A Trojan Horse in Drug Development: Targeting of Thapsigargins Towards Prostate Cancer Cells

ISSN: 1875-5992 (Online)
ISSN: 1871-5206 (Print)

Volume 16, 12 Issues, 2016

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Anti-Cancer Agents in Medicinal Chemistry

Formerly: Current Medicinal Chemistry - Anti-Cancer Agents

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Michelle Prudhomme
Universite Blaise Pascal - C.N.R.S
Aubiere Cedex

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A Trojan Horse in Drug Development: Targeting of Thapsigargins Towards Prostate Cancer Cells

Anti-Cancer Agents in Medicinal Chemistry, 9(3): 276-294.

Author(s): S. Brogger Christensen, Dorthe Mondrup Skytte, Samuel R. Denmeade, Craig Dionne, Jesper Vuust Moller, Poul Nissen and John T Isaacs.

Affiliation: Department of Medicinal Chemistry, Faculty of Pharmaceutical Sciences, University of Copenhagen, Universitetsparken 2, DK-2100 Copenhagen, Denmark.


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.


Prostate cancer, targeted drugs, thapsigargin, PSA, hK2, Prodrug, SERCA.

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Article Details

Volume: 9
Issue Number: 3
First Page: 276
Last Page: 294
Page Count: 19
DOI: 10.2174/1871520610909030276
Price: $58

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