EGFR and HER2 small molecules inhibitors as potential therapeutics in veterinary oncology / Inhibidores EGFR y HER2 como tratamientos potenciales en oncología veterinaria

SUMMARY EGFR and HER2 receptors are crucial signaling molecules tyrosine kinase involved in human cancer. Aberrant signaling is associated with a variety of cancers, frequently with poor prognosis. Currently, EGFR and HER2 receptors are being targeted by small molecules, which offer a huge benefit to those patients afflicted by aggressive forms of cancer, improving their prognosis. Both human and canine cancers share molecular, biological, histopathological, and clinical similarities, including EGFR and HER2 expression in some forms of cancer. However, despite the use of one tyrosine kinase inhibitor approved to treat canine mastocytoma, canine cancers overexpressed EGFR and HER2 do not yet have targeted therapy, leading to high morbidity and mortality. Targeting EGFR and HER2 receptors in canine cancers using comparative approaches in human cancer could lead to better outcomes.

RESUMEN El receptor de factor de crecimiento epidérmico (Epidermal growth factor receptor, EGFR) y el receptor 2 del factor de crecimiento epidérmico (HER2 epidermal growth factor receptor 2) son moléculas señalizadoras cruciales pertenecientes a la familia de proteínas tirosina quinasa involucradas en el cáncer en humanos. La señalización aberrante de dichos receptores se encuentra asociada con una variedad de tumores, frecuentemente asociados a mal pronóstico. Actualmente, EGFR y HER2 son tratados específicamente a través de pequeñas moléculas inhibidoras, las cuales ofrecen un gran beneficio a aquellos pacientes que padecen formas agresivas de cáncer, y de esta manera su pronóstico mejora. Tanto el cáncer en medicina humana como veterinaria comparte similitudes moleculares, biológicas, histopatológicas y clínicas, las cuales incluyen la expresión tanto de EGFR y HER2 en algunas formas de cáncer. Sin embrago, a pesar del uso de un inhibidor tirosina quinasa aprobado para el manejo del mastocitoma canino los tumores que se caracterizan por la sobre-expresión de EGFR y HER2 aún no cuentan con un inhibidor específico, lo cual conduce a alta morbilidad y mortalidad.

Prognostic value of long non-coding RNA TP73-AS1 expression in different types of cancer: a systematic review and meta-analysis

Background: TP73 antisense RNA 1 (TP73-AS1), a newly discovered long non-coding RNA (lncRNA), has been reported to be upregulated in various kinds of tumors, and shows a variable influence on living quality and prognosis of patients. Thus, we conducted a meta-analysis to evaluate the overall prognostic value of the lncRNA TP73-AS1 in cancer patients. Results: A systematic literature retrieval was carried out using the PubMed, Cochrane Library, EMBASE, and Web of Science databases. We calculated the pooled hazard ratio (HR) and odds ratio (OR) with 95% confidence intervals (CIs) to evaluate the association of TP73-AS1 expression with prognostic and clinicopathological parameters. A total of 15 studies including 1057 cancer patients were finally selected for the meta-analysis. The results demonstrated that high TP73-AS1 expression was significantly associated with shorter overall survival (OS) (HR = 1.97, 95% CI: 1.68­2.31, P b 0.001). According to a fixed-effects or random-effects model, elevated TP73-AS1 expression markedly predicted advanced clinical stage (OR = 3.30, 95% CI: 2.35­4.64, P b 0.001), larger tumor size (OR = 2.37, 95% CI: 1.75­3.22, P b 0.001), earlier lymph node metastasis (OR = 3.28, 95% CI: 1.59­6.76, P = 0.001), and distant metastasis (OR = 4.94, 95% CI: 2.61­9.37, P b 0.001). Conclusions: High lncRNA TP73-AS1 expression appears to be predictive of a worse OS and clinicopathologic features for patients with various types of malignant tumors. These results provide a basis for utilizing TP73- AS1 expression as an unfavorable indicator to predict survival outcomes.

El ácido valproico como agente sensibilizador al tratamiento anticáncer / Valproic acid as a sensitizing agent in anticancer treatment

Resumen El ácido valproico es un fármaco antiepiléptico con más de 50 años de uso clínico. En la década pasada se descubrieron sus efectos anticancerígenos. El análisis de grupos de pacientes que utilizaron este fármaco durante años ha mostrado que disminuye la frecuencia de cáncer de cabeza y cuello. Estudios recientes evidencian el efecto anticáncer al combinar el ácido valproico con la quimioterapia, terapia biológica e inhibidores de sistemas antioxidantes, con resultados excepcionales. En esta revisión se analiza el metabolismo del ácido valproico y su aplicación contra el cáncer.

