Lysocellin, a metabolite of the novel drug 'alopestatin', induces G1 arrest and prevents cytotoxicity induced by etoposide

Int J Oncol. 2006 Apr;28(4):823-9.

Abstract

We report here that lysocellin, a polyether antibiotic from a streptomycete, induces G1 phase arrest in human osteosarcoma MG63 cells. Lysocellin up-regulates p21WAF1/Cip1 and down-regulates cyclin D1 at the mRNA level. In addition, cyclin D1 is down-regulated by the proteasome-dependent signal pathway in MG63 cells. In drug combination studies, we found that lysocellin treatment weakened the cytotoxic activity of etoposide in MG63 cells using a colony-formation assay. To study the in vivo efficacy of lysocellin, we isolated a novel compound related to lysocellin from the same streptomycete, and found that the novel drug is converted to lysocellin in vivo and decreases etoposide-induced alopecia in a neonatal rat model. We raise the possibility that this novel drug, named 'alopestatin', may be a promising agent against alopecia.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alopecia / chemically induced
  • Alopecia / prevention & control
  • Animals
  • Animals, Newborn
  • Antineoplastic Agents, Phytogenic / pharmacology
  • Antineoplastic Agents, Phytogenic / toxicity
  • Area Under Curve
  • Blotting, Northern
  • Blotting, Western
  • Cell Cycle / drug effects
  • Cell Line, Tumor
  • Cell Proliferation / drug effects*
  • Cell Survival / drug effects
  • Cyclin D1 / genetics
  • Cyclin D1 / metabolism
  • Cyclin-Dependent Kinase Inhibitor p21 / genetics
  • Cyclin-Dependent Kinase Inhibitor p21 / metabolism
  • Dose-Response Relationship, Drug
  • Down-Regulation / drug effects
  • Etoposide / pharmacology*
  • Etoposide / toxicity
  • Female
  • Furans / administration & dosage
  • Furans / blood
  • Furans / metabolism
  • Furans / pharmacokinetics
  • Furans / pharmacology
  • G1 Phase / drug effects*
  • Gene Expression / drug effects
  • Humans
  • Male
  • Osteosarcoma / genetics
  • Osteosarcoma / metabolism
  • Osteosarcoma / pathology
  • Proteasome Endopeptidase Complex / metabolism
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Rats
  • Rats, Sprague-Dawley
  • Signal Transduction / drug effects
  • Up-Regulation / drug effects

Substances

  • Antineoplastic Agents, Phytogenic
  • CDKN1A protein, human
  • Cyclin-Dependent Kinase Inhibitor p21
  • Furans
  • RNA, Messenger
  • alopestatin
  • Cyclin D1
  • lysocellin
  • Etoposide
  • Proteasome Endopeptidase Complex