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Published on: March 5, 2018
Procaspase-3 activation as an anti-cancer strategy: structure-activity relationship of procaspase-activating compound
Quinn P Peterson1, Danny C Hsu, David R Goode
1Department of Biochemistry, Roger Adams Laboratory, University of Illinois, Urbana, Illinois 61801, USA.
Abstract:
A goal of personalized medicine as applied to oncology is to identify compounds that exploit a defined molecular defect in a cancerous cell. A compound called procaspase-activating compound 1 (PAC-1) was reported that enhances the activity of procaspase-3 in vitro and induces apoptotic death in cancer cells in culture and in mouse xenograft models. Experimental evidence indicates that PAC-1 activates procaspase-3 in vitro through chelation of inhibitory zinc ions. Described herein is the synthesis and biological activity of a family of PAC-1 derivatives where key functional groups have been systematically altered. Analysis of these compounds reveals a strong correlation between the in vitro procaspase-3 activating effect and their ability to induce death in cancer cells in culture. Importantly, we also show that a fluorescently labeled version of PAC-1 co-localizes with sites of caspase-3 activity in cancer cells. The data presented herein further bolster the hypothesis that PAC-1 induces apoptosis in cancer cells through the direct activation of procaspase-3, has implications for the design and discovery of next-generation procaspase-3 activating compounds, and sheds light on the anti-apoptotic role of cellular zinc.
Insights
Procaspase-activating compound 1 (PAC-1) and its derivatives induce cancer cell death by directly activating procaspase-3. This targeted approach in oncology exploits molecular defects and highlights zinc's anti-apoptotic role.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Personalized medicine in oncology aims to target cancer cells' specific molecular defects.
- Procaspase-activating compound 1 (PAC-1) activates procaspase-3 in vitro and induces cancer cell death.
- PAC-1's mechanism involves chelating inhibitory zinc ions, thereby activating procaspase-3.
Purpose of the Study:
- To synthesize and evaluate PAC-1 derivatives with systematically altered functional groups.
- To establish a correlation between procaspase-3 activation and cancer cell death induction.
- To investigate the localization of PAC-1 in cancer cells relative to caspase-3 activity.
Main Methods:
- Synthesis of a series of PAC-1 derivatives.
- In vitro assays to measure procaspase-3 activation.
- Cell culture experiments to assess cancer cell death.
- Xenograft models in mice.
- Fluorescence microscopy using a labeled PAC-1 derivative.
Main Results:
- A strong correlation was observed between in vitro procaspase-3 activation and cancer cell death.
- Fluorescently labeled PAC-1 localized with caspase-3 activity sites in cancer cells.
- The synthesized PAC-1 derivatives demonstrated varying degrees of procaspase-3 activation and cytotoxicity.
Conclusions:
- PAC-1 induces apoptosis in cancer cells via direct procaspase-3 activation.
- These findings support the development of novel procaspase-3 activating compounds for cancer therapy.
- The study provides insights into the anti-apoptotic function of cellular zinc.
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