Abstract Valproic acid is an antiepileptic drug with more than 50 years of clinical use. In the past decade, its anticancer effects were discovered. Analyses in groups of patients who used this drug for years have shown that it decreases the frequency of head and neck cancer. Recent studies show the anticancer effect of combining valproic acid with chemotherapy, biological therapy and antioxidant systems inhibitors, with exceptional results. In this review, we analyze the metabolism of valproic acid and its application against cancer.

Diversity, Ethnobotanical Potential and Sustainability Assessment of Plants Used by Traditional Healers to Treat Cancer in Boyo Division, North-West Region, Cameroon

Aims: Cancer is the second leading cause of death globally. Therefore, the knowledge on medicinal plants used to cure human cancer could be of great importance for their widespread use and scientific validation. The present study records information on anticancer plants in Boyo Division, in the western highland of Cameroon. Methods: Thirty traditional healers, were interviewed to document their know-how on the type of human cancer allegedly cured, the plant species used as well as their use pattern. Guided field walks were made to the collection sites for plant and its habitat characterization as well as herbarium voucher collection. Ethnobotanical quantitative tools were used to analyze and summarize collected data. Sustainability of harvest was assessed using a vulnerability index based on seven parameters. Results: A total of 25 medicinal plants cited were identified as belonging to 13 families and 23 genera. The most represented families were Asteraceae (28%), Lamiaceae (16%), Fabaceae (12%) and Acanthaceae (8%). Out of the seven categories of cancer diseases reported, the highest number of plants species were reported to treat stomach, pancreas, liver, skin and breast cancers, with informant consensus factor (ICF) ranging from 0.79 to 0.82. Leaves (60%) and bark (20%) were the major plant parts used mostly in form of decoction (45.45%) and concoction (38.18%). The result of Relative frequency citations (RFCs) revealed that 9 of the 25 plants species cited were the most frequently used with fidelity levels ranging from 92% (Geniosporum rotundifolium and Ocimum tenuiflorum Aframomum melegueta and Entada abyssinica) to 100% (Coleus blumei, Ocimum gratissimum, Eremomastax speciosa, and Dichrocephala integrifolia). Six species were assessed as vulnerable (Vi ≥ 2), while two species were rated as highly vulnerable namely G. rotundifolium (Vi = 2.71) and E. abyssinica (Vi = 2.85). Conclusion: New traditionally effective anticancer plants were identified in the present study, some of which were already vulnerable for exploitation in their actual habitat. Plants with high ICF, RFCs and FL values should be subjected to further phytochemical and pharmacological investigations for scientific validation while those with high Vulnerability index should be recommended for participatory domestication by the main users.

Evaluation of the cytotoxic effect of crude aqueous and ethanolic extracts isolated from Lentinus sp. on human cancer cell lines

Aims@#The aim of this study was to evaluate some chemical properties and the cytotoxic effect of aqueous and ethanolic crude polysaccharides extracted from five Lentinus sp. on human cancer cell lines. It was hypothesized that other species of the genus Lentinus could show the pharmacological actions as presence in Lentinus edodes, especially anticancer properties. @*Methodology and results@#Crude extracts of dried fruit bodies and mycelia from L. edodes, Lentinus sajor-caju, Lentinus swartzii, Lentinus squarrosulus and Lentinus velutinus were extracted using two solvents, hot water and 95% ethanol, and evaluated for their total carbohydrates, proteins, reducing sugar, phenol contents, and cytotoxicity. The yield of crude extracts was 33.6-205.3 mg/g dry weight of a sample. Cytotoxicity was determined with 10 mg/mL of crude aqueous and 1 mg/mL of crude ethanolic extracts by using the [3-(4,5-dimethylthiazol-2-yl)-2, 5- diphenyltetrazolium bromide] (MTT) method. All extracts showed non-cytotoxicity against the normal cell lines, LLC-MK2 and L929 cells. While, the extracts of L. edodes, L. sajor-caju, L. squarrosulus and L. velutinus displayed the cytotoxicity against the human cancer cell lines. @*Conclusion, significance and impact of study@#The crude aqueous and ethanolic extract from fruit bodies of L. velutinus and the ethanolic extract from fruit bodies of L. sajor-caju and L. squarrosulus displayed the adverse effect against the human cancer cell lines. Hence, these extracts are a potential source of bioactive compounds for cancer treatment.

