Modulating Roles of Amiloride in Irradiation-Induced Antiproliferative Effects in Glioblastoma Multiforme Cells Involving Akt Phosphorylation and the Alternative Splicing of Apoptotic Genes

Tang, Jen‐Yang; Chang, Hsueh‐Wei; Chang, Jan‐Gowth

doi:10.1089/dna.2013.1998

Cited by 12 publications

(10 citation statements)

References 34 publications

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“…We found that their combination had more than additive effects on the suppression of esophageal cancer cell growth in vitro and in nude mouse xenografts. Indeed, previous studies have used combination of amiloride with other agents (such as radiation or morphine) to control glioblastoma or pain (Tang et al, 2013; Ouyang et al, 2012). Thus, future study is needed to further explore the activity of these combined agents in controlling esophageal cancer.…”

Section: Discussionmentioning

confidence: 99%

Amiloride and guggulsterone suppression of esophageal cancer cell growth in vitro and in nude mouse xenografts

Guan

Hoque

2014

Front. Biol.

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Esophageal adenocarcinoma is increasing in the US and Western countries and frequent gastresophageal reflux or gastresophageal reflux disease carrying gastric acid and bile acid could contribute to esophageal adenocarcinogenesis. This study was designed to detect the expression of gastric acid-inducing gene Na + /H + exchanger-1 (NHE-1) ex vivo and then to explore targeting of NHE-1 expression or activity to control esophageal cancer cell viability in vitro and in nude mouse xenografts. The data showed that NHE-1 was highly expressed in esophageal adenocarcinoma tissues (66 of 101 cases [65.3%], but not in normal esophageal squamous cell epithelium (1 of 26 cases [3.8%]). Knockdown of NHE-1 expression using NHE-1 shRNA or inhibition of NHE-1 activity using the NHE-1 inhibitor amiloride suppressed viability and induced apoptosis in esophageal cancer cells. Molecularly, amiloride inhibited expression of cyclooxygenase-2 and matrix metallopeptidase-9 but not NHE-1 mRNA in esophageal cancer cells. A combination of amiloride and guggulsterone (a natural bile acid receptor inhibitor) showed more than additive effects in suppressing esophageal cancer cell growth in vitro and in nude mouse xenografts. This study suggests that inhibition of NHE-1 expression or activity or combination of amiloride and guggulsterone could be useful in control of esophageal adenocarcinoma.

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Section: Discussionmentioning

confidence: 99%

Amiloride and guggulsterone suppression of esophageal cancer cell growth in vitro and in nude mouse xenografts

Guan

Hoque

2014

Front. Biol.

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“…Actually, caffeine and digoxin have been used in clinical application. Tang et al suggested that 0.2 mM amiloride modulated cell radiosensitivity and RNA splicing of the apoptotic peptidase activating factor 1 (APAF1) [80]. 1.0 μ m NB-506 mediated splicing inhibition by preventing complete phosphorylation of the SF2/ASF SR protein, affected apoptosis and tumour progression [81].…”

Section: Small Molecules As Drugs For Regulating Rna Splicing In Cancermentioning

confidence: 99%

Function, clinical application, and strategies of Pre-mRNA splicing in cancer

et al. 2018

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Pre-mRNA splicing is a fundamental process that plays a considerable role in generating protein diversity. Pre-mRNA splicing is also the key to the pathology of numerous diseases, especially cancers. In this review, we discuss how aberrant splicing isoforms precisely regulate three basic functional aspects in cancer: proliferation, metastasis and apoptosis. Importantly, clinical function of aberrant splicing isoforms is also discussed, in particular concerning drug resistance and radiosensitivity. Furthermore, this review discusses emerging strategies how to modulate pathologic aberrant splicing isoforms, which are attractive, novel therapeutic agents in cancer. Last we outline current and future directions of isoforms diagnostic methodologies reported so far in cancer. Thus, it is highlighting significance of aberrant splicing isoforms as markers for cancer and as targets for cancer therapy.

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“…Gene expression profiling data revealed that metformin’s impact on GBM cells mainly involves RNA binding and splicing pathways (Yang 2016); however, this may be an indirect effect through diverse cellular machinery. Another relevant compound is the anti-hypertensive agent amiloride, which can lead to apoptosis and radio-sensitivity through the modulation of APAF1 splicing (Tang et al 2013). Among the analogous of FR901464, Pladienolide B reduced tumor size in glioblastoma U251 xenografts (Mizui et al 2004).…”

Section: Cancer Therapy Via Splicing Modulationmentioning

confidence: 99%

RNA processing as an alternative route to attack glioblastoma

et al. 2017

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Genomic analyses have become an important tool to identify new avenues for therapy. This is especially true for cancer types with extremely poor outcomes, since our lack of effective therapies offers no tangible clinical starting point to build upon. The highly malignant brain tumor glioblastoma (GBM) exemplifies such a refractory cancer, with only 15 month average patient survival. Analyses of several hundred GBM samples compiled by the TCGA (The Cancer Genome Atlas) have produced an extensive transcriptomic map, identified prevalent chromosomal alterations, and defined important driver mutations. Unfortunately, clinical trials based on these results have not yet delivered an improvement on outcome. It is, therefore, necessary to characterize other regulatory routes known for playing a role in tumor relapse and response to treatment. Alternative splicing affects more than 90% of the human coding genes and it is an important source for transcript variation and gene regulation. Mutations and alterations in splicing factors are highly prevalent in multiple cancers, demonstrating the potential for splicing to act as a tumor driver. As a result, numerous genes are expressed as cancer-specific splicing isoforms that are functionally distinct from the canonical isoforms found in normal tissue. These include genes that regulate cancer-critical pathways such as apoptosis, DNA repair, cell proliferation, and migration. Splicing defects can even induce genomic instability, a common characteristic of cancer, and a driver of tumor evolution. Importantly, components of the splicing machinery are targetable; multiple drugs can inhibit splicing factors or promote changes in splicing which could be exploited to begin improving clinical outcomes. Here, we review the current literature and present a case for exploring RNA processing as therapeutic route for the treatment of GBM.

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Modulating Roles of Amiloride in Irradiation-Induced Antiproliferative Effects in Glioblastoma Multiforme Cells Involving Akt Phosphorylation and the Alternative Splicing of Apoptotic Genes

Cited by 12 publications

References 34 publications

Amiloride and guggulsterone suppression of esophageal cancer cell growth in vitro and in nude mouse xenografts

Amiloride and guggulsterone suppression of esophageal cancer cell growth in vitro and in nude mouse xenografts

Function, clinical application, and strategies of Pre-mRNA splicing in cancer

RNA processing as an alternative route to attack glioblastoma

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