Self-Triggered Apoptosis Enzyme Prodrug Therapy (STAEPT): Enhancing Targeted Therapies via Recurrent Bystander Killing Effect by Exploiting Caspase-Cleavable Linker

Seung Woo Chung, Jeong Uk Choi, Young Seok Cho, Ha Rin Kim, Tae Hyung Won, Peter Dimitrion, Ok Cheol Jeon, Seong Who Kim, In-San Kim, Sang Yoon Kim, Youngro Byun

Research output: Contribution to journalArticle

6 Citations (Scopus)

Abstract

Tumor heterogeneity is associated with the therapeutic failures of targeted therapies. To overcome such heterogeneity, a novel targeted therapy is proposed that could kill tumor populations with diverse phenotypes by delivering nonselective cytotoxins to target-positive cells as well as to the surrounding tumor cells via a recurrent bystander killing effect. A representative prodrug is prepared that targets integrin αvβ3 and releases cytotoxins upon entering cells or by caspase-3. This allows the prodrug to kill integrin αvβ3-positive cells and upregulate caspase-3, which in turn, activates the prodrug to release a cytotoxin that could subsequently diffuse into and kill the neighboring tumor cells. Apoptotic cells further upregulate and release caspase-3, which activate more prodrugs leading to another round of adjacent cell death and caspase-3 release. Thus, the bystander killing effect could occur repeatedly, leading to augmented and widespread anticancer activity. This strategy provides an avenue that could advance the current targeted therapy.

Original languageEnglish
Article number1800368
JournalAdvanced Science
Volume5
Issue number7
DOIs
Publication statusPublished - 2018 Jul 1

Keywords

  • bystander killing effects
  • cancer therapies
  • caspases
  • prodrugs
  • target therapies

ASJC Scopus subject areas

  • Medicine (miscellaneous)
  • Chemical Engineering(all)
  • Materials Science(all)
  • Biochemistry, Genetics and Molecular Biology (miscellaneous)
  • Engineering(all)
  • Physics and Astronomy(all)

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    Chung, S. W., Choi, J. U., Cho, Y. S., Kim, H. R., Won, T. H., Dimitrion, P., Jeon, O. C., Kim, S. W., Kim, I-S., Kim, S. Y., & Byun, Y. (2018). Self-Triggered Apoptosis Enzyme Prodrug Therapy (STAEPT): Enhancing Targeted Therapies via Recurrent Bystander Killing Effect by Exploiting Caspase-Cleavable Linker. Advanced Science, 5(7), [1800368]. https://doi.org/10.1002/advs.201800368