-Methyladenosine modification: a novel pharmacological target for anti-cancer drug development

-Methyladenosine (mA) modification is the most pervasive modification of human mRNA molecules. It is reversible regulation of mA modification methyltransferase, demethylase and proteins that preferentially recognize mA modification as "writers", "erasers" and "readers", respectively. Altered expression levels of the mA modification key regulators substantially affect their function, leading to significant phenotype changes in the cell and organism. Recent studies have proved that the mA modification plays significant roles in regulation of metabolism, stem cell self-renewal, and metastasis in a variety of human cancers. In this review, we describe the potential roles of mA modification in human cancers and summarize their underlying molecular mechanisms. Moreover, we will highlight potential therapeutic approaches by targeting the key mA modification regulators for cancer drug development.

Human polyomaviruses and cancer: an overview

The name of the family Polyomaviridae, derives from the early observation that cells infected with murine polyomavirus induced multiple (poly) tumors (omas) in immunocompromised mice. Subsequent studies showed that many members of this family exhibit the capacity of mediating cell transformation and tumorigenesis in different experimental models. The transformation process mediated by these viruses is driven by viral pleiotropic regulatory proteins called T (tumor) antigens. Similar to other viral oncoproteins T antigens target cellular regulatory factors to favor cell proliferation, immune evasion and downregulation of apoptosis. The first two human polyomaviruses were isolated over 45 years ago. However, recent advances in the DNA sequencing technologies led to the rapid identification of additional twelve new polyomaviruses in different human samples. Many of these viruses establish chronic infections and have been associated with conditions in immunosuppressed individuals, particularly in organ transplant recipients. This has been associated to viral reactivation due to the immunosuppressant therapy applied to these patients. Four polyomaviruses namely, Merkel cell polyomavirus (MCPyV), Trichodysplasia spinulosa polyomavirus (TSPyV), John Cunningham Polyomavirus (JCPyV) and BK polyomavirus (BKPyV) have been associated with the development of specific malignant tumors. However, present evidence only supports the role of MCPyV as a carcinogen to humans. In the present review we present a summarized discussion on the current knowledge concerning the role of MCPyV, TSPyV, JCPyV and BKPyV in human cancers.

Anti-proliferation activity of terpenoids isolated from Euphorbia kansui in human cancer cells and their structure-activity relationship / 中国天然药物

Euphorbia kansui is a commonly used traditional Chinese medicine for the treatment of edema, pleural effusion, and asthma, etc. According to the previous researches, terpenoids in E. kansui possess various biological activities, e.g., anti-virus, anti-allergy, antitumor effects. In this work, twenty five terpenoids were isolated from E. kansui, including thirteen ingenane- and eight jatrophane-type diterpenoids (with two new compounds, kansuinin P and Q) and four triterpenoids. Eighteen of them were analyzed by MTS assay for in vitro anticancer activity in five human cancer cell lines. Structure-activity relationship for 12 ingenane-type diterpenoids in colorectal cancer Colo205 cells were preliminary studied. Significant anti-proliferation activities were observed in human melanoma cells breast cancer MDA-MB-435 cells and Colo205 cells. More than half of the isolated ingenane-type diterpenoids showed inhibitory activities in MDA-MB-435 cells. Eight ingenane- and one jatrophane-type diterpenoids possessed much lower IC values in MDA-MB-435 cells than positive control staurosporine. Preliminary structure-activity relationship analysis showed that substituent on position 20 was important for the activity of ingenane-type diterpenoids in Colo205 cells and substituent on position 3 contributed more significant biological activity of the compounds than that on position 5 in both MDA-MB-435 and Colo205 cells.

Potential of four marine-derived fungi extracts as anti-proliferative and cell death-inducing agents in seven human cancer cell lines

