scholarly journals In silico investigations revealed four potential colon cancer drugs from phytochemicals in Zingiber officinale

2016 ◽  
Vol 8 (3) ◽  
pp. 435
Author(s):  
Fortunatus Chidolue Ezebuo ◽  
Colin B Lukong ◽  
Ikemefuna C Uzochukwu ◽  
Irene N Okafor
Keyword(s):  
Colon Cancer ◽  
Binding Site ◽  
Ex Vivo ◽  
Dihydropyrimidine Dehydrogenase ◽  
Zingiber Officinale ◽  
Cancer Drug ◽  
Cancer Drugs ◽  
Tumor Necrosis Factor Ligand

<p align="left">Cancer is a difficult disease to treat, and few effective drugs are available. Hence, it is of great importance to develop effective anti-cancer therapeutic agents with well-defined pharmacokinetic properties.<strong> </strong>Although, ginger (<em>Zingiber officinale</em>) has a number of proven pharmacological activities, its effect on colon cancer has not received much attention.  This study therefore investigated the potential colon cancer drug of compounds found in ginger. Dihydropyrimidine dehydrogenase was modeled using comparative homology modeling and virtual screening was performed locally on a Linux platform using AutoDock Vina<sup>®</sup>. The results showed that human dihydropyrimidine dehydrogenase is a homolog of pig dihydropyrimidine dehydrogenase. The leads of potential colon cancer drugs were beta-sitosterol, 6-Shogoal, Alloaromadedrene, and Zingiberol. They had similar binding site with levamisole for tumor necrosis factor ligand superfamily member 6 with His 148 and Tyr 192 common at their binding site whereas they had  different binding sites from 5-fluorouracil for dihydropyrimidine dehydrogenase. The leads had better bioactivities compared with reference drugs (5-flourouracil and Levamisole) approved clinically for the treatment of colon cancer. <em>In vitro</em>, <em>ex vivo</em> and/or <em>in vivo</em> validations of the leads against colon cancer are recommended. <strong></strong></p>

scholarly journals Coherent Raman Scattering Microscopy in Oncology Pharmacokinetic Research

2021 ◽  
Vol 12 ◽  
Author(s):  
Junjie Zeng ◽  
Wenying Zhao ◽  
Shuhua Yue
Keyword(s):  
Raman Scattering ◽  
High Speed ◽  
Cancer Drug ◽  
Cancer Drugs ◽  
High Speed Imaging ◽  
Coherent Raman Scattering ◽  
Anti Cancer ◽  
Coherent Raman

The high attrition rates of anti-cancer drugs during clinical development remains a bottleneck problem in pharmaceutical industry. This is partially due to the lack of quantitative, selective, and rapid readouts of anti-cancer drug activity in situ with high resolution. Although fluorescence microscopy has been commonly used in oncology pharmacological research, fluorescent labels are often too large in size for small drug molecules, and thus may disturb the function or metabolism of these molecules. Such challenge can be overcome by coherent Raman scattering microscopy, which is capable of chemically selective, highly sensitive, high spatial resolution, and high-speed imaging, without the need of any labeling. Coherent Raman scattering microscopy has tremendously improved the understanding of pharmaceutical materials in the solid state, pharmacokinetics of anti-cancer drugs and nanocarriers in vitro and in vivo. This review focuses on the latest applications of coherent Raman scattering microscopy as a new emerging platform to facilitate oncology pharmacokinetic research.

scholarly journals Development of A Novel Highly Selective TLR8 Agonist for Cancer Immunotherapy

2020 ◽  
Author(s):  
Yuxun Wang ◽  
Heping Yang ◽  
Huanping Li ◽  
Shuda Zhao ◽  
Yikun Zeng ◽  
...  
Keyword(s):  
Immune Responses ◽  
Drug Targets ◽  
Ex Vivo ◽  
Single Agent ◽  
Cancer Drug ◽  
Phase I Clinical Trials ◽  
Tlr Agonists ◽  
Favorable Safety

