A trojan horse in drug development: Targeting of thapsigargins towards prostate cancer cells

S. Brøgger Christensen, Dorthe Mondrup Skytte, Samuel R. Denmeade, Craig Dionne, Jesper Vuust Møller, Poul Nissen, John T. Isaacs

Research output: Contribution to journalReview articlepeer-review

76 Scopus citations


Available chemotherapeutics take advantage of the fast proliferation of cancer cells. Consequently slow growth makes androgen refractory prostate cancer resistant towards available drugs. No treatment is available at the present, when the cancer has developed metastases outside the prostate (T4 stage). Cytotoxins killing cells irrespective of the phase of the cell cycle will be able to kill slowly proliferating prostate cancer cells. Lack of selectivity, however, prevents their use as systemic drugs. Prostate cancer cells secrete characteristic proteolytic enzymes, e.g. PSA and hK2, with unusual substrate specificity. Conjugation of cytotoxins with peptides, which are selective substrates for PSA or hK2, will afford prodrugs, from which the active drug only will be released in close vicinity of the cancer cells. Based on this strategy prodrugs targeted at prostate cancer cells have been constructed and evaluated as potential drugs for prostate cancer. The potency of the thapsigargins as apoptotic agents make these naturally occurring sesquiterpene lactones attractive lead compounds. Intensive studies on structure-activity relationships and chemistry of the thapsigargins have enabled construction of potent derivatives enabling conjugation with peptides. Studies on the mechanism of action of the thapsigargins have revealed that the cytoxicity is based on their ability to inhibit the intracellular sarco-/endoplasmtic calcium pump.

Original languageEnglish (US)
Pages (from-to)276-294
Number of pages19
JournalAnti-Cancer Agents in Medicinal Chemistry
Issue number3
StatePublished - 2009


  • PSA
  • Prodrug
  • Prostate cancer
  • Targeted drugs
  • Thapsigargin
  • hK2

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology
  • Cancer Research


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