Possible pharmacotherapy for nifedipine‐induced gingival overgrowth: 18α‐glycyrrhetinic acid inhibits human gingival fibroblast growth

Background and Purpose This investigation aimed to establish the basis of a pharmacotherapy for nifedipine‐induced gingival overgrowth. Gingival overgrowth has been attributed to the enhanced growth of gingival fibroblasts. In this study, we investigated the effects of 18‐α‐glycyrrhetinic acid (18α‐...

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Published in:British journal of pharmacology 2016-03, Vol.173 (5), p.913-924
Main Authors: Takeuchi, R, Hiratsuka, K, Arikawa, K, Ono, M, Komiya, M, Akimoto, Y, Fujii, A, Matsumoto, H
Format: Article
Language:English
Subjects:
Aged
Apoptosis - drug effects
Calcium Channel Blockers - adverse effects
Cell Count
Cell Cycle - drug effects
Cell Proliferation - drug effects
Cells, Cultured
DNA - metabolism
Female
Fibroblasts - cytology
Fibroblasts - drug effects
Fibroblasts - metabolism
Gingiva - cytology
Gingival Overgrowth - chemically induced
Gingival Overgrowth - drug therapy
Glycyrrhetinic Acid - analogs & derivatives
Glycyrrhetinic Acid - pharmacology
Humans
Male
Middle Aged
Nifedipine - adverse effects
Research Paper
Research Papers
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Summary:Background and Purpose This investigation aimed to establish the basis of a pharmacotherapy for nifedipine‐induced gingival overgrowth. Gingival overgrowth has been attributed to the enhanced growth of gingival fibroblasts. In this study, we investigated the effects of 18‐α‐glycyrrhetinic acid (18α‐GA) on growth, the cell cycle, and apoptosis and on the regulators of these processes in gingival fibroblasts isolated from patients who presented with nifedipine‐induced gingival overgrowth. Experimental Approach Gingival fibroblasts were cultured in medium containing 1% FBS with/without 10 μM 18α‐GA for 24 or 48 h, and the cell number, cell cycle phase distribution, relative DNA content, apoptotic cell number and morphological characteristics of the cells undergoing apoptosis were measured together with the levels of proteins that regulate these processes and the level of caspase activity. Key Results 18α‐GA significantly decreased cell numbers and significantly increased the percentage of cells in the sub‐G1 and G0/G1 phases of the cell cycle and the number of apoptotic cells. Nuclear condensation and fragmentation of cells into small apoptotic bodies appeared in the fibroblasts treated with 18α‐GA. In addition, 18α‐GA significantly decreased the protein levels of cyclins A and D1, CDKs 2 and 6, phosphorylated Rb (ser780 and ser807/811), Bcl‐xL and Bcl‐2 and increased the protein levels of p27, cytosolic cytochrome c, pro‐caspase‐3, and cleaved caspase‐3 and the activities of caspases 3 and 9. Conclusions and Implications 18α‐GA inhibited gingival fibroblast growth by suppressing the G1/S phase transition and inducing apoptosis. In conclusion, 18α‐GA may be used as a pharmacotherapy for nifedipine‐induced gingival overgrowth.
ISSN:0007-1188
1476-5381
DOI:10.1111/bph.13410