Thapsigargin, Origin, Chemistry, Structure-Activity Relationships and Prodrug Development

Nt, Quynh Doan; Sb, Christensen

doi:10.2174/1381612821666151002112824

Cited by 55 publications

(32 citation statements)

References 40 publications

(82 reference statements)

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“…Due to this activity, TGN induces acute responses in a large number of cell types (1819). Thus, TGN did not receive much attention as a pharmacological agent that modulates immune responses.…”

Section: Resultsmentioning

confidence: 99%

Thapsigargin Increases IL-2 Production in T Cells at Nanomolar Concentrations

Kim

Jung

et al. 2018

Immune Netw

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Thapsigargin (TGN) is a potent and selective inhibitor of sarco-endoplasmic Ca2+-ATPase, leading to rapid elevation of cytoplasmic Ca2+ concentration. Previous reports have shown that TGN increases the production of various cytokines from macrophages and dendritic cells. Here, we examine the effects of TGN on murine T cells. Nanomolar concentrations of TGN are a significant inducer of IL-2 production with full activity at 50 nM. Micromolar concentrations of TGN, however, are inhibitory to IL-2 production and T cell proliferation. The IL-2 production-inducing activity of TGN is much more prominent when T cells are primed with concanavalin A or anti-CD3 mAb, and is due to the increase of cytoplasmic Ca2+ concentration. TGN at 50 nM does not affect interferon-gamma or IL-4 production from T cells. Thus, the present study shows that low nanomolar concentrations of TGN could be useful in potentiating IL-2 production from antigen-primed T cells.

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Section: Resultsmentioning

confidence: 99%

Thapsigargin Increases IL-2 Production in T Cells at Nanomolar Concentrations

Kim

Jung

et al. 2018

Immune Netw

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“…Among the different pharmacological calcium modulators investigated, thapsigargin showed the highest cytotoxic effects. This compound is currently being assessed as a potential anticancer drug [30, 33]. It is a strong inhibitor of sarco-endoplasmic reticulum Ca 2+ -ATP-ases (SERCA) and triggers store-operated Ca 2+ -entry [30, 31].…”

Section: Discussionmentioning

confidence: 99%

“…It is a strong inhibitor of sarco-endoplasmic reticulum Ca 2+ -ATP-ases (SERCA) and triggers store-operated Ca 2+ -entry [30, 31]. Upon depletion of the ER Ca 2+ stores, thapsigargin triggers the opening of plasma membrane Ca 2+ channels and an ER stress response [33–35]. This is followed by activation of apoptotic pathways within the ER and the mitochondria.…”

Section: Discussionmentioning

confidence: 99%

“…Thereby, thapsigargin induces apoptosis, which could further enhance the apoptotic effects caused by conventional chemotherapeutics like CDDP or TOPO. Recently, analogues of thapsigargin have been developed for the treatment of prostate cancer and hepatocellular carcinoma [33]. Structure-activity relationships enabled design of equipotent analogues containing a linker coupled with peptides that are substrates for either prostate specific antigen (PSA) or prostate specific membrane antigen (PSMA), which enables specific targeting of the prodrug to prostate cancer cells and hepatocellular carcinoma cells.…”

Section: Discussionmentioning

confidence: 99%

“…Structure-activity relationships enabled design of equipotent analogues containing a linker coupled with peptides that are substrates for either prostate specific antigen (PSA) or prostate specific membrane antigen (PSMA), which enables specific targeting of the prodrug to prostate cancer cells and hepatocellular carcinoma cells. Results from a first phase I trial using a thapsigargin-based PSMA-activated prodrug in advanced solid cancers have been recently published [33, 37]. …”

Section: Discussionmentioning

confidence: 99%

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Calcium-regulatory proteins as modulators of chemotherapy in human neuroblastoma

et al. 2017

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Neuroblastoma (NB) is a pediatric cancer treated with poly-chemotherapy including platinum complexes (e.g. cisplatin (CDDP), carboplatin), DNA alkylating agents, and topoisomerase I inhibitors (e.g. topotecan (TOPO)). Despite aggressive treatment, NB may become resistant to chemotherapy. We investigated whether CDDP and TOPO treatment of NB cells interacts with the expression and function of proteins involved in regulating calcium signaling. Human neuroblastoma cell lines SH-SY5Y, IMR-32 and NLF were used to investigate the effects of CDDP and TOPO on cell viability, apoptosis, calcium homeostasis, and expression of selected proteins regulating intracellular calcium concentration ([Ca2+]i). In addition, the impact of pharmacological inhibition of [Ca2+]i-regulating proteins on neuroblastoma cell survival was studied. Treatment of neuroblastoma cells with increasing concentrations of CDDP (0.1−10 μM) or TOPO (0.1 nM−1 μM) induced cytotoxicity and increased apoptosis in a concentration- and time-dependent manner. Both drugs increased [Ca2+]i over time. Treatment with CDDP or TOPO also modified mRNA expression of selected genes encoding [Ca2+]i-regulating proteins. Differentially regulated genes included S100A6, ITPR1, ITPR3, RYR1 and RYR3. With FACS and confocal laser scanning microscopy experiments we validated their differential expression at the protein level. Importantly, treatment of neuroblastoma cells with pharmacological modulators of [Ca2+]i-regulating proteins in combination with CDDP or TOPO increased cytotoxicity. Thus, our results confirm an important role of calcium signaling in the response of neuroblastoma cells to chemotherapy and suggest [Ca2+]i modulation as a promising strategy for adjunctive treatment.

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Study of the Oxidative Cleavage Proposed in the Biogenesis of Transtaganolides/Basiliolides: Pyran‐2‐one Aromaticity‐Mediated Regioselective Control and Biogenetic Implications

2020

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The synthetic feasibility of the oxidative cleavage: epoxidation of 7‐O‐geranylscopoletin followed by electrocyclic ring‐opening, proposed in the biogenesis of transtaganolides/basiliolides is studied. Unlike the proposed pericyclic reactions, this pathway has not yet been addressed. Three synthetic strategies have been tested consisting of: i) Baeyer–Villiger oxidation of p‐quinoids, ii) hydrolysis of quinone monoketals, or iii) direct fragmentation by using oxygen donors. Oxidation of the benzene ring of hydroxylated coumarins has been achieved using peroxyacids, but cleavage took place between undesired positions. The aromaticity conservation of the pyran‐2‐one cycle during oxidation is the controlling factor of these observed regioselectivities. The use of a 4,5‐dihydroxy‐2‐methoxycinnamate model, in which the pyran‐2‐one ring does not exert influence on oxidation, has allowed the design of a synthetic sequence toward an analogue of the natural pyran‐2‐one isolated from Thapsia transtagana, key in the biogenesis. Mechanistic proposals for the obtained results as well as their biogenetic implications are raised.

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Thapsigargin, Origin, Chemistry, Structure-Activity Relationships and Prodrug Development

Cited by 55 publications

References 40 publications

Thapsigargin Increases IL-2 Production in T Cells at Nanomolar Concentrations

Thapsigargin Increases IL-2 Production in T Cells at Nanomolar Concentrations

Calcium-regulatory proteins as modulators of chemotherapy in human neuroblastoma

Study of the Oxidative Cleavage Proposed in the Biogenesis of Transtaganolides/Basiliolides: Pyran‐2‐one Aromaticity‐Mediated Regioselective Control and Biogenetic Implications

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