ABSTRACTToll-like receptors (TLRs) are a family of proteins that recognize pathogen associated molecular patterns (PAMPs). Their primary function is to activate innate immune responses while also involved in facilitating adaptive immune responses. Different TLRs exert distinct functions by activating varied immune cascades. Several TLRs are being pursued as cancer drug targets. We discovered a novel, highly potent and selective small molecule TLR8 agonist DN052. DN052 exhibited strong in vitro cellular activity with EC50 at 6.7 nM and was highly selective for TLR8 over other TLRs including TLR4, 7 and 9. The selectivity profile distinguished DN052 from all other TLR agonists currently in clinical development. DN052 displayed excellent in vitro ADMET and in vivo PK profiles. DN052 potently inhibited tumor growth as a single agent. Moreover, combination of DN052 with the immune checkpoint inhibitor, selected targeted therapeutics or chemotherapeutic drugs further enhanced efficacy of single agents. Mechanistically, treatment with DN052 resulted in strong induction of pro-inflammatory cytokines in ex vivo human PBMC assay and in vivo monkey study. GLP toxicity studies in rats and monkeys demonstrated favorable safety profile. This led to the advancement of DN052 into phase I clinical trials.

scholarly journals Development of a novel TLR8 agonist for cancer immunotherapy

2020 ◽  
Vol 1 (1) ◽  
Author(s):  
Yuxun Wang ◽  
Heping Yang ◽  
Huanping Li ◽  
Shuda Zhao ◽  
Yikun Zeng ◽  
...  
Keyword(s):  
Immune Responses ◽  
Drug Targets ◽  
Ex Vivo ◽  
Phase 1 ◽  
Single Agent ◽  
Cancer Drug ◽  
Favorable Safety ◽  
Molecular Patterns

Abstract Toll-like receptors (TLRs) are a family of proteins that recognize pathogen associated molecular patterns (PAMPs). Their primary function is to activate innate immune responses while also involved in facilitating adaptive immune responses. Different TLRs exert distinct functions by activating varied immune cascades. Several TLRs are being pursued as cancer drug targets. We discovered a novel, highly potent and selective small molecule TLR8 agonist DN052. DN052 exhibited strong in vitro cellular activity with EC50 at 6.7 nM and was highly selective for TLR8 over other TLRs including TLR4, 7 and 9. DN052 displayed excellent in vitro ADMET and in vivo PK profiles. DN052 potently inhibited tumor growth as a single agent. Moreover, combination of DN052 with the immune checkpoint inhibitor, selected targeted therapeutics or chemotherapeutic drugs further enhanced efficacy of single agents. Mechanistically, treatment with DN052 resulted in strong induction of pro-inflammatory cytokines in ex vivo human PBMC assay and in vivo monkey study. GLP toxicity studies in rats and monkeys demonstrated favorable safety profile. This led to the advancement of DN052 into phase 1 clinical trials.

scholarly journals Patient-Derived Organoids as a Model for Cancer Drug Discovery

2021 ◽  
Vol 22 (7) ◽  
pp. 3483
Author(s):  
Colin Rae ◽  
Francesco Amato ◽  
Chiara Braconi
Keyword(s):  
Drug Testing ◽  
Ex Vivo ◽  
Three Dimensional ◽  
Tumour Microenvironment ◽  
In Vitro Models ◽  
Personalized Therapy ◽  
Cancer Drug ◽  
Patient Response

In the search for the ideal model of tumours, the use of three-dimensional in vitro models is advancing rapidly. These are intended to mimic the in vivo properties of the tumours which affect cancer development, progression and drug sensitivity, and take into account cell–cell interactions, adhesion and invasiveness. Importantly, it is hoped that successful recapitulation of the structure and function of the tissue will predict patient response, permitting the development of personalized therapy in a timely manner applicable to the clinic. Furthermore, the use of co-culture systems will allow the role of the tumour microenvironment and tissue–tissue interactions to be taken into account and should lead to more accurate predictions of tumour development and responses to drugs. In this review, the relative merits and limitations of patient-derived organoids will be discussed compared to other in vitro and ex vivo cancer models. We will focus on their use as models for drug testing and personalized therapy and how these may be improved. Developments in technology will also be considered, including the use of microfluidics, 3D bioprinting, cryopreservation and circulating tumour cell-derived organoids. These have the potential to enhance the consistency, accessibility and availability of these models.

MicroRNA targeting for the therapy of colitis-associated colon cancer.

