Gene of the month: Axl

2016 ◽  
Vol 69 (5) ◽  
pp. 391-397 ◽  
Author(s):  
Matthew Brown ◽  
James R M Black ◽  
Rohini Sharma ◽  
Justin Stebbing ◽  
David J Pinato
Keyword(s):  
Cancer Progression ◽  
Anticancer Agents ◽  
Second Messengers ◽  
Acquired Resistance ◽  
Metastatic Recurrence ◽  
Molecular Determinant ◽  
Migration Resistance ◽  
Axl Receptor Tyrosine Kinase ◽  
Intracellular Second Messengers ◽  
Main Ligand

The interaction between Axl receptor tyrosine kinase and its main ligand Gas6 has been implicated in the progression of a wide number of malignancies. More recently, overexpression of Axl has emerged as a key molecular determinant underlying the development of acquired resistance to targeted anticancer agents. The activation of Axl is overexpression-dependent and controls a number of hallmarks of cancer progression including proliferation, migration, resistance to apoptosis and survival through a complex network of intracellular second messengers. Axl has been noted to influence clinically meaningful end points including metastatic recurrence and survival in the vast majority of tumour types. With Axl inhibitors having gained momentum as novel anticancer therapies, we provide an overview of the biological and clinical relevance of this molecular pathway, outlining the main directions of research.

scholarly journals Regulation of Rho GTPases by RhoGDIs in Human Cancers

Cells ◽  
2019 ◽  
Vol 8 (9) ◽  
pp. 1037 ◽  
Author(s):  
Cho ◽  
Kim ◽  
Baek ◽  
Kim ◽  
Lee
Keyword(s):  
Cell Migration ◽  
Cancer Progression ◽  
Anticancer Agents ◽  
Rho Gtpases ◽  
Rho Gtpase ◽  
Regulatory Mechanisms ◽  
Malignant Phenotype ◽  
Cellular Processes ◽  
Human Cancers

Rho GDP dissociation inhibitors (RhoGDIs) play important roles in various cellular processes, including cell migration, adhesion, and proliferation, by regulating the functions of the Rho GTPase family. Dissociation of Rho GTPases from RhoGDIs is necessary for their spatiotemporal activation and is dynamically regulated by several mechanisms, such as phosphorylation, sumoylation, and protein interaction. The expression of RhoGDIs has changed in many human cancers and become associated with the malignant phenotype, including migration, invasion, metastasis, and resistance to anticancer agents. Here, we review how RhoGDIs control the function of Rho GTPases by regulating their spatiotemporal activity and describe the regulatory mechanisms of the dissociation of Rho GTPases from RhoGDIs. We also discuss the role of RhoGDIs in cancer progression and their potential uses for therapeutic intervention.

scholarly journals A Case of Recurrent Breast Cancer with Solitary Metastasis to the Urinary Bladder

2014 ◽  
Vol 2014 ◽  
pp. 1-3
Author(s):  
Carsten Nieder ◽  
Adam Pawinski
Keyword(s):  
Breast Cancer ◽  
Urinary Bladder ◽  
Cancer Progression ◽  
Metastatic Disease ◽  
Lobular Carcinoma ◽  
Palliative Radiotherapy ◽  
Life Time ◽  
Recurrent Breast Cancer ◽  
Endocrine Treatment ◽  
Metastatic Recurrence

Elderly patients with breast cancer often present with symptomatic, locoregionally advanced rather than screening-detected disease, thereby increasing the risk of metastatic recurrence during their remaining life time. Typical sites of metastases include lungs, bones, liver, and brain. Here we present a patient who developed a solitary urinary bladder metastasis five years after primary diagnosis of stage T4 N0 estrogen receptor-positive lobular carcinoma, while on continued adjuvant endocrine treatment (91 years of age). Anemia and increased serum creatinine resulting from hydronephrosis led to diagnosis of metastatic disease, which was confirmed by transurethral resection. The patient responded clinically to palliative radiotherapy and a different type of endocrine therapy. One year after diagnosis of metastatic disease, she died without signs of cancer progression.

Regulation of the Cerebral Circulation: Role of Endothelium and Potassium Channels

1998 ◽  
Vol 78 (1) ◽  
pp. 53-97 ◽  
Author(s):  
FRANK M. FARACI ◽  
DONALD D. HEISTAD
Keyword(s):  
Potassium Channels ◽  
Cerebral Circulation ◽  
Second Messengers ◽  
Chronic Hypertension ◽  
Major Mechanism ◽  
Disease States ◽  
Vasoactive Factors ◽  
New Concepts ◽  
Intracellular Second Messengers

Faraci, Frank M., and Donald D. Heistad. Regulation of the Cerebral Circulation: Role of Endothelium and Potassium Channels. Physiol. Rev. 78: 53–97, 1998. — Several new concepts have emerged in relation to mechanisms that contribute to regulation of the cerebral circulation. This review focuses on some physiological mechanisms of cerebral vasodilatation and alteration of these mechanisms by disease states. One mechanism involves release of vasoactive factors by the endothelium that affect underlying vascular muscle. These factors include endothelium-derived relaxing factor (nitric oxide), prostacyclin, and endothelium-derived hyperpolarizing factor(s). The normal vasodilator influence of endothelium is impaired by some disease states. Under pathophysiological conditions, endothelium may produce potent contracting factors such as endothelin. Another major mechanism of regulation of cerebral vascular tone relates to potassium channels. Activation of potassium channels appears to mediate relaxation of cerebral vessels to diverse stimuli including receptor-mediated agonists, intracellular second messengers, and hypoxia. Endothelial- and potassium channel-based mechanisms are related because several endothelium-derived factors produce relaxation by activation of potassium channels. The influence of potassium channels may be altered by disease states including chronic hypertension, subarachnoid hemorrhage, and diabetes.

PACAP38 Modulates Activity of NMDA Receptors in Cultured Chick Cortical Neurons

1997 ◽  
Vol 78 (4) ◽  
pp. 2231-2234 ◽  
Author(s):  
Guo Jun Liu ◽  
Barry W. Madsen
Keyword(s):  
Nmda Receptor ◽  
Nmda Receptors ◽  
Cortical Neurons ◽  
Second Messengers ◽  
Channel Activity ◽  
Patch Clamp Technique ◽  
Low Concentrations ◽  
Channel Opening ◽  
Pituitary Adenylate Cyclase ◽  
Intracellular Second Messengers

Liu, Guo Jun and Barry W. Madsen. PACAP38 modulates activity of NMDA receptors in cultured chick cortical neurons. J. Neurophysiol. 78: 2231–2234, 1997. The outside-out recording mode of the patch-clamp technique was used to study modulatory effects of pituitary adenylate cyclase-activating polypeptide (PACAP38) on N-methyl-d-aspartate (NMDA) receptor activity in cultured chick cortical neurons. Biphasic concentration-dependent effects of PACAP38 on channel opening frequency induced by NMDA (20 μM) and glycine (1 μM) were found, with low concentrations (0.5–2 nM) of PACAP38 increasing activity and higher concentrations (10–1,000 nM) causing inhibition. These effects were reversible, reduced with higher concentrations of glycine (2–10 μM) but not by 200 μM NMDA, and inhibited by 10 μM 7-chlorokynurenic acid. In addition, 1 μM PACAP6–38 (a PACAP antagonist) inhibited channel activity due to 20 μM NMDA and 1 μM glycine by 66%, and this inhibition was reduced to 13% in the additional presence of 2 nM PACAP38. These observations suggest thatPACAP38 has a direct modulatory effect on the NMDA receptor that is independent of intracellular second messengers and probably mediated through the glycine coagonist site(s).

scholarly journals Synthesis, Characterization and Docking Study of Novel Pyrimidine Derivatives as Anticancer Agents

2020 ◽  
Vol 20 (5) ◽  
pp. 1163
Author(s):  
Manal Mohamed Talaat El-Saidi ◽  
Ahmed Ali El-Sayed ◽  
Erik Bjerregaard Pedersen ◽  
Mohamed Abdelhamid Tantawy ◽  
Nadia Ragab Mohamed ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cancer Progression ◽  
Anticancer Agents ◽  
Hydrophobic Interactions ◽  
B Cell Lymphoma ◽  
Docking Study ◽  
Receptor Protein ◽  
Binding Modes ◽  
Dependent Protein ◽  
Base Ring

New compounds 5 and 9 using DNA bases e.g. Adenine 1 and Guanine 6 derivatives have been synthesized. The use of simple methods to synthesize compounds 5 and 9 were done using pyrimidine as an alternative DNA base ring. Another design to synthesize new simple pyrimidine rings utilizing thiourea and ethylcyano acetate to afford 6-amino-2-thiouracil was adopted. The reaction of thiouracil 10 with chloro cyano or chloro ester and ketone, resulted in the formation of adduct compounds 18-21, rather than the formation of compound 17. All the synthesized compounds were subjected to docking study, in order to gain insights into their binding modes against cyclin-dependent protein kinase 2 (CDK-2) that is involved heavily in cell cycle regulation and receptor protein B-cell lymphoma 2 (BCL-2) which is involved in cell apoptosis. These targets were selected based on their key roles in cancer progression via the regulation of the cell cycle and DNA replication. Molecular-docking analyses showed that compound 14e was the best docked ligand against both targets, as it displayed the lowest binding energy, critical hydrogen bonds and hydrophobic interactions with the targets.

Recent Progress on Apoptotic Activity of Triazoles

2021 ◽  
Vol 22 ◽  
Author(s):  
Pelin Çıkla-Süzgün ◽  
Ş. Güniz Küçükgüzel
Keyword(s):  
Cancer Progression ◽  
Anticancer Agents ◽  
Heterocyclic Compounds ◽  
Rational Design ◽  
Vital Role ◽  
Anticancer Activities ◽  
The Past ◽  
Small Molecule Drugs ◽  
Apoptotic Activity ◽  
New Generation

Abstract: Apoptosis, often called programmed cell death, is a self-directed cell destruction process. It differs from classical necrosis by activation of caspases. Apoptosis is directly related to cancer progression and plays a vital role in carcinogenesis. All cytotoxic drugs and radiation therapy programs initiates apoptosis in tumor cells. Today, studies show that heterocyclic compounds that contain triazole funtionality have anticancer activities. Triazoles are 5-membered rings, which contain two carbon and three nitrogen atoms Therefore, many researchers have synthesized these small active compounds as target structures and evaluated their apoptotic activities. The present review describs more recent medicinal aspects of triazoles as anticancer agents reported during the past few years. We hope that the bioactivity of triazole derivatives will be beneficial for the rational design of new generation of small molecule drugs.

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