scholarly journals Pharmacological inhibition of tumor anabolism and host catabolism as a cancer therapy

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Alejandro Schcolnik-Cabrera ◽  
Alma Chavez-Blanco ◽  
Guadalupe Dominguez-Gomez ◽  
Mandy Juarez ◽  
Ariana Vargas-Castillo ◽  
...  
Keyword(s):  
Cancer Cells ◽  
Drug Combination ◽  
Cell Cycle Progression ◽  
De Novo ◽  
In Vivo Evaluation ◽  
Fat Loss ◽  
Normal Tissues ◽  
Animal Metabolism ◽  
Energetic Expenditure

AbstractThe 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.

scholarly journals Oncogenic role of ALX3 in cervical cancer cells through KDM2B-mediated histone demethylation of CDC25A

BMC Cancer ◽  
2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Jinhong Qi ◽  
Li Zhou ◽  
Dongqing Li ◽  
Jingyuan Yang ◽  
He Wang ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cervical Cancer ◽  
Cell Growth ◽  
Cancer Cells ◽  
Cell Cycle Progression ◽  
Cervical Squamous Cell Carcinoma ◽  
Cycle Progression ◽  
Normal Tissues ◽  
Positive Regulator ◽  
Cervical Cancer Cells

Abstract Background Cell division cycle 25A (CDC25A) is a well-recognized regulator of cell cycle progression and is involved in cancer development. This work focused on the function of CDC25A in cervical cancer cell growth and the molecules involved. Methods A GEO dataset GSE63514 comprising data of cervical squamous cell carcinoma (CSCC) tissues was used to screen the aberrantly expressed genes in cervical cancer. The CDC25A expression in cancer and normal tissues was predicted in the GEPIA database and that in CSCC and normal cells was determined by RT-qPCR and western blot assays. Downregulation of CDC25A was introduced in CSCC cells to explore its function in cell growth and the cell cycle progression. The potential regulators of CDC25A activity and the possible involved signaling were explored. Results CDC25A was predicted to be overexpressed in CSCC, and high expression of CDC25A was observed in CSCC cells. Downregulation of CDC25A in ME180 and C33A cells reduced cell proliferation and blocked cell cycle progression, and it increased cell apoptosis. ALX3 was a positive regulator of CDC25A through transcription promotion. It recruited a histone demethylase, lysine demethylase 2B (KDM2B), to the CDC25A promoter, which enhanced CDC25A expression through demethylation of H3k4me3. Overexpression of ALX3 in cells blocked the inhibitory effects of CDC25A silencing. CDC25A was found as a positive regulator of the PI3K/Akt signaling pathway. Conclusion This study suggested that the ALX3 increased CDC25A expression through KDM2B-mediated demethylation of H3K4me3, which induced proliferation and cell cycle progression of cervical cancer cells.

scholarly journals Apelin Over-Expression Promotes Proliferation and Angiogenesis of Gastric Cancer Cells

2021 ◽  
Author(s):  
Li-Jun Tian ◽  
Hong-Zhi Liu ◽  
Qiang Zhang ◽  
Dian-Zhong Geng ◽  
Jing Yang ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Cyclin D1 ◽  
Cancer Cells ◽  
Signaling Pathway ◽  
Cox Regression ◽  
Gastric Cancer Cells ◽  
Over Expression ◽  
Normal Tissues

Abstract Background: Apelin is a recently identified endogenous ligand associated with proliferation and angiogenesis of several cancers. However, only few studies have reported on the functions and the role of apelin in gastric cancer (GC). Therefore, in the present study, we investigated the association and the mechanisms underlying Apelin expression and proliferation of GC cells both in vitro and in vivo.Methods: We enrolled 178 postoperative care GC patients to investigate clinicopathological and immunohistochemical factors associated with Apelin expression. The relationship between Survival of patients and apelin expression was evaluated using Kaplan-Meier method and Cox regression analyses. The expression of apelin mRNA and its proteins in GC tissues and cell lines were analyzed using quantitative real-time reverse transcription-polymerase chain reaction (RT-PCR), western blot and ELISA. The role and mechanisms underlying regulation of Apelin expression in human GC cells were evaluated through several in vitro and in vivo experiments. Results: Apelin was over expressed in human GC cells, relative to adjacent normal tissues. The over expression of apelin was associated with vessel invasion (P <0.01), lymph node metastasis (P <0.01), late-staged tumor (T) (P <0.05), worse pathological type (P <0.05), nerve invasion (P <0.05). In addition, expression of apelin strongly and positively correlated with that of vascular endothelial growth factor (VEGF). Over-expression of apelin promoted proliferation and invasion of MGC-803 cell via the ERK/Cyclin D1/MMP-9 signaling pathway. Apelin over-expression also promoted angiogenesis of GC cells, accelerating growth of subcutaneous xenograft of the cancer cells in vivo.Conclusions: Over-expression of apelin promotes proliferation and metastasis of GC cells via the ERK/Cyclin D1/MMP-9 signaling pathway and is associated with adverse events of the cancer. Consequently, apelin is a potential therapeutic target for human GC.