2015 ◽  
Vol 33 (3_suppl) ◽  
pp. 571-571
Author(s):  
Christos Polytarchou ◽  
Daniel W. Hommes ◽  
Tiziana Palumbo ◽  
Maria Hatziapostolou ◽  
Georgios Koukos ◽  
...  
Keyword(s):  
Colon Cancer ◽  
Disease Activity ◽  
Inflammatory Responses ◽  
Therapeutic Potential ◽  
Ex Vivo ◽  
Clinicopathological Parameters ◽  
Specific Chemical ◽  
Colonic Biopsies

571 Background: Inflammatory Bowel Diseases (IBD) consist of ulcerative colitis (UC) and Crohn’s Disease (CD), which are characterized by activation of inflammatory responses. Patients with longstanding UC are at high risk of developing colorectal cancer. The identification of novel molecular targets with therapeutic potential for UC and UC-related dysplasia are of major importance. Methods: Using a high throughput functional suppressor screen of the human microRNAome, we identified microRNAs involved in the regulation nuclear factor kappa beta (NF-κB). We correlated microRNA expression levels with different clinicopathological parameters in 401 colonic specimens derived from patients with UC, CD, irritable bowel syndrome (IBS), sporadic colon cancer (CRC), colitis-associated cancer (CAC) and control subjects. Bioinformatic and molecular analyses were employed for the study of micoRNA-regulated signaling pathways. A microRNA specific chemical inhibitor was used to treat colonic biopsies ex vivo and murine CAC development in vivo. Results: The microRNA screen identified miR-214 as master regulator of NF-κB. MiR-214 levels are increased in colonic tissues from UC and CAC, but not from CD, IBS and CRC patients and positively correlate with UC disease activity and duration. STAT3 regulates miR-214 expression in colonocytes in vitro and STAT3 and miR-214 levels positively correlate in UC and CAC. MiR-214 regulates the expression of phosphatase and tensin homolog (PTEN) and PDZ and LIM domain 2 (PDLIM2) and both are decreased in colonic tissues of UC and CAC patients. MiR-214 is amplified through a feedback loop circuit and its overexpression increases the tumorigenic and invasive phenotype of colon cancer cells. A chemical miR-214 inhibitor perturbs this circuit in colonic biopsies from UC patients ex vivo while intracolonic delivery suppresses CAC growth in mice. Conclusions: Our findings demonstrate a gene controlling the inflammatory response specifically in UC and CAC. The miR-214 molecular circuit activity correlates with UC disease activity and duration. Activation of this circuit contributes to colitis-associated colon carcinogenesis, and its suppression has therapeutic potential for patients with UC-related dysplasia.

Bioinformatics Approaches for Anti-cancer Drug Discovery

2019 ◽  
Vol 21 (1) ◽  
pp. 3-17 ◽  
Author(s):  
Kening Li ◽  
Yuxin Du ◽  
Lu Li ◽  
Dong-Qing Wei
Keyword(s):  
Drug Discovery ◽  
Cancer Therapy ◽  
Biological Network ◽  
Computational Prediction ◽  
Cancer Drug ◽  
Cancer Drugs ◽  
Cancer Drug Discovery ◽  
Anti Cancer

Drug discovery is important in cancer therapy and precision medicines. Traditional approaches of drug discovery are mainly based on in vivo animal experiments and in vitro drug screening, but these methods are usually expensive and laborious. In the last decade, omics data explosion provides an opportunity for computational prediction of anti-cancer drugs, improving the efficiency of drug discovery. High-throughput transcriptome data were widely used in biomarkers’ identification and drug prediction by integrating with drug-response data. Moreover, biological network theory and methodology were also successfully applied to the anti-cancer drug discovery, such as studies based on protein-protein interaction network, drug-target network and disease-gene network. In this review, we summarized and discussed the bioinformatics approaches for predicting anti-cancer drugs and drug combinations based on the multi-omic data, including transcriptomics, toxicogenomics, functional genomics and biological network. We believe that the general overview of available databases and current computational methods will be helpful for the development of novel cancer therapy strategies.

