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Cancers (Basel) July 8, 2020; 12 (7):

Mambalgin-2 Induces Cell Cycle Arrest and Apoptosis in Glioma Cells via Interaction with ASIC1a.

Bychkov M , Shulepko M , Osmakov D , Andreev Y , Sudarikova A , Vasileva V , Pavlyukov MS , Latyshev YA , Potapov AA , Kirpichnikov M , Shenkarev ZO , Lyukmanova E .

Gliomas are fast growing and highly invasive brain tumors, characterized by tumor microenvironment acidification that drives glioma cell growth and migration. Channels containing Acid-sensing Ion Channel 1a subunit (ASIC1a) mediate amiloride-sensitive cation influx in late stage glioma cells, but not in normal astrocytes. Thus, selective targeting of ASIC1a can be a perspective strategy for glioma treatment. Here, ASIC1a expression in U251 MG and A172 glioma cells, but not in normal astrocytes, was demonstrated. Recombinant analog of mambalgin-2 from black mamba Dendroaspis polylepis inhibited amiloride-sensitive currents at ASIC1a both in Xenopus laevis oocytes and in U251 MG cells, while its mutants with impaired activity towards this channel did not. Mambalgin-2 inhibited U251 MG and A172 glioma cells growth with EC50 in the nanomolar range without affecting the proliferation of normal astrocytes. Notably, mambalgin-2 mutants did not affect glioma cell proliferation, pointing on ASIC1a as the main molecular target of mambalgin-2 in U251 MG and A172 cells. Mambalgin-2 induced a cell cycle arrest, inhibited Cyclin D1 and cyclin-dependent kinases (CDK) phosphorylation and caused apoptosis in U251 MG and A172 cells. Moreover, mambalgin-2 inhibited the growth of low-passage primary cells from a patient with glioblastoma. Altogether, our data point to mambalgin-2 as a useful hit for the development of new drugs for glioma treatment.

PubMed ID: 32650495
PMC ID: PMC7408772
Article link: Cancers (Basel)
Grant support: [+]

Species referenced: Xenopus
Genes referenced: actb asic1 asic2 asic3 asic4 ccnd1 cdk4 cdk6 rpl13a

Disease Ontology terms: brain glioma

Article Images: [+] show captions
References [+] :
Arvanitis, The blood-brain barrier and blood-tumour barrier in brain tumours and metastases. 2020, Pubmed