Synthetic chenodeoxycholic acid derivatives inhibit glioblastoma multiform tumor growth in vitro and in vivo.

Abstract

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.

• Authors: Su-Bog Yee, Won Jae Yeo, Bong Soo Park, Ji Young Kim, Soo Jin Baek, Yoon Cheong Kim, Su Young Seo, Sang Hwa Lee, Jae Hong Kim, Hongsuk Suh, Nam Deuk Kim, Young Jin Lim, Young Hyun Yoo
• Journal: International journal of oncology (Int J Oncol) Vol. 27 Issue 3 Pg. 653-9 (Sep 2005) ISSN: 1019-6439 [Print] Greece
• PMID: 16077913 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• HS 1200
• HS-1199
• Chenodeoxycholic Acid
• Poly(ADP-ribose) Polymerases
• CASP3 protein, human
• Casp3 protein, mouse
• Caspase 3
• Caspases

Topics

• Animals
• Apoptosis (drug effects)
• Blotting, Western
• Brain Neoplasms (metabolism, pathology, prevention & control)
• Caspase 3
• Caspases (metabolism)
• Cell Line, Tumor
• Cell Nucleus (drug effects, metabolism)
• Cell Survival (drug effects)
• Chenodeoxycholic Acid (analogs & derivatives, pharmacology, therapeutic use)
• DNA Fragmentation (drug effects)
• Enzyme Activation (drug effects)
• Glioblastoma (metabolism, pathology, prevention & control)
• Humans
• Mice
• Mice, Inbred NOD
• Mice, SCID
• Poly(ADP-ribose) Polymerases (metabolism)
• Survival Analysis
• Time Factors
• Xenograft Model Antitumor Assays (methods)