scholarly journals Anticancer Activity of Cynomorium coccineum

Cancers ◽  
2018 ◽  
Vol 10 (10) ◽  
pp. 354 ◽  
Author(s):  
Mouna Sdiri ◽  
Xiangmin Li ◽  
William Du ◽  
Safia El-Bok ◽  
Yi-Zhen Xie ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Death ◽  
Anticancer Activity ◽  
Cancer Cells ◽  
Cell Lines ◽  
Cancer Cell ◽  
Cell Cycle Progression ◽  
Cycle Progression

The extensive applications of Cynomorium species and their rich bioactive secondary metabolites have inspired many pharmacological investigations. Previous research has been conducted to examine the biological activities and numerous interesting pharmaceutical activities have been reported. However, the antitumor activities of these species are unclear. To understand the potential anticancer activity, we screened Cynomorium coccineum and Cynomorium songaricum using three different extracts of each species. In this study, the selected extracts were evaluated for their ability to decrease survival rates of five different cancer cell lines. We compared the cytotoxicity of the three different extracts to the anticancer drug vinblastine and one of the most well-known medicinal mushrooms Amaurederma rude. We found that the water and alcohol extracts of C. coccineum at the very low concentrations possessed very high capacity in decreasing the cancer cells viability with a potential inhibition of tumorigenesis. Based on these primitive data, we subsequently tested the ethanol and the water extracts of C. coccineum, respectively in in vitro and in vivo assays. Cell cycle progression and induction of programmed cell death were investigated at both biological and molecular levels to understand the mechanism of the antitumor inhibitory action of the C. coccineum. The in vitro experiments showed that the treated cancer cells formed fewer and smaller colonies than the untreated cells. Cell cycle progression was inhibited, and the ethanol extract of C. coccineum at a low concentration induced accumulation of cells in the G1 phase. We also found that the C. coccineum’s extracts suppressed viability of two murine cancer cell lines. In the in vivo experiments, we injected mice with murine cancer cell line B16, followed by peritoneal injection of the water extract. The treatment prolonged mouse survival significantly. The tumors grew at a slower rate than the control. Down-regulation of c-myc expression appeared to be associated with these effects. Further investigation showed that treatment with C. coccineum induced the overexpression of the tumor suppressor Foxo3 and other molecules involved in inducing autophagy. These results showed that the C. coccineum extract exerts its antiproliferative activity through the induction of cell death pathway. Thus, the Cynomorium plants appear to be a promising source of new antineoplastic compounds.

CD44 targeting biocompatible and biodegradable hyaluronic acid cross-linked zein nanogels for curcumin delivery to cancer cells: In vitro and in vivo evaluation

2018 ◽  
Vol 280 ◽  
pp. 20-30 ◽  
Author(s):  
Hae-Yong Seok ◽  
N. Sanoj Rejinold ◽  
Kamali Manickavasagam Lekshmi ◽  
Kondareddy Cherukula ◽  
In-Kyu Park ◽  
...  
Keyword(s):  
Hyaluronic Acid ◽  
Cancer Cells ◽  
In Vivo Evaluation ◽  
Cd44 Targeting

scholarly journals In vivo evaluation of the interaction between the Escherichia coli IGP synthase subunits using the Bacterial Two-Hybrid system

2020 ◽  
Vol 367 (14) ◽  
Author(s):  
Sofia Chioccioli ◽  
Patrizia Bogani ◽  
Sara Del Duca ◽  
Lara Mitia Castronovo ◽  
Alberto Vassallo ◽  
...  
Keyword(s):  
Escherichia Coli ◽  
Hybrid System ◽  
De Novo ◽  
Glycerol Phosphate ◽  
In Vivo Evaluation ◽  
Igp Synthase ◽  
Imidazole Glycerol Phosphate ◽  
Two Hybrid

