A Trojan horse in drug development: targeting of thapsigargins towards prostate cancer cells

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S Brøgger Christensen1, Dorthe Mondrup Skytte, Samuel R Denmeade

  • 1Department of Medicinal Chemistry, University of Copenhagen, Denmark. sbc@farma.ku.dk

Anti-Cancer Agents in Medicinal Chemistry
|March 12, 2009
PubMed

Insights

New prodrugs target slow-growing prostate cancer cells by releasing cytotoxins near tumors. This strategy utilizes prostate-specific enzymes to activate potent thapsigargin derivatives, offering hope for advanced disease.

Area of Science:

  • Oncology
  • Drug Development
  • Biochemistry

Background:

  • Androgen-refractory prostate cancer with metastases is untreatable due to slow cell proliferation and lack of drug selectivity.
  • Existing chemotherapeutics target rapidly dividing cells, rendering them ineffective against slow-growing prostate cancer.
  • Prostate cancer cells release specific enzymes like prostate-specific antigen (PSA) and human kallikrein 2 (hK2).

Purpose of the Study:

  • To develop novel prodrugs for treating advanced prostate cancer, including metastatic and androgen-refractory stages.
  • To create a targeted drug delivery system that selectively releases cytotoxic agents near cancer cells.
  • To leverage prostate-specific enzymes for targeted drug activation.

Main Methods:

  • Conjugation of cytotoxic agents with peptides that are selective substrates for PSA and hK2.
  • Utilizing thapsigargins, potent apoptotic agents, as lead compounds for prodrug development.
  • Investigating structure-activity relationships and chemical modifications of thapsigargins for peptide conjugation.

Main Results:

  • Successfully constructed and evaluated prodrugs targeted at prostate cancer cells.
  • Thapsigargin derivatives demonstrated potent apoptotic activity.
  • Mechanism of action identified as inhibition of the intracellular sarco-/endoplasmic calcium pump.

Conclusions:

  • Targeted prodrugs offer a promising strategy for treating advanced prostate cancer by selectively releasing cytotoxins.
  • Thapsigargin-based prodrugs show potential as novel therapeutic agents for prostate cancer.
  • The development of these prodrugs addresses the unmet need for effective treatments in late-stage prostate cancer.

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