OBJECTIVE@#To evaluate the in vitro anticancer activity of crude ethyl acetate extracts of the culture of four marine-derived fungi Aspergillus similanensis KUFA 0013 (E1), Neosartorya paulistensis KUFC 7897 (E2), Neosartorya siamensis KUFA 0017 (E4) and Talaromyces trachyspermus KUFC 0021 (E3) on a panel of seven human cancer cell lines.@*METHODS@#Effects on cell proliferation, induction of DNA damage and cell death were assessed by MTT and clonogenic assays, comet assay and nuclear condensation assay, respectively.@*RESULTS@#The proliferation of HepG2, HCT116 and A375 cells decreased after incubation with the extracts E2 and E4. The anti-proliferative effect was confirmed by morphologic alterations and by clonogenic assay. Both extracts also induced cell death in HepG2 and HCT116 cells. Doxorubicin was used as a positive control and showed in vitro anticancer activity.@*CONCLUSIONS@#This study demonstrated, for the first time, that extracts of Neosartorya paulistensis and Neosartorya siamensis have selective anti-proliferative and cell death activities in HepG2, HCT16 and A375 cells. The bioactivity of these extracts suggests a potential for biotechnological applications and substantiates that both should be further considered for the elucidation of the molecular targets and signal transduction pathways involved.

Potential of four marine-derived fungi extracts as anti-proliferative and cell death-inducing agents in seven human cancer cell lines

Objective: To evaluate the in vitro anticancer activity of crude ethyl acetate extracts of the culture of four marine-derived fungi Aspergillus similanensis KUFA 0013 (E1), Neosartorya paulistensis KUFC 7897 (E2), Neosartorya siamensis KUFA 0017 (E4) and Talaromyces trachyspermus KUFC 0021 (E3) on a panel of seven human cancer cell lines. Methods: Effects on cell proliferation, induction of DNA damage and cell death were assessed by MTT and clonogenic assays, comet assay and nuclear condensation assay, respectively. Results: The proliferation of HepG2, HCT116 and A375 cells decreased after incubation with the extracts E2 and E4. The anti-proliferative effect was confirmed by morphologic alterations and by clonogenic assay. Both extracts also induced cell death in HepG2 and HCT116 cells. Doxorubicin was used as a positive control and showed in vitro anticancer activity. Conclusions: This study demonstrated, for the first time, that extracts of Neosartorya paulistensis and Neosartorya siamensis have selective anti-proliferative and cell death activities in HepG2, HCT16 and A375 cells. The bioactivity of these extracts suggests a potential for biotechnological applications and substantiates that both should be further considered for the elucidation of the molecular targets and signal transduction pathways involved.

In vitro cytotoxic activity of leaves extracts of Holarrhena antidysenterica against some human cancer cell lines.

In vitro cytotoxic potential of extracts (95% and 50% ethanolic extract and hot water extract at concentration of 100 µg/ml) from leaves of Holarrhena antidysenterica was evaluated against fourteen human cancer cell lines — A-549, COLO-205, DU-145, HeLa, HEP-2, IMR-32, KB, MCF-7, NCI-H23, OVCAR-5, SiHa, SK-N-MC, SW-620 and ZR-75-1 from nine different tissues (breast, colon, cervix, CNS, lung, liver, oral, ovary and prostate) using SRB assay. The 95% ethanolic extract displayed maximum anti-proliferative effect in the range of 73-92% against eight human cancer cell lines, while 50% ethanolic extract showed cytotoxic activity in the range of 70-94% against seven human cancer cell lines. However, the hot water extract did not show any activity. Among the fractions of 95% and 50% ethanolic extract, significant cytotoxic activity was found in the chloroform soluble fraction of 95% ethanolic extract at 100 µg/ml; it inhibited the growth in the range of 71-99% of seven human cancer cell lines from five different tissues viz., OVCAR-5 (ovary), HT-29 (colon), SK-N-MC (neuroblastoma), HEP-2 (liver), COLO-205 (colon), NIH-OVCAR-3 (ovary) and A-549 (lung). The cytotoxic activity of chloroform soluble fraction was found to be higher than 5-flurouracil, adriamycin, mitomycin-c and paclitaxel (anticancer drugs used as positive controls). Further in vivo studies and identification of active components from the chloroform fraction and their exact mechanism of action could be useful in designing new anticancer therapeutic agents.

Anti-proliferative efficacy comparison of conjugated linoleic acid on human cancer cell lines / 동물의과학연구지

The anti-proliferative efficacy of t,t-conjugated linoleic acid (t,t-CLA), c9,t11-CLA, and t10,c12-CLA was compared in several human cancer cell lines. Gastric NCI-N87, liver Hep3B, pancreas Capan-2, and lung NCI-H522 cancer cells were incubated with 50 microM CLA isomers over a period of 6 days. The t,t-CLA inhibited the growth of all cancer cell lines to different extents, but c9,t11-CLA and t10,c12-CLA inhibited or stimulated the growth of the cancer cell lines. NCI-N87 cells were the most sensitive to growth inhibition and apoptosis from all CLA isomers tested. In NCI-N87 cells, CLA isomers reduced the release of arachidonic acid (AA) via the inhibition of cytosolic phospholipase A2 (cPLA2) activity, consequently reducing the production of PGE2 through the inhibition of cyclooxygenase-2 (COX-2). The efficacies of CLA isomers were in the following order (from most to least effective): t,t-CLA, t10,c12-CLA and c9,t11-CLA. Overall, these results imply that the anti-proliferative efficacy of t,t-CLA on cancer cells, especially NCI-N87 cells, was greater than other CLA isomers due to its induction of apoptosis through the inhibition of cPLA2 and COX-2 activities.

