Modulation of cyclic adenosine monophosphate (cAMP) signalling and its therapeutic potential: pharmacological characterisation of PDE inhibitors
type: CreativeWork
description: The alteration of intracellular cyclic adenosine monophosphate (cAMP) levels plays important regulatory roles in both physiological and pathological conditions, such as cancer. As the most aggressive form of brain tumour, glioblastoma is currently incurable due to limited treatment modalities. Low level of intracellular cAMP levels has been reported to be a feature of brain tumours. Thus, it is hypothesised that increasing cAMP concentrations by targeting regulatory proteins involved in the cAMP signalling pathways may offer advantages in preventing or treating glioblastoma. The overarching goal of this study, therefore, is to determine the dynamic effects of cAMP modulation on glioblastoma cell proliferation. The efficacies of compounds targeting various proteins involved in cAMP pathways were first investigated. The mechanisms explored were elevation of cAMP level through phosphodiesterases (PDEs) inhibition, adenylyl cyclase (AC) activation, as well as modulation via β-adrenoceptor (β-AR) and G proteins. A series of compounds were evaluated applying various assaying techniques and pharmacological tools using cAMP accumulation assays, cell proliferation, caspase-3/7 activation, and flow cytometry to determine cell cycle. It was demonstrated that increasing cAMP levels by multiple PDE inhibition or AC stimulation resulted in cell growth suppression on both rat and human glioblastoma models. The study was also extended to identify the role of possible crosstalk between calcium through SOCE (store-operated calcium entry) and cAMP pathways, which both were found to contribute to cell growth modulation. The effect of the elevation of intracellular cAMP on cell proliferation was further explored through the direct activation of adenosine A2A receptor (A2AR) and inhibition of cAMP degradation via PDE10A. Previous computational studies revealed that the triazoloquinazoline-based compounds (compound 1-6), initially known as PDE10A inhibitors, are bound at the orthosteric s…
abstract: The alteration of intracellular cyclic adenosine monophosphate (cAMP) levels plays important regulatory roles in both physiological and pathological conditions, such as cancer. As the most aggressive form of brain tumour, glioblastoma is currently incurable due to limited treatment modalities. Low level of intracellular cAMP levels has been reported to be a feature of brain tumours. Thus, it is hypothesised that increasing cAMP concentrations by targeting regulatory proteins involved in the cAMP signalling pathways may offer advantages in preventing or treating glioblastoma. The overarching goal of this study, therefore, is to determine the dynamic effects of cAMP modulation on glioblastoma cell proliferation. The efficacies of compounds targeting various proteins involved in cAMP pathways were first investigated. The mechanisms explored were elevation of cAMP level through phosphodiesterases (PDEs) inhibition, adenylyl cyclase (AC) activation, as well as modulation via β-adrenoceptor (β-AR) and G proteins. A series of compounds were evaluated applying various assaying techniques and pharmacological tools using cAMP accumulation assays, cell proliferation, caspase-3/7 activation, and flow cytometry to determine cell cycle. It was demonstrated that increasing cAMP levels by multiple PDE inhibition or AC stimulation resulted in cell growth suppression on both rat and human glioblastoma models. The study was also extended to identify the role of possible crosstalk between calcium through SOCE (store-operated calcium entry) and cAMP pathways, which both were found to contribute to cell growth modulation. The effect of the elevation of intracellular cAMP on cell proliferation was further explored through the direct activation of adenosine A2A receptor (A2AR) and inhibition of cAMP degradation via PDE10A. Previous computational studies revealed that the triazoloquinazoline-based compounds (compound 1-6), initially known as PDE10A inhibitors, are bound at the orthosteric s…
author: Safitri, Dewi
language: eng
keywords: cAMP, phosphodiesterase, glioblastoma, GPCR, proliferation
license: https://apollo8-f-pro.lib.cam.ac.uk/bitstreams/9a6f3445-f704-4d74-a224-7ebfe7e1d5ab/download
license: https://www.rioxx.net/licenses/all-rights-reserved/
date published: 2021-04-29
date modified: 2026-07-22T22:24:31Z
provider: Cambridge University
publisher: Networked Digital Library of Theses and Dissertations
type: WebPage
source organization: University of Cambridge

PropertyValue
property ID: DOI
value: 10.17863/CAM.76914