Lysocellin, a metabolite of the novel drug 'alopestatin', induces G1 arrest and prevents cytotoxicity induced by etoposide.
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.
Takahara
Yoshinori
Y
Department of Molecular-Targeting Cancer Prevention, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kawaramachi-Hirokoji, Kyoto 602-8566, Japan.
Yogosawa
Shingo
S
Maruyama
Sakiko
S
Watanabe
Noriko
N
Yokoyama
Hirofumi
H
Fukasawa
Kazuteru
K
Sukenaga
Yoshikazu
Y
Kamiyama
Jun
J
Izumi
Moriatsu
M
Wakada
Miki
M
Zhang
Helin
H
Yoshizawa
Kaname
K
Kawa
Shigeyuki
S
Nikaido
Toshio
T
Sakai
Toshiyuki
T
D000505:Alopecia / Q000139:chemically induced / Q000517:prevention & control; D000818:Animals; D000831:Animals, Newborn; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology / Q000633:toxicity; D019540:Area Under Curve; D015152:Blotting, Northern; D015153:Blotting, Western; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects; D019938:Cyclin D1 / Q000235:genetics / Q000378:metabolism; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation / Q000187:drug effects; D005047:Etoposide / Q000494:pharmacology* / Q000633:toxicity; D005260:Female; D005663:Furans / Q000008:administration & dosage / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology; D016193:G1 Phase / Q000187:drug effects*; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D008297:Male; D012516:Osteosarcoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects; D015854:Up-Regulation / Q000187:drug effects
D000972:Antineoplastic Agents, Phytogenic; C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D005663:Furans; D012333:RNA, Messenger; C510660:alopestatin; D019938:Cyclin D1; C009818:lysocellin; D005047:Etoposide; D046988:Proteasome Endopeptidase Complex