Synthetic chenodeoxycholic acid derivatives inhibit glioblastoma multiform tumor growth in vitro and in vivo.
We previously reported that the synthetic chenodeoxycholic acid (CDCA) derivatives showed apoptosis-inducing activity on various cancer cells in vitro. This study was undertaken to explore whether synthetic CDCA derivatives, HS-1199 and HS-1200, had an anticancer effect on malignant glioblastoma cells. We administered them in culture to U-118MG, U-87MG, T98G, and U-373MG cells. The tested glioblastoma cells showed several lines of apoptotic manifestations, such as activation of caspase-3, degradation of DFF, production of poly(ADP-ribose) polymerase cleavage, nuclear condensation, inhibition of proteasome activity, reduction of mitochondrial membrane potential and the release of cytochrome c to cytosol and translocation of AIF to nuclei. Between the two synthetic derivatives, HS-1200 showed a stronger apoptosis-inducing effect than HS-1199. In vivo efficacy of HS-1200 was tested in U87MG cells inoculated into non-obese diabetic and severe combined immunodeficient (NOD/SCID) mice. The HS-1200 treatment significantly inhibited the increase of tumor size in NOD/SCID mice and prolonged the life spans. This study supports the possibility of synthetic CDCA derivatives as a potential chemotherapeutic agent.
Yee
Su-Bog
SB
Medical Science Research Center and College of Medicine (BK21 program), Dong-A University, Busan 602-714, South Korea.
Yeo
Won Jae
WJ
Park
Bong Soo
BS
Kim
Ji Young
JY
Baek
Soo Jin
SJ
Kim
Yoon Cheong
YC
Seo
Su Young
SY
Lee
Sang Hwa
SH
Kim
Jae Hong
JH
Suh
Hongsuk
H
Kim
Nam Deuk
ND
Lim
Young Jin
YJ
Yoo
Young Hyun
YH
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D001932:Brain Neoplasms / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D002635:Chenodeoxycholic Acid / Q000031:analogs & derivatives / Q000494:pharmacology* / Q000627:therapeutic use; D053938:DNA Fragmentation / Q000187:drug effects; D004789:Enzyme Activation / Q000187:drug effects; D005909:Glioblastoma / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D006801:Humans; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D016019:Survival Analysis; D013997:Time Factors; D023041:Xenograft Model Antitumor Assays / Q000379:methods
C479128:HS 1200; C503536:HS-1199; D002635:Chenodeoxycholic Acid; D011065:Poly(ADP-ribose) Polymerases; C505407:CASP3 protein, human; C505409:Casp3 protein, mouse; D053148:Caspase 3; D020169:Caspases