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

Abstract

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.

Critical Roles of Hydrophobicity and Orientation of Side Chains for Inactivation of Sarcoplasmic Reticulum Ca2+-ATPase with Thapsigargin and Thapsigargin Analogs

“…These desubstituted derivatives were prepared by previously described methods (17,28,29), but we note that the unavailability of desoctanoyl Tg forced us to use as a model compound the previously described dihydronortrilobolide, which differs from desoctanoyl Tg by having a saturated bond between C-4 and C-5 (30). From the activity/inhibitor concentration curves, we find for all desubstituted compounds substantial reductions in the affinity, from a subnanomolar value (0.2 nM) for unmodified Tg to 3.5-113 nM after loss of the side chains.…”

“…These calculations provide support for the previously suggested pharmacophore model (17), according to which a major part of the binding energy comes from the interaction of Ca 2ϩ -ATPase with the separately spaced Tg side chains. According to these calculations, less contribution will come from the guaianolide tricyclic ring, its major role being to serve as a scaffold to bring the side chains in correct position for hydrophobic interactions inside the binding cavity (17,30). In a previous study, Wictome et al (32) assigned an important role of the lactone ring to the binding mechanism based on a drastic (micromolar) reduction in binding affinity upon dehydration of the OH-7 and OH-11 groups.…”

“…This may be feasible with the aid of a fragment-based approach (31) by synthesizing compounds where the interacting pharmacophore is built on a central skeleton placing the side chains in approximately the same topological position as in Tg (30). Furthermore, a linker at O-8 may allow for more flexibility in drug design to target prostate cancer cells by providing inhibitors that in addition to binding at the Tg site also interact at the same location as CPA and BHQ.…”

The Medicinal Value of Biodiversity: New Hits to Fight Cancer

“…Studies indicate that their selectivity against tumor cells is achieved by different mechanisms, including modulation of specific signaling pathways, induction of oxidative stress, and epigenetic, antiangiogenic and antimetastatic activities. For instance, thapsigargin has been shown to inhibit the sarco/endoplasmic reticulum (ER) calcium ATPase (SERCA) pump, thus increasing intracellular Ca 2+ levels, which ultimately lead to ER stress and cell death (Christensen et al, 2009;Winther et al, 2010). Artemisinin has shown promising antitumor properties in vitro and in vivo, entering phase I-II clinical trials against metastatic breast and colorectal cancers.…”

Novel Insights into the Mechanisms of Regulation of Tyrosine Kinase Receptors by Ras Interference 1

“…The following are some examples of ongoing clinical trails based on plant extracts (Artemsia annua, Thapsia and Tanacetum parthenum, among others): laryngeal carcinomas, uveal melanomas, pituitary macrodenomas, lupus nephritis and breast, colorectal and nonsmall cell lung cancers (Berger et al, 2005;Lu, 2002;Singh and Panwar, 2006;Zhang et al, 2008). Even though the mechanism of action is still not fully understood, it seems that these plant extracts target the sarco/ER calcium ATPase pump, proteases secreted by cancer cells, NF-kB signaling, p53 and transferrin receptor activity (Christensen et al, 2009;Denmeade and Isaacs, 2005;Efferth, 2006;Gopal et al, 2009;Hehner et al, 1998;Nakase et al, 2009;Pajak et al, 2008).…”