Anti-proliferative effect of leaf extracts of Eucalyptus citriodora against human cancer cells in vitro and in vivo.

Six different extracts from Eucalyptus citriodora leaves were investigated for their anticancer effect. Extracts were prepared using a range of polar and non-polar solvents to leach out maximum active components. Phytochemical analysis of the extracts revealed the presence of anthraquinones, cardiac glycosides, flavonoids, saponins and tannins. Cytotoxic activity of different extracts was tested in vitro against seven human cancer cell lines from seven different tissues, such as SW-620 (colon), HOP-62 (lung), PC-3 (prostate), OVCAR-5 (ovary), HeLa (cervix), IMR-32 (neuroblastoma) and HEP-2 (liver). The ethyl acetate, chloroform and 50% methanolic extract displayed highest anti-proliferative effect in a dose-dependent manner. In vivo anti-tumor activity was evaluated against murine tumor (solid) model of Ehrlich ascites carcinoma and Sarcoma 180. The results showed that ethyl acetate and aqueous extracts suppressed the growth of Ehrlich ascites carcinoma (29.79% and 18.48%, respectively), but showed little growth inhibition in case of Sarcoma 180 (13. 86% and 8.57%, respectively). The activity might be due to the flavonoids, tannins and saponins that are present in all the extracts of the plant. Further investigation is required for the isolation of active principle(s) from the ethyl acetate extract, which has shown significant in vitro and in vivo anticancer potential.

Antiproliferative effect of cucurbitacin B extracted from trichosanthes cucumerina L. on human cancer cell lines.

Objective: To determine the antiproliferative effect of cucurbitacin B extracted from Trichosanthes cucumerina L. on human cancer cell lines. Methods: Two human lung non-small cell (adenocarcinoma) cancer cell lines i.e., LK87, and QG95, two human colon adenocarcinoma cell lines i.e., HCT15, and HT29, including one renal cancer cell line, A498, and one pancreatic cancer cell line, NOR-P, were used in this study. The viability of cells was assessed by using WST-8 which is based on detection of LDH released from damaged cells and reacts with WST-8 to form a yellow color. Cells were treated with the compound at various concentration from 1 through 100 µg/ml. Results: The ED50 values (effective doses that are required for 50% inhibition growth of tumor cells) of the compound on human cancer cell lines ranged from approximately 69 µg/ml in HCT15 cells up to 231 µg/ml in QG95 cells. The inhibition of proliferation of this compound on these human cancer cell lines was observed to be in a dose dependent manner. Conclusion: It could be concluded from this observation that this compound has a modest direct toxic effect to these cell lines with the highest toxic effect on human colon cancer cells.

Assay of superoxide dismutase activity in animal tissues.

Convenient assays for superoxide dismutase have necessarily been of the indirect type. It was observed that among the different methods used for the assay of superoxide dismutase in rat liver homogenate, namely the xanthine–xanthine oxidase ferricytochrome c, xanthine-xanthine oxidase nitroblue tetrazolium, and pyrogallol autoxidation methods, a modified pyrogallol autoxidation method appeared to be simple, rapid and reproducible. The xanthine-xanthine oxidase ferricytochrome c method was applicable only to dialysed crude tissue homogenates. The xanthine-xanthine oxidase nitroblue tetrazolium method, either with sodium carbonate solution, pH 10·2, or potassium phosphate buffer, pH 7·8, was not applicable to rat liver homogenate even after extensive dialysis. Using the modified pyrogallol autoxidation method, data have been obtained for superoxide dismutase activity in different tissues of rat. The effect of age, including neonatal and postnatal development on the activity, as well as activity in normal and cancerous human tissues were also studied. The pyrogallol method has also been used for the assay of iron-containing superoxide dismutase in Escherichia coli and for the identification of superoxide dismutase on polyacrylamide gels after electrophoresis.