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Review
. 2015 May:97:2-7.
doi: 10.1016/j.steroids.2014.07.009. Epub 2014 Jul 24.

Targeting thapsigargin towards tumors

Nhu Thi Quynh Doan  1 , Eleonora Sandholdt Paulsen  1 , Pankaj Sehgal  2 , Jesper Vuust Møller  2 , Poul Nissen  3 , Samuel R Denmeade  4 , John T Isaacs  4 , Craig A Dionne  5 , Søren Brøgger Christensen  6
Affiliations
Review

Targeting thapsigargin towards tumors

Nhu Thi Quynh Doan et al. Steroids. 2015 May.

Abstract

The skin irritating principle from Thapsia garganica was isolated, named thapsigargin and the structure elucidated. By inhibiting the sarco/endoplasmic reticulum Ca(2+) ATPase (SERCA) thapsigargin provokes apoptosis in almost all cells. By conjugating thapsigargin to peptides, which are only substrates for either prostate specific antigen (PSA) or prostate specific membrane antigen (PSMA) prodrugs were created, which selectively affect prostate cancer cells or neovascular tissue in tumors. One of the prodrug is currently tested in clinical phase II. The prodrug under clinical trial has been named mipsagargin.

Keywords: Prodrug; Prostate specific antigen (PSA); Prostate specific membrane antigen (PSMA); Sarco/endoplasmic reticulum (SERCA); Targeting drugs; Thapsigargin.

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Figures

Fig. 1
Fig. 1
Thapsia garganica photographed ultimo June when the fruits are ripened and dry.
Fig. 2
Fig. 2
Structure of thapsigargin (1), thapsigargicin (3), thapsitranstagin (4), thapsivillosin A–E (5–9), thapsivillosin G–K (10–14) and 2-acetoxytrilobolide (15).
Fig. 3
Fig. 3
Structure of trilobolide (16), nortrilobolide (17) and thapsivillosin F (18).
Fig. 4
Fig. 4
A representative example of a thapsanes, tethered lipid and a C19 diterpenoid isolated from T. garganica.
Fig. 5
Fig. 5
The pharmacophore of thapsigargin, the carbon atoms marked with red are in a group forming hydrophobic interactions with SERCA, the oxygen atoms marked with blue form water mediated hydrogen bonds to the backbone of SERCA.
Fig. 6
Fig. 6
Structure of G115 (19) and the PSA cleavage product 20. In spite of the ionic structure of 20 this molecule is able to penetrate the cell membrane and induce apoptosis. The linker is marked with magenta.
Fig. 7
Fig. 7
Structure of G202 (21) and the major PMSA cleavage product 22. In spite of the zwitterionic structure of 22 this molecule is able to penetrate the cell membrane and induce apoptosis. The linker is marked with magenta.
Fig. 8
Fig. 8
Cartoon displaying the mechanism of action of the prodrug (depicted as a grenade). When the prodrug (the grenade) appears in the neovascular tissue the peptide is cleaved (the pin is removed) (A), the active drug diffuses into the cell (B), and kills the cell (C).
Scheme 1
Scheme 1
Conversion of thapsigargin (1) into thapsigargin epoxide (2).
See this image and copyright information in PMC

References

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