FPTB, a novel CA-4 derivative, induces cell apoptosis of human chondrosarcoma cells through mitochondrial dysfunction
Ju-Fang Liu1, Yi-Chin Fong, Kai-Wei Chang
1Graduate Institute of Pharmaceutical Chemistry, China Medical University, Taichung, Taiwan.
Abstract:
Chondrosarcoma is a malignant primary bone tumor that responds poorly to both chemotherapy and radiation therapy. The aim of this study was to elucidate the mechanism of the novel Combretastatin A-4 derivative, 2-(furanyl)-5-(pyrrolidinyl)-1-(3,4,5-trimethoxybenzyl)benzoimidazole (FPTB)-induced human chondrosarcoma cells apoptosis. FPTB induced cell apoptosis in human chondrosarcoma cell line but not primary chondrocytes. FPTB induced up-regulation of Bax and Bak, down-regulation of Bcl-2 and Bcl-XL and dysfunction of mitochondria in chondrosarcoma. FPTB also triggered endoplasmic reticulum (ER) stress, as indicated by changes in cytosol-calcium levels. We found that FPTB increased glucose-regulated proteins (GRP)78 but not GRP94 expression. In addition, treatment of cells with FPTB induced calpain expression and activity. Transfection of cells with GRP78 or calpain siRNA reduced FPTB-mediated cell apoptosis. Therefore, FPTB-induced apoptosis in chondrosarcoma cells through the mitochondria dysfunction and involves caspase-9 and caspase-3-mediated mechanism. FPTB also induced cell death mediated by increasing ER stress, GPR78 activation, and Ca(2+) release, which subsequently triggers calpain, caspase-12 and caspase-3 activity, resulting in apoptosis.
Insights
A novel compound, FPTB, effectively induces apoptosis in human chondrosarcoma cells by disrupting mitochondria and triggering endoplasmic reticulum stress. This targeted cell death mechanism offers potential for new chondrosarcoma treatments.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- Chondrosarcoma is a primary bone cancer with limited treatment options.
- Chemotherapy and radiation therapy show poor efficacy against chondrosarcoma.
- Understanding novel therapeutic mechanisms is crucial for improving patient outcomes.
Purpose of the Study:
- To investigate the apoptosis-inducing mechanism of a novel Combretastatin A-4 derivative, FPTB, in human chondrosarcoma cells.
- To determine if FPTB selectively targets cancer cells over normal chondrocytes.
- To elucidate the molecular pathways involved in FPTB-induced cell death.
Main Methods:
- Utilized human chondrosarcoma cell lines and primary chondrocytes.
- Assessed apoptosis induction via FPTB treatment.
- Analyzed changes in apoptosis-related proteins (Bax, Bak, Bcl-2, Bcl-XL).
- Investigated mitochondrial function and endoplasmic reticulum (ER) stress markers (GRP78, GRP94, Ca2+ levels).
- Examined calpain and caspase activation.
- Employed siRNA to silence GRP78 and calpain expression.
Main Results:
- FPTB induced apoptosis specifically in human chondrosarcoma cells, not primary chondrocytes.
- FPTB altered mitochondrial function by upregulating Bax/Bak and downregulating Bcl-2/Bcl-XL.
- FPTB triggered ER stress, evidenced by increased GRP78 expression and altered calcium levels.
- FPTB increased calpain and caspase-3/9 activity, with caspase-12 involvement in ER stress-mediated apoptosis.
- Silencing GRP78 or calpain partially inhibited FPTB-induced apoptosis.
Conclusions:
- FPTB induces apoptosis in chondrosarcoma cells via mitochondrial dysfunction and caspase-mediated pathways.
- FPTB-induced cell death is also mediated by ER stress, GRP78 activation, and subsequent calpain and caspase cascade activation.
- FPTB demonstrates potential as a targeted therapeutic agent for chondrosarcoma.
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