BH3 mimetics inhibit growth of chondrosarcoma--a novel targeted-therapy for candidate models.

Abstract

BACKGROUND:

Chondrosarcoma is refractory to conventional chemotherapy. BH-3 mimetics ABT-737 and ABT-263 are synthetic small-molecule inhibitors of anti-apoptotic proteins B-cell lymphoma-2 (Bcl2) and Bcl-xL, which play a critical role in survival of chondrosarcoma cells.

MATERIALS AND METHODS:

Chondrosarcoma cell lines SW-1353 and CS-1 were used as the disease model. We used immunoblotting to assess the expression of target molecules Bcl2 and Bcl-xL, and the apoptotic inducers Bcl2-associated X (Bax) and Bcl2-antagonist/killer (Bak). In vitro growth inhibition by BH-3 mimetics was confirmed by photomicroscopic cell counting and 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium, inner salt (MTS) assay. Apoptotic induction was confirmed by Enzyme-Linked ImmunoSorbent Assay (ELISA). In vivo growth inhibition was assessed in a non-obese diabetic/severe combined immunodeficient (NOD/SCID) mouse model.

RESULTS:

Expression of the target and effector molecules was confirmed in chondrosarcoma cell lines. BH3 mimetics significantly inhibited cell growth and induced apoptosis in vitro. Administration of ABT-263 inhibited chondrosarcoma growth and improved survival in a mouse model.

CONCLUSION:

BH3 mimetics represent a novel treatment modality for chondrosarcoma.

• Authors: Takeshi Morii, Kouki Ohtsuka, Hiroaki Ohnishi, Kazuo Mochizuki, Akira Yoshiyama, Takayuki Aoyagi, Francis J Hornicek, Shoichi Ichimura
• Journal: Anticancer research (Anticancer Res) Vol. 34 Issue 11 Pg. 6423-30 (Nov 2014) ISSN: 1791-7530 [Electronic] Greece
• PMID: 25368242 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright© 2014 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.

Chemical References

• ABT-737
• Aniline Compounds
• Antineoplastic Agents
• Bax protein (53-86)
• Biphenyl Compounds
• Nitrophenols
• Peptide Fragments
• Piperazines
• Proto-Oncogene Proteins
• Proto-Oncogene Proteins c-bcl-2
• Sulfonamides
• bcl-2 Homologous Antagonist-Killer Protein
• bcl-2-Associated X Protein
• navitoclax

Topics

• Aniline Compounds (pharmacology)
• Animals
• Antineoplastic Agents (pharmacology)
• Apoptosis (drug effects)
• Biphenyl Compounds (pharmacology)
• Blotting, Western
• Bone Neoplasms (drug therapy, metabolism, secondary)
• Cell Proliferation (drug effects)
• Chondrosarcoma (drug therapy, metabolism, pathology)
• Disease Models, Animal
• Humans
• Male
• Mice
• Mice, Inbred NOD
• Mice, SCID
• Middle Aged
• Molecular Mimicry
• Molecular Targeted Therapy
• Nitrophenols (pharmacology)
• Peptide Fragments (pharmacology)
• Piperazines (pharmacology)
• Proto-Oncogene Proteins (pharmacology)
• Proto-Oncogene Proteins c-bcl-2 (antagonists & inhibitors)
• Sulfonamides (pharmacology)
• Tumor Cells, Cultured
• Xenograft Model Antitumor Assays
• bcl-2 Homologous Antagonist-Killer Protein (antagonists & inhibitors)
• bcl-2-Associated X Protein (antagonists & inhibitors)