ABSTRACT Histidine biosynthesis is one of the most characterized metabolic routes for its antiquity and its central role in cellular metabolism; indeed, it represents a cross-road between nitrogen metabolism and de novo synthesis of purines. This interconnection is due to the activity of imidazole glycerol phosphate synthase, a heterodimeric enzyme constituted by the products of two his genes, hisH and hisF, encoding a glutamine amidotransferase and a cyclase, respectively. Despite their interaction was suggested by several in vitro experiments, their in vivo complex formation has not been demonstrated. On the contrary, the analysis of the entire Escherichia coli interactome performed using the yeast two hybrid system did not suggest the in vivo interaction of the two IGP synthase subunits. The aim of this study was to demonstrate the interaction of the two proteins using the Bacterial Adenylate Cyclase Two-Hybrid (BACTH) system. Data obtained demonstrated the in vivo interaction occurring between the proteins encoded by the E. coli hisH and hisF genes; this finding might also open the way to pharmaceutical applications through the design of selective drugs toward this enzyme.

scholarly journals When cholesterol meets histamine, it gives rise to dendrogenin A: a tumour suppressor metabolite1

2016 ◽  
Vol 44 (2) ◽  
pp. 631-637 ◽  
Author(s):  
Marc Poirot ◽  
Sandrine Silvente-Poirot
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Metabolic Pathway ◽  
Protective Role ◽  
Tumour Suppressor ◽  
Human Tissues ◽  
Normal Tissues ◽  
Steroidal Alkaloid

Dendrogenin A (DDA) is the first steroidal alkaloid (SA) to be identified in human tissues to date and arises from the stereoselective enzymatic conjugation of 5,6α-epoxycholesterol (5,6α-EC) with histamine (HA). DDA induces the re-differentiation of cancer cells in vitro and in vivo and prevents breast cancer (BC) and melanoma development in mice, evidencing its protective role against oncogenesis. In addition, DDA production is lower in BCs compared with normal tissues, suggesting a deregulation of its biosynthesis during carcinogenesis. The discovery of DDA reveals the existence of a new metabolic pathway in mammals which lies at the crossroads of cholesterol and HA metabolism and which leads to the production of this metabolic tumour suppressor.

scholarly journals Genotoxic effects of the carbamate insecticide Pirimor-50® in Vicia faba root tip meristems and human lymphocyte culture after direct application and treatment with its metabolic extracts

2016 ◽  
Vol 67 (4) ◽  
pp. 266-276 ◽  
Author(s):  
Rafael Valencia-Quintana ◽  
Sandra Gómez-Arroyo ◽  
Juana Sánchez-Alarcón ◽  
Mirta Milić ◽  
José Luis Gómez Olivares ◽  
...  
Keyword(s):  
Vicia Faba ◽  
Human Lymphocyte ◽  
Cell Cycle Progression ◽  
Lymphocyte Culture ◽  
Root Tip ◽  
Genotoxic Effects ◽  
Animal Metabolism ◽  
Index Ratio

Abstract The aim of the study was to evaluate genotoxic effects of Pirimor-50®, a pirimicarb-based formulation (50 % active ingredient), in human lymphocyte cultures and Vicia faba root meristems. Furthermore, the objective was to examine a combined influence of insecticide treatment with mammalian microsomal S9 and vegetal S10 metabolic fractions or S10 mix metabolic transformation extracts (after Vicia faba primary roots treatment with Pirimor-50®). We used sister chromatid exchange assay-SCE and measured cell cycle progression and proliferation (proportion of M1-M3 metaphases and replication index ratio-RI). Two processes were used for plant promutagen activation: in vivo activation-Pirimor-50® was applied for 4 h to the plant and then S10 mix was added to lymphocytes; and, in vitro activation-lymphocytes were treated with Pirimor-50® and S10 or S9 for 2 h. Direct treatment induced significantly higher SCE frequencies in meristems at 0.01 mg mL-1. In lymphocytes, significantly higher SCE was at 1 mg mL-1 with decrease in RI and M1-M3 metaphase proportions at 0.5 mg mL-1 and cell division stop at 2.5 mg mL1. S10 mix lymphocyte treatment showed significantly elevated SCE values at 2-2.5 mg mL-1, with cell death at 3 mg mL-1. Lymphocyte treatment with Pirimor-50® together with S9 or S10 showed slightly elevated SCE frequency but had a significant influence on RI decrease, with lowest values in S9 treatment. Since no data are available on the genotoxicity of Pirimor-50®, this study is one of the first to evaluate and compare its direct effect in two bioassays, animal and vegetal, and also the effect of plant and animal metabolism on its genotoxic potential.

scholarly journals Distribution and vulnerability of transcriptional outputs across the genome in Myc-amplified medulloblastoma cells

