Rutin increases alpha-tubulin acetylation via histone deacetylase 6 inhibition

Cetin O., SARI S., Erdem-Yurter H., BORA G.

DRUG DEVELOPMENT RESEARCH, cilt.83, sa.4, ss.993-1002, 2022 (SCI-Expanded) identifier identifier identifier

  • Yayın Türü: Makale / Tam Makale
  • Cilt numarası: 83 Sayı: 4
  • Basım Tarihi: 2022
  • Doi Numarası: 10.1002/ddr.21927
  • Dergi Adı: DRUG DEVELOPMENT RESEARCH
  • Derginin Tarandığı İndeksler: Science Citation Index Expanded (SCI-EXPANDED), Scopus, Academic Search Premier, Agricultural & Environmental Science Database, BIOSIS, Biotechnology Research Abstracts, CAB Abstracts, Chemical Abstracts Core, EMBASE, International Pharmaceutical Abstracts, MEDLINE, Veterinary Science Database
  • Sayfa Sayıları: ss.993-1002
  • Anahtar Kelimeler: drug repurposing, HDAC6, microtubule, neurodegenerative diseases, rutin, alpha-tubulin acetylation, PROTEIN, HDAC6, DOCKING, MODEL, DYNAMICS
  • Hacettepe Üniversitesi Adresli: Evet

Özet

Microtubules are dynamic cytoskeletal filaments composed of alpha-(alpha) and beta (beta)-tubulin proteins. alpha-tubulin proteins are posttranslationally acetylated, and loss of acetylation is associated with axonal transport defects, a common alteration contributing to the pathomechanisms of several neurodegenerative diseases. Restoring alpha-tubulin acetylation by pharmacological inhibition of HDAC6, a primary alpha-tubulin deacetylase, can rescue impaired transport. Therefore, HDAC6 is considered a promising therapeutic target for neurodegenerative diseases, but currently, there is no clinically approved inhibitor for this purpose. In this study, using drug repurposing strategy, we aimed to identify compounds possessing HDAC6 inhibition activity and inducing alpha-tubulin acetylation. We systematically analyzed the FDA-approved library by utilizing virtual screening and consensus scoring approaches. Inhibition activities of promising compounds were tested using in vitro assays. Motor neuronlike NSC34 cells were treated with the candidate compounds, and alpha-tubulin acetylation levels were determined by Western blot. Our results demonstrated that rutin, a natural flavonoid, inhibits cellular HDAC6 activity without inducing any toxicity, and it significantly increases alpha-tubulin acetylation level in motor neuron-like cells.