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

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.

• Authors: Yoshinori Takahara, Shingo Yogosawa, Sakiko Maruyama, Noriko Watanabe, Hirofumi Yokoyama, Kazuteru Fukasawa, Yoshikazu Sukenaga, Jun Kamiyama, Moriatsu Izumi, Miki Wakada, Helin Zhang, Kaname Yoshizawa, Shigeyuki Kawa, Toshio Nikaido, Toshiyuki Sakai
• Journal: International journal of oncology (Int J Oncol) Vol. 28 Issue 4 Pg. 823-9 (Apr 2006) ISSN: 1019-6439 [Print] Greece
• PMID: 16525630 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

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

Topics

• Alopecia (chemically induced, prevention & control)
• Animals
• Animals, Newborn
• Antineoplastic Agents, Phytogenic (pharmacology, 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, metabolism)
• Cyclin-Dependent Kinase Inhibitor p21 (genetics, metabolism)
• Dose-Response Relationship, Drug
• Down-Regulation (drug effects)
• Etoposide (pharmacology, toxicity)
• Female
• Furans (administration & dosage, blood, metabolism, pharmacokinetics, pharmacology)
• G1 Phase (drug effects)
• Gene Expression (drug effects)
• Humans
• Male
• Osteosarcoma (genetics, metabolism, pathology)
• Proteasome Endopeptidase Complex (metabolism)
• RNA, Messenger (genetics, metabolism)
• Rats
• Rats, Sprague-Dawley
• Signal Transduction (drug effects)
• Up-Regulation (drug effects)