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Allosteric and Orthosteric Activators of mG luR8 Differentially Affect the Chemotherapeutic‐Induced Human Neuroblastoma SH ‐ SY 5Y Cell Damage: The Impact of Cell Differentiation State
Author(s) -
Jantas Danuta,
Grygier Beata,
Zatorska Justyna,
Lasoń Władysław
Publication year - 2018
Publication title -
basic and clinical pharmacology and toxicology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.805
H-Index - 90
eISSN - 1742-7843
pISSN - 1742-7835
DOI - 10.1111/bcpt.13041
Subject(s) - sh sy5y , neuroblastoma , cisplatin , irinotecan , pharmacology , cancer research , doxorubicin , allosteric modulator , chemistry , cancer cell , allosteric regulation , microbiology and biotechnology , cancer , biology , cell culture , receptor , medicine , biochemistry , chemotherapy , colorectal cancer , genetics
The participation of group III metabotropic glutamate receptors ( mG luRs) in cancer growth and progression is still an understudied issue. Based on our recent data on high expression of mG luR8 in human neuroblastoma SH ‐ SY 5Y cells, in this study, we evaluated the effect of an mG luR8‐specific positive allosteric modulator ( PAM : AZ 12216052) and orthosteric agonist [(S)‐3,4‐ DCPG ((S)‐3,4‐dicarboxyphenylglycine)] on chemotherapeutic (doxorubicin, irinotecan or cisplatin)‐evoked cell damage in undifferentiated ( UN ‐) and retinoic acid‐differentiated ( RA ‐) SH ‐ SY 5Y cells. The data showed that AZ 12216052 as well as a group III mG luR antagonist ( UBP 1112) but not (S)‐3,4‐ DCPG partially inhibited the cell damage evoked by doxorubicin, irinotecan or cisplatin in UN ‐ SH ‐ SY 5Y cells. In RA ‐ SH ‐ SY 5Y, we observed only a modest protective effect of mG luR8 PAM . In contrast, both types of mG luR8 activators significantly enhanced toxic effects of doxorubicin and irinotecan in RA ‐ SH ‐ SY 5Y cells. These data suggest that in undifferentiated neuroblastoma malignant cells, some mG luR8 modulators can decrease cytotoxic effects of chemotherapeutics which exclude them from the group of putative anticancer agents. On the other hand, in SH ‐ SY 5Y cells differentiated to a more mature neuron‐like phenotype, that is non‐malignant cells, the mG luR8 activators can aggravate the chemotherapeutic neurotoxicity which is a well‐known undesired effect of these drugs. Our pharmacological data add new observations to the unexplored field of research on the role of mG luR8 in cancer, pointing to complexity of response which could be mediated by particular types of mG luR8 ligands at least in neuroblastoma cells.