Inhibitory effect of M50054, a novel inhibitor of apoptosis, on anti-Fas-antibody-induced hepatitis and chemotherapy-induced alopecia.
M50054, 2,2'-methylenebis (1,3-cyclohexanedione), was identified as a novel inhibitor of apoptosis (programmed cell death) using an in vitro cell death assay system induced in human Fas-expressing WC8 cells by soluble human Fas ligand. Furthermore, M50054 inhibited the apoptotic cell death of U937, a human monocytic leukemic cell line, induced by anticancer agents such as etoposide; it was also confirmed that M50054 inhibited apoptotic features such as DNA fragmentation and phosphatidylserine exposure in these cells. These anti-apoptotic effects were attributable to inhibition of caspase-3 activation. Additionally, M50054 significantly inhibited anti-Fas-antibody-induced elevation of plasma alanine aminotransferase and aspartate aminotransferase. Alopecia (hair loss) symptoms were also significantly improved with topical treatment with M50054. In conclusion, M50054 inhibits apoptosis induced by a variety of stimuli via inhibition of caspase-3 activation, and may thus be effective for hepatitis and chemotherapy-induced alopecia.
Tsuda
T
T
Research Center, Mochida Pharmaceutical Co., Ltd., 722 Jimba-aza-Uenohara, Gotemba, Shizuoka 412-8524, Japan. toshi-t@mochida.co.jp
Ohmori
Y
Y
Muramatsu
H
H
Hosaka
Y
Y
Takiguchi
K
K
Saitoh
F
F
Kato
K
K
Nakayama
K
K
Nakamura
N
N
Nagata
S
S
Mochizuki
H
H
D000505:Alopecia / Q000139:chemically induced / Q000188:drug therapy*; D000818:Animals; D000970:Antineoplastic Agents / Q000633:toxicity*; D017209:Apoptosis / Q000187:drug effects*; D019556:COS Cells; D053148:Caspase 3; D061945:Caspase Inhibitors; D003512:Cyclohexanones / Q000494:pharmacology*; D004789:Enzyme Activation / Q000187:drug effects; D005047:Etoposide / Q000633:toxicity; D053222:Fas Ligand Protein; D005260:Female; D006505:Hepatitis / Q000188:drug therapy*; D006801:Humans; D008562:Membrane Glycoproteins / Q000494:pharmacology; D051379:Mice; D008807:Mice, Inbred BALB C; D020298:U937 Cells; D019014:fas Receptor / Q000502:physiology*
C456599:2,2'-methylenebis(1,3-cyclohexanedione); D000970:Antineoplastic Agents; D061945:Caspase Inhibitors; D003512:Cyclohexanones; C505661:FASLG protein, human; D053222:Fas Ligand Protein; C505658:Fasl protein, mouse; D008562:Membrane Glycoproteins; D019014:fas Receptor; D005047:Etoposide; C505407:CASP3 protein, human; C505409:Casp3 protein, mouse; D053148:Caspase 3