====== Temozolomide resistance ======

{{rss>https://pubmed.ncbi.nlm.nih.gov/rss/search/16uwQpOeqFYO8R4rLAk9AjJuhluycOZ2QFpa-rdy6y4QvrBcSe/?limit=15&utm_campaign=pubmed-2&fc=20241128041821}}

see [[Temozolomide resistance in glioblastoma]].
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Understanding the mechanistic basis for glioma [[temozolomide resistance]] is an important obstacle in developing an effective form of [[chemotherapy]].
[[Glycogenolysis]] is known to play an essential role in [[cell proliferation]] and potassium [[homeostasis]] and involves the glycogen phosphorylase isoenzyme BB ([[GPBB]]). 
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
((Xu J, Zhang Y, Guo X, Sun T. Glycogenolysis in Acquired Glioma Resistance to Temozolomide: A Role for the [Ca2+]i-dependent Activation of Na,K-ATPase/ERK1/2 Signaling. Front Pharmacol. 2018 Aug 7;9:873. doi: 10.3389/fphar.2018.00873. PMID: 30131700; PMCID: PMC6090282.))