Synthetic chenodeoxycholic acid derivative HS-1200-induced apoptosis of p815 mastocytoma cells is augmented by co-treatment with lactacystin.
The antitumor activity of a synthetic chenodeoxycholic acid derivative, HS-1200, on the p815 mastocytoma cell line was investigated. We present several lines of evidence indicating that HS-1200 at 35 microM induced apoptosis of p815 cells. Reduction of mitochondrial membrane potential, the release of cytochrome to cytosol, activation of caspase-3, nuclear condensation, production of poly(ADP-ribose) polymerase cleavage, generation of DNA fragmentation and nuclear condensation were demonstrated. Importantly, HS-1200 inhibited proteasome activity. Next, the combination treatment of HS-1200 or a proteasome inhibitor lactacystin was undertaken. Although the single treatment of 20 microM HS-1200 or 1 microM lactacystin induced apoptosis slightly, the combination treatment of them augmented prominently the extent of apoptosis. The combination therapy of HS-1200 and lactacystin could be potentially a therapeutic strategy reducing the extent and severity of treatment-related toxicity.
Seo
Su Yeong
SY
Department of Microbiology and Immunology, Dong-A University College of Medicine and Institute of Medical Science, Seo Gu, Busan, South Korea.
Jun
Eun Joo
EJ
Jung
Sung Moon
SM
Kim
Ki-Ho
KH
Lim
Young Jin
YJ
Park
Bong Soo
BS
Kim
Jae-Kon
JK
Lee
Sungeun
S
Suh
Hongsuk
H
Kim
Nam Deuk
ND
Yoo
Young Hyun
YH
D000111:Acetylcysteine / Q000031:analogs & derivatives* / Q000494:pharmacology*; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D045744:Cell Line, Tumor; D002635:Chenodeoxycholic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology*; D003546:Cysteine Endopeptidases / Q000378:metabolism; D053938:DNA Fragmentation; D004357:Drug Synergism; D034801:Mastocytoma; D008564:Membrane Potentials / Q000187:drug effects; D051379:Mice; D008928:Mitochondria / Q000187:drug effects / Q000502:physiology; D009097:Multienzyme Complexes / Q000378:metabolism; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex
D000970:Antineoplastic Agents; C479128:HS 1200; D009097:Multienzyme Complexes; D002635:Chenodeoxycholic Acid; C067713:lactacystin; D011065:Poly(ADP-ribose) Polymerases; C505409:Casp3 protein, mouse; D053148:Caspase 3; D020169:Caspases; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex; D000111:Acetylcysteine