Abstract 364: TRPV4 Channel Acts as a Negative Regulator of Angiogenesis by Modulation of Rho/Rho Kinase Pathway

2016 ◽  
Vol 36 (suppl_1) ◽  
Author(s):  
Holly C Cappelli ◽  
Roslin J Thoppil ◽  
Ravi K Adapala ◽  
Sailaja Paruchuri ◽  
Charles K Thodeti
Keyword(s):  
Tumor Growth ◽  
Kinase Inhibitor ◽  
Ex Vivo ◽  
Rho Kinase ◽  
Aortic Ring ◽  
Negative Regulator ◽  
Cancer Drug ◽  
Kinase Pathway

Angiogenesis, the formation new blood vessels from pre-existing ones, is critical for maintenance of normal cardiovascular physiology. However, excessive or insufficient angiogenesis can contribute to various diseases including cancer, atherosclerosis, and retinopathy. While the mechanism by which angiogenesis occurs is well established, little is known about the mechanisms that negatively regulate this process. Therefore, we investigated the role of mechanosensitive ion channel, TRPV4, in the regulation of angiogenesis by employing in vitro, ex vivo, and in vivo techniques. In the present study, we first cultured aortic ring explants isolated from wild-type (WT) and TRPV4KO mice and found a significant increase in the sprouting from TRPV4KO aortic rings after 5 days. Next, we found that endothelial cells (EC) isolated from TRPV4KO mice (TRPV4KO EC) exhibited increased proliferation, migration, as well as abnormal angiogenesis in vitro, compared to their WT counterparts. Further, in vivo Matrigel plug assays revealed abnormal vascular growth in TRPV4KO mice. Mechanistically, we found that absence of TRPV4 results in a significant increase in basal Rho activity and that pharmacological inhibition of the Rho/Rho kinase pathway was able to normalize the abnormal tube formation exhibited by TRPV4KO EC in vitro . To confirm these findings, we examined tumor growth in TRPV4KO mice treated with Rho kinase inhibitor, Y-27632, and anti-cancer drug Cisplatin, alone and in combination. We found that Y-27632 treatment, in conjunction with Cisplatin but not alone, was able to significantly reduce the abnormal tumor growth seen in TRPV4KO mice, suggesting that Rho kinase inhibition may have normalized the tumor vasculature and improved the delivery of Cisplatin. Taken together, these data suggest that TRPV4 is a negative regulator of angiogenesis and potentially a novel target for pathological and/or therapeutic angiogenesis.

scholarly journals Penapisan Virtual Senyawa–Senyawa dalam Famili Zingiberaeae sebagai Antiinflamasi Menggunakan Protokol EE_COX2_V.1.0

2017 ◽  
Vol 2 (2) ◽  
pp. 60-67
Author(s):  
Esti Mulatsari ◽  
Esti Mumpuni ◽  
Feriza Sandayu
Keyword(s):  
Virtual Screening ◽  
Binding Site ◽  
In Silico ◽  
Zingiber Officinale ◽  
Curcuma Xanthorrhiza ◽  
Cox 2

Berbagai penelitian tentang sifat-sifat anti-inflamasi dan anti-kanker dari berbagai senyawa dalam tanaman familia Zingiberaceae telah dilakukan baik secara in vivo maupun in vitro. Enzim yang diinduksi dan diekspresikan pada sel-sel inflamasi dan kanker dianggap sebagai target obat yang ideal untuk menghambat peradangan dan tumorgenesis, salah satunya adalah enzim siklooksigenase-2 (COX-2). Dalam penelitian ini telah dilakukan penapisan virtual senyawa dalam tanaman Kaemferia galanga, Curcuma domestica Val., Zingiber officinale dan Curcuma xanthorrhiza. Tujuan dari penelitian ini adalah untuk mengetahui aktivitas senyawa-senyawa tersebut sebagai penghambat enzim COX-2 secara in-silico. Penelitian ini menggunakan EE_COX2_V.1.0, protokol Structure Based Virtual Screening (SBVS) yang telah divalidasi oleh Mumpuni et al. 2014. Protokol EE_COX2_V.1.0 menggunakan berbagai aplikasi terintegrasi seperti SPORES, PLANTS, BkChem, OpenBabel dan PyMOL. Elusidasi moda ikatan dilakukan terhadap senyawa representatif aktif dan tidak aktif untuk melihat interaksi asam amino dalam binding site senyawa. Berdasarkan skor ChemPLP sebagai hasil dari simulasi docking yang dilakukan pada 27 senyawa, ada 3 senyawa yang berpotensi aktif dalam menghambat COX-2, senyawa tersebut antara lain 2-butil-3- (4-metoksifenil) -2- asam propenoat dengan 6 residu asam amino aktif, 6-shogaol dengan 10 residu asam amino aktif dan desmetoksikurkumin dengan 4 residu asam amino yang aktif.

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