2021 ◽  
Author(s):  
Rui Yang ◽  
Wenzhe Wang ◽  
Meichen Dong ◽  
Kristen Roso ◽  
Paula Greer ◽  
...  
Keyword(s):  
Cancer Cells ◽  
Tumor Cells ◽  
Target Genes ◽  
De Novo ◽  
Inhibitory Effect ◽  
Nucleotide Synthesis ◽  
High Level ◽  
The Impact

Myc plays a central role in tumorigenesis by orchestrating the expression of genes essential to numerous cellular processes1-4. While it is well established that Myc functions by binding to its target genes to regulate their transcription5, the distribution of the transcriptional output across the human genome in Myc-amplified cancer cells, and the susceptibility of such transcriptional outputs to therapeutic interferences remain to be fully elucidated. Here, we analyze the distribution of transcriptional outputs in Myc-amplified medulloblastoma (MB) cells by profiling nascent total RNAs within a temporal context. This profiling reveals that a major portion of transcriptional action in these cells was directed at the genes fundamental to cellular infrastructure, including rRNAs and particularly those in the mitochondrial genome (mtDNA). Notably, even when Myc protein was depleted by as much as 80%, the impact on transcriptional outputs across the genome was limited, with notable reduction mostly only in genes involved in ribosomal biosynthesis, genes residing in mtDNA or encoding mitochondria-localized proteins, and those encoding histones. In contrast to the limited direct impact of Myc depletion, we found that the global transcriptional outputs were highly dependent on the activity of Inosine Monophosphate Dehydrogenases (IMPDHs), rate limiting enzymes for de novo guanine nucleotide synthesis and whose expression in tumor cells was positively correlated with Myc expression. Blockage of IMPDHs attenuated the global transcriptional outputs with a particularly strong inhibitory effect on infrastructure genes, which was accompanied by the abrogation of MB cells proliferation in vitro and in vivo. Together, our findings reveal a real time action of Myc as a transcriptional factor in tumor cells, provide new insight into the pathogenic mechanism underlying Myc-driven tumorigenesis, and support IMPDHs as a therapeutic vulnerability in cancer cells empowered by a high level of Myc oncoprotein.

scholarly journals Five-Decade Update on Chemopreventive and Other Pharmacological Potential of Kurarinone: a Natural Flavanone

2021 ◽  
Vol 12 ◽  
Author(s):  
Shashank Kumar ◽  
Kumari Sunita Prajapati ◽  
Mohd Shuaib ◽  
Prem Prakash Kushwaha ◽  
Hardeep Singh Tuli ◽  
...  
Keyword(s):  
Cancer Cells ◽  
Cell Cycle Progression ◽  
Therapeutic Potential ◽  
Experimental Models ◽  
Xenograft Models ◽  
Inhibitory Potential ◽  
Pharmacological Potential

In the present article we present an update on the role of chemoprevention and other pharmacological activities reported on kurarinone, a natural flavanone (from 1970 to 2021). To the best of our knowledge this is the first and exhaustive review of kurarinone. The literature was obtained from different search engine platforms including PubMed. Kurarinone possesses anticancer potential against cervical, lung (non-small and small), hepatic, esophageal, breast, gastric, cervical, and prostate cancer cells. In vivo anticancer potential of kurarinone has been extensively studied in lungs (non-small and small) using experimental xenograft models. In in vitro anticancer studies, kurarinone showed IC50 in the range of 2–62 µM while in vivo efficacy was studied in the range of 20–500 mg/kg body weight of the experimental organism. The phytochemical showed higher selectivity toward cancer cells in comparison to respective normal cells. kurarinone inhibits cell cycle progression in G2/M and Sub-G1 phase in a cancer-specific context. It induces apoptosis in cancer cells by modulating molecular players involved in apoptosis/anti-apoptotic processes such as NF-κB, caspase 3/8/9/12, Bcl2, Bcl-XL, etc. The phytochemical inhibits metastasis in cancer cells by modulating the protein expression of Vimentin, N-cadherin, E-cadherin, MMP2, MMP3, and MMP9. It produces a cytostatic effect by modulating p21, p27, Cyclin D1, and Cyclin A proteins in cancer cells. Kurarinone possesses stress-mediated anticancer activity and modulates STAT3 and Akt pathways. Besides, the literature showed that kurarinone possesses anti-inflammatory, anti-drug resistance, anti-microbial (fungal, yeast, bacteria, and Coronavirus), channel and transporter modulation, neuroprotection, and estrogenic activities as well as tyrosinase/diacylglycerol acyltransferase/glucosidase/aldose reductase/human carboxylesterases 2 inhibitory potential. Kurarinone also showed therapeutic potential in the clinical study. Further, we also discussed the isolation, bioavailability, metabolism, and toxicity of Kurarinone in experimental models.

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