: in silico and in vitro studies revealed new insights about the mechanism of action.

Chronic myeloid leukemia (CML) is caused by constitutively active fusion protein BCR-ABL1, and targeting ABL1 is a promising therapy option. Imatinib, dasatinib, and nilotinib have all been shown to work effectively in clinical trials. ABL1 mutations, particularly the T315I gate-keeper mutation, cause resistance in patients. As a result, broad-spectrum ABL1 medicines are desperately needed. In order to screen potential drugs targeting CML, mebendazole (MBZ) was subjected to the in vitro test against CML cell lines (K562 and FEPS) and computational assays. The antiproliferative effect of MBZ and the combination with tyrosine kinase inhibitors (TKIs) was tested using end-point viability assays, cell cycle distribution analysis, cell membrane, and mitochondrial dyes. By interrupting the cell cycle and causing cell death, MBZ and its combination with imatinib and dasatinib have a significant antiproliferative effect. We identified MBZ as a promising "new use" drug targeting wild-type and mutant ABL1 using molecular docking. Meanwhile, we determined which residues in the allosteric site are important in ABL1 drug development. These findings may not only serve as a model for repositioning current authorized medications but may also provide ABL1-targeted anti-CML treatments a fresh lease of life.

Kinase Inhibitor Screening Displayed ALK as a Possible Therapeutic Biomarker for Gastric Cancer.

Despite advances in cancer chemotherapy, gastric cancer (GC) continues to have high recurrence rates and poor prognosis with limited treatment options. Understanding the etiology of GC and developing more effective, less harmful therapeutic approaches are vital and urgent. Therefore, this work describes a novel kinase target in malignant gastric cells as a potential therapeutic strategy. Our results demonstrate that among 147 kinase inhibitors (KI), only three molecules were significantly cytotoxic for the AGP-01 cell line. Hence, these three molecules were further characterized in their cellular mode of action. There was significant cell cycle impairment due to the expression modulation of genes such as TP53, CDKN1A, CDC25A, MYC, and CDK2 with subsequent induction of apoptosis. In fact, the Gene Ontology analysis revealed a significant enrichment of pathways related to cell cycle regulation (GO:1902749 and GO:1903047). Moreover, the three selected KIs significantly reduced cell migration and Vimentin mRNA expression after treatment. Surprisingly, the three KIs share the same target, ALK and INSR, but only the ALK gene was found to have a high expression level in the gastric cancer cell line. Additionally, lower survival rates were observed for patients with high ALK expression in TCGA-STAD analysis. In summary, we hypothesize that ALK gene overexpression can be a promising biomarker for prognosis and therapeutic management of gastric adenocarcinoma.

The Relevance of Aurora Kinase Inhibition in Hematological Malignancies.

Aurora kinases are a family of serine/threonine protein kinases that play a central role in eukaryotic cell division. Overexpression of aurora kinases in cancer and their role as major regulators of the cell cycle quickly inspired the idea that their inhibition might be a potential pathway when treating oncologic patients. Over the past couple of decades, the search for designing and testing of molecules capable of inhibiting aurora activities fueled many pre-clinical and clinical studies. In this study, data from the past 10 years of in vitro and in vivo investigations, as well as clinical trials, utilizing aurora kinase inhibitors as therapeutics for hematological malignancies were compiled and discussed, aiming to highlight potential uses of these inhibitors as a novel monotherapy model or alongside conventional chemotherapies. While there is still much to be elucidated, it is clear that these kinases play a key role in oncogenesis, and their manageable toxicity and potentially synergistic effects still render them a focus of interest for future investigations in combinatorial clinical trials.

PARP1 Is Overexpressed in Hematological Malignant Cell Lines: A Framework for Experimental Oncology.

BACKGROUND/AIM: Experimental oncology commonly uses cells as oncological models, providing a framework for the testing of drugs, and investigation of cytotoxicity, mutagenesis and carcinogenesis. Investigations into poly-ADP-ribose polymerase 1 (PARP1) inhibition have become ever more relevant due to its approval as a therapeutic option for tumors with BRCA1/2 DNA repair-associated mutation and the seemingly high PARP expression levels in some tumor subtypes. In this study, we aimed to determine PARP1 gene expression of different hematological cancer-derived cell lineages and compare them to that of normal cell lines. MATERIALS AND METHODS: PARP1 gene expression in seven different neoplastic lineages, representing three different hematological disorders (chronic myeloid leukemia, Burkitt lymphoma and acute lymphoblastic leukemia), was quantified by quantitative real-time polymerase chain reaction. RESULTS: All hematological malignant lineages in this study overexpressed PARP1 when compared to the normal cell line MRC-5, with Burkitt's lymphoma cells having the highest expression values (fold change: 93). CONCLUSION: Overexpression of PARP1 in hematological malignant lineages is a finding of crucial importance to future studies exploring possible cellular oncogenic pathways and supports investigations into the effectiveness of PARP1 inhibitors against hematological disorders.

Kinase Inhibition in Relapsed/Refractory Leukemia and Lymphoma Settings: Recent Prospects into Clinical Investigations.

Cancer is still a major barrier to life expectancy increase worldwide, and hematologic neoplasms represent a relevant percentage of cancer incidence rates. Tumor dependence of continuous proliferative signals mediated through protein kinases overexpression instigated increased strategies of kinase inhibition in the oncologic practice over the last couple decades, and in this review, we focused our discussion on relevant clinical trials of the past five years that investigated kinase inhibitor (KI) usage in patients afflicted with relapsed/refractory (R/R) hematologic malignancies as well as in the pharmacological characteristics of available KIs and the dissertation about traditional chemotherapy treatment approaches and its hindrances. A trend towards investigations on KI usage for the treatment of chronic lymphoid leukemia and acute myeloid leukemia in R/R settings was observed, and it likely reflects the existence of already established treatment protocols for chronic myeloid leukemia and acute lymphoid leukemia patient cohorts. Overall, regimens of KI treatment are clinically manageable, and results are especially effective when allied with tumor genetic profiles, giving rise to encouraging future prospects of an era where chemotherapy-free treatment regimens are a reality for many oncologic patients.

Telomerase (hTERT) Overexpression Reveals a Promising Prognostic Biomarker and Therapeutical Target in Different Clinical Subtypes of Pediatric Acute Lymphoblastic Leukaemia.

Acute Lymphoblastic Leukemia (ALL) is a neoplasm of the hematopoietic system defined as a clonal expansion of an abnormal lymphoid precursor cell. It mostly affects children under five years of age and is the most common tumor to afflict pediatric patients. The expression of the human telomerase gene (hTERT) in patients with ALL has been studied as a biomarker and could become a new therapeutic target. We evaluate the role of hTERT gene expression in ALL pediatric patients, through quantitative real-time PCR technique, and the possible correlation between hTERT expression and clinical variables: gender, age, white blood cells (WBC), gene fusions, and immunophenotyping. The analysis between healthy controls and ALL patients (N = 244) was statistically significant (p < 0.001), demonstrating hTERT overexpression in these patients. In comparison with the usual set of clinical variables, the data were not statistically significant (p > 0.05), indicating that hTERT is equally overexpressed among patients regardless of gender, age, gene fusions, and immunophenotyping. Moreover, patients who presented a higher hTERT expression level had a significant (p < 0.0001) lower overall survival rate. In summary, hTERT expression emerges as an important molecular pathway in leukemogenesis regardless patient's clinical variables, thus, the data here presented pointed it as a valuable biomarker in pediatric acute lymphoblastic leukemia and a promising target for new therapeutic and prognostic measures.

22ß-hydroxytingenone induces apoptosis and suppresses invasiveness of melanoma cells by inhibiting MMP-9 activity and MAPK signaling.

ETHNOPHARMACOLOGICAL RELEVANCE: 22ß-hydroxytingenone (22-HTG) is a quinonemethide triterpene isolated from Salacia impressifolia (Miers) A. C. Smith (family Celastraceae), which has been used in traditional medicine to treat a variety of diseases, including dengue, renal infections, rheumatism and cancer. However, the anticancer effects of 22-HTG and the underlying molecular mechanisms in melanoma cells have not yet been elucidated. AIM OF THE STUDY: The present study investigated apoptosis induction and antimetastatic potencial of 22-HTG in SK-MEL-28 human melanoma cells. MATERIALS AND METHODS: First, the in vitro cytotoxic activity of 22-HTG in cultured cancer cells was evaluated. Then, cell viability was determined using the trypan blue assay in melanoma cells (SK-MEL-28), which was followed by cell cycle, annexin V-FITC/propidium iodide assays (Annexin/PI), as well as assays to evaluate mitochondrial membrane potential, production of reactive oxygen species (ROS) using flow cytometry. Fluorescence microscopy using acridine orange/ethidium bromide (AO/BE) staining was also performed. RT-qPCR was carried out to evaluate the expression of BRAF, NRAS, and KRAS genes. The anti-invasiveness potential of 22-HTG was evaluated in a three-dimensional (3D) model of reconstructed human skin. RESULTS: 22-HTG reduced viability of SK-MEL-28 cells and caused morphological changes, as cell shrinkage, chromatin condensation, and nuclear fragmentation. Furthermore, 22-HTG caused apoptosis, which was demonstrated by increased staining with AO/BE and Annexin/PI. The apoptosis may have been caused by mitochondrial instability without the involvement of ROS production. The expression of BRAF, NRAS, and KRAS, which are important biomarkers in melanoma development, was reduced by the 22-HTG treatment. In the reconstructed skin model, 22-HTG was able to decrease the invasion capacity of melanoma cells in the dermis. CONCLUSIONS: Our data indicate that 22-HTG has anti-tumorigenic properties against melanoma cells through the induction of cell cycle arrest, apoptosis and inhibition of invasiveness potential, as observed in the 3D model. As such, the results provide new insights for future work on the utilization of 22-HTG in malignant melanoma treatment.

PARP Inhibitors as Therapeutic Options for Tyrosine Kinase-dependent Leukemia: A Review.

The idea of utilizing poly-ADP-ribose polymerase inhibitors (PARPi) as therapeutics for cancer has grown in popularity since its original approval for clinical usage in treatment of BRCA DNA repair-associated-mutated ovarian cancer. In this study, we evaluated experimental data regarding in vitro studies utilizing PARPi as a treatment for tyrosine kinase (TK)-dependent leukemia. Studies from 2015 to 2019 were compiled and the ones with most relevant TK pathways and PARP inhibition were analyzed. PARPi showed activity against many leukemia cell lines and samples from patients with primary leukemia, especially when combined with other signaling pathway inhibitor drugs, improving upon the hypothesis that the utilization of PARPi has potential as a new therapeutic approach in treatment of primary leukemia and TK-dependent leukemia.

MAPK14 (p38α) inhibition effects against metastatic gastric cancer cells: A potential biomarker and pharmacological target.

Gastric cancer has been considering one of the worst cancer types since it is diagnosed in advanced stages, currently in the metastatic stage. Therefore, the challenge is to find out a biomarker and a pharmacology target that would help face this worldwide health issue. In this sense, the mitogen-activated protein kinase (MAPK) signaling pathway has become an important aim of the studies in several cancers. Therefore, we evaluated the role of MAPK14 (p38α) inhibitor SB-245392 in the cellular process, such as proliferation, cell death, and cell migration, and whether MAPK14 gene could be a potential biomarker in gastric cancer models. The results clearly suggest that p38α inhibition significantly impairs the cell proliferation, induces modest apoptosis and strongly inhibits cell migration of gastric cancer cell (AGP-01). Gene expression analysis showed that c-MYC level was decreased and TP53 was increased after SB-245392 treatment. Furthermore, MAPK14 was found in high levels in gastric cancer samples compared to normal samples in the TCGA database, especially in advanced stages (stage 3 and 4), which is significantly associated with low rate survival of the patients. In conclusion, the MAPK14 could be a potential biomarker for advanced gastric cancer as well as a pharmacological target, which could improve the survival rate of patients.

22ß-hydroxytingenone reduces proliferation and invasion of human melanoma cells.

Melanoma is a skin cancer with high invasive potential and high lethality. Considering that quinonemethide triterpenes are described as promising anticancer agents, the aim of this study was to evaluate the effect of 22ß-hydroxytingenone (22-HTG) against human melanoma cells. Alamar blue assay was performed in order to evaluate its cytotoxic effect. Thus, subtoxic concentrations (1.0, 2.0, and 2.5 µM) were used to evaluate the effect of this compound on proliferation, migration, metabolism, and invasion. IC50 value against SK-MEL-28 cell line was 4.35, 3.72, and 3.29 µM after 24, 48, and 72 h of incubation, respectively. 22-HTG reduced proliferation, migration and invasion by melanoma cells, with decreased activity of metalloproteinases (MMP-2 and MMP-9). Futhermore, 22-HTG decreased expression of lactate dehydrogenase (LDHA), an enzyme associated with cell metabolism. Howerver, the small reduction in LDHA enzyme activity must have occurred by the cytotoxic effect of 22-HTG. According to the results, 22-HTG interferes with important characteristics of cancer, with anti-proliferative, and anti-invasive effect against melanoma cells. The data suggest that 22-HTG is an effective substance against melanoma cells and it should be considered as a potential anticancer agent.

Establishment of Drug-resistant Cell Lines as a Model in Experimental Oncology: A Review.

Many types of cancer are initially susceptible to chemotherapy, but during treatment, patients may develop resistance to therapy. Knowing that acquisition of drug resistance is a major clinical problem in antineoplastic treatment, the present work aimed to present, through a literature review, the development of chemoresistant cells lines as a model in experimental oncology. A total of 110 drug-resistant cell lines, mainly from lung tumors and leukemias, have been developed. In addition, it has been observed that the drugs used for induction of resistance represented the drugs used for first-line treatment of each neoplasia, since the ideal chemotherapeutic treatment to induce resistance in vitro aims at a better modulation of the therapeutic response in order to better study the mechanisms of resistance.