Abstract:
:Understanding the mechanistic basis for temozolomide (TMZ)-induced glioma resistance is an important obstacle in developing an effective form of chemotherapy for this type of tumor. Glycogenolysis is known to play an essential role in cellular proliferation and potassium homeostasis and involves the glycogen phosphorylase isoenzyme BB (GPBB). In this investigation, plasma GPBB was correlated with TMZ-resistance. Elevated plasma GPBB concentrations were found to be more frequent in a TMZ-resistant cohort of patients with poor survival rates. TMZ inhibits cell proliferation and induces TMZ resistance by upregulating the expression of O(6)-methylguanine-DNA methyltransferase (MGMT). This process requires glycogenolysis, which was confirmed herein by treatment with 1,4-dideoxy-1,4-imino-D-arabinitol hydrochloride, a glycogenolysis inhibitor and a special GPBB inhibitor. Acute TMZ treatment leads to upregulation of [Ca2+]i, extracellular-regulated kinase (ERK)1/2 phosphorylation, and chronic TMZ treatment leads to upregulation of the expression of Na,K-ATPase, ERK1/2, and MGMT protein. Upregulation was abolished for each of these by inhibitors of transient receptor potential channel 1 and the inositol trisphosphate receptor. L-channel [Ca2+]i inhibitors and RyR antagonists had no such effect. These results demonstrate that [Ca2+]i-dependent glycogenolysis participates in acquired glioma TMZ-resistance by upregulating MGMT via a Na,K-ATPase/ERK1/2 signaling pathway. GPBB and glycogenolysis may therefore represent novel therapeutic targets for overcoming TMZ-resistant gliomas.
journal_name
Front Pharmacoljournal_title
Frontiers in pharmacologyauthors
Xu J,Zhang Y,Guo X,Sun Tdoi
10.3389/fphar.2018.00873subject
Has Abstractpub_date
2018-08-07 00:00:00pages
873issn
1663-9812journal_volume
9pub_type
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abstract::Using pharmacogenetics in guiding drug therapy experiences a steady increase in uptake, although still leads to discussions as to its clinical use. Psychiatry constitutes a field where pharmacogenomic testing might help in guiding drug therapy. To address current challenges, this minireview provides an update regardin...
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pub_type: 杂志文章,评审
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journal_title:Frontiers in pharmacology
pub_type: 杂志文章
doi:10.3389/fphar.2013.00098
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abstract::Introduction: Chronic hepatitis B (HBV) and C (HCV) virus infection is associated with the activation of hepatic stellate cells (HSCs) toward a myofibroblastic phenotype, resulting in excessive deposition of extracellular matrix, the development of liver fibrosis, and its progression toward cirrhosis. The gold standar...
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doi:10.3389/fphar.2019.01515
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journal_title:Frontiers in pharmacology
pub_type: 杂志文章
doi:10.3389/fphar.2020.00097
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abstract:UNLABELLED:Gender-related differences in the pharmacological effects of drug are an emerging topic. This review examines gender differences in both pharmacokinetic and pharmacodynamic aspects of methadone, a long-acting opioid agonist that is prescribed as a treatment for opioid dependence and the management of chronic...
journal_title:Frontiers in pharmacology
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doi:10.3389/fphar.2015.00122
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abstract::[This corrects the article DOI: 10.3389/fphar.2018.00361.]. ...
journal_title:Frontiers in pharmacology
pub_type: 杂志文章,已发布勘误
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pub_type: 杂志文章,评审
doi:10.3389/fphar.2020.614048
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pub_type: 杂志文章
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abstract:Background:The CYP2D6 gene locus has been extensively studied over decades, yet a portion of variability in CYP2D6 activity cannot be explained by known sequence variations within the gene, copy number variation, or structural rearrangements. It was proposed that rs5758550, located 116 kb downstream of the CYP2D6 gene ...
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