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Imaging Caspase-3 Activation as a Marker of Apoptosis-Targeted Treatment Response in Cancer

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Abstract

Purpose

We tested whether positron emission tomography (PET) with the caspase-3-targeted isatin analog [18F]WC-4-116 could image caspase-3 activation in response to an apoptosis-inducing anticancer therapy.

Procedures

[18F]WC-4-116 uptake was determined in etoposide-treated EL4 cells. Biodistribution studies with [18F]WC-4-116 and [18F]ICMT-18, a non-caspase-3-targeted tracer, as well as [18F]WC-4-116 microPET imaging assessed responses in Colo205 tumor-bearing mice treated with death receptor 5 (DR5)-targeted agonist antibodies. Immunohistochemical staining and enzyme assays confirmed caspase-3 activation. Two-way analysis of variance or Student’s t test assessed for treatment-related changes in tracer uptake.

Results

[18F]WC-4-116 increased 8 ± 2 fold in etoposide-treated cells. The [18F]WC-4-116 % ID/g also increased significantly in tumors with high caspase-3 enzyme activity (p < 0.05). [18F]ICMT-18 tumor uptake did not differ in tumors with high or low caspase-3 enzyme activity.

Conclusions

[18F]WC-4-116 uptake in vivo reflects increased caspase-3 activation and may be useful for detecting caspase-3-mediated apoptosis treatment responses in cancer.

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Acknowledgments

The authors thank the staff of the Washington University School of Medicine Cyclotron Facility for isotope production, Nicole Fettig, Amanda Klaas, Margaret Morris, Lori Strong, and Ann Stroncek of the Small Animal Imaging Facility for performing the scans, Katherine Spayd for manuscript editing, and Novartis for providing the DR5 targeted antibody and tumor cells as gifts. Amgen provided reagents and funding for imaging M413-treated mice. NIH K08 EB006702 (PI: DLC), the Damon Runyon Clinical Investigator Award (PI: DLC) and NIH R33 CA121952 (PI: RHM) also provided support for these studies.

Conflict of Interest

The authors declare that they have no conflicts of interest.

Author information

Authors and Affiliations

  1. Division of Radiological Sciences and Nuclear Medicine, Mallinckrodt Institute of Radiology, Washington University School of Medicine, Campus Box 8225, 510 S. Kingshighway Blvd., St. Louis, MO, 63110, USA

    Delphine L. Chen, Jacquelyn T. Engle, Elizabeth A. Griffin, Wenhua Chu, Dong Zhou & Robert H. Mach

  2. Department of Internal Medicine, Washington University School of Medicine, St. Louis, MO, USA

    Delphine L. Chen

  3. Division of Biostatistics, Washington University School of Medicine, St. Louis, MO, USA

    J. Philip Miller

Authors
  1. Delphine L. Chen
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  2. Jacquelyn T. Engle
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  3. Elizabeth A. Griffin
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  4. J. Philip Miller
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  5. Wenhua Chu
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  6. Dong Zhou
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  7. Robert H. Mach
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Corresponding author

Correspondence to Delphine L. Chen.

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Chen, D.L., Engle, J.T., Griffin, E.A. et al. Imaging Caspase-3 Activation as a Marker of Apoptosis-Targeted Treatment Response in Cancer. Mol Imaging Biol 17, 384–393 (2015). https://doi.org/10.1007/s11307-014-0802-8

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  • DOI: https://doi.org/10.1007/s11307